RB 
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End»crinol«gy  and  metabolism 


ENDOCRINOLOGY 
AND  METABOLISM 

PRESENTED  IN  THEIR  SCIENTIFIC 
AND  PRACTICAL  CLIN  CAL  ASPECTS 
BY    NINETY- EIGHT    CONTRIBUTORS 

EDITED  BY 

LEWELLYS  P.  BARKER,  M.D.  (Toronto). 
LL.D.  (QjjEENS;  McGill) 

PROFESSOR    OF     MEHICIXE,     JOHNS     HOPKINS     UNIVERSITY,     190.')-1914  ;     PIIYSICIAN-IN-CHIEF,      JOHNS     HOPKINS 

HOSPITAL,    1905-1914  ;    PKESIDEXT    of    ASSOCIATION-    OF    AMERICAN    PHYSICIANS,    1912-1913  ;     PUESIDENT 

OF    AMERICAN    XEUROtiOGICAL    ASSOCIATION,     1915;     PRESIDENT    OK    SOUTMERN     MEDICAL    ASSOCU- 

TlOX,     1919;     PROFESSOR     OF     CLINICAL     MEDICINE,     JOHNS     HOPKINS     UNlVERtrlTT,     1914* 

1921  ;    AND    VISITING    PHYSICIAN,    JOHNS    HOPKINS     HOSPITAL 


ASSOCIATE    EDITORS 


ENDOCRINOLOGY 

R.    G.    HOSKINS 

PH.D.  (HARVARD).  M.D,  (JOHNS  HOPKINS)  i 

PROFESSOR    OF    PHYSIOLOGY,    STARLING-OHIO    MEDICAL 
COLLEGE,      1910-1913  ;      ASSOCIATE      PROFESSOR     OP 
PHYSIOLOGY,      NORTHWESTERN     UNIVERSITY     MED- 
ICAL    SCHOOL,     1913-1916 ;      professor     op 

PHYSIOLOGY,     IBID.,     1916-1918  ;     ASSOCIATE 
IN    PHY.SIOLOGY.    JOHNS    HOPKINS    UNIVER- 
SITY, 1920-1921 ;  professor  and  head 

OF      DEPARTMENT      OP       PHY.SIOLOOY, 

OHIO      STATE      UNIVERSITY.      1921  ; 

EDITOR-IN-CHIEF  "ENDOCKIH- 

OLOGY,"    1917-. 


METABOLISM 

HERMAN   O.   MOSENTHAL 

M.D.  (COLUMBIA  UNIVERSITY) 

ASSOCIATE      PHYSICIAN,      JOHNS      HOPKINS      HOSPITAL, 
1914-1918  ;     ASSOCIATE     PROFE-s%OR     OP     MEDICINE, 
JOH.VS       HOPKINS    UNIVERSITY,      1914-1918;      AS- 
SOCIATE    IN     MEDICINE,      COLLEGE     OP    PHYSI- 
CIANS      AND       SURGEONS,       COLUMBIA       UNI- 
VERSITY,     1910-1920;      ASSOCIATB     pro- 
fessor     AND      ATTE.VDING       PHYSICIAN, 
NEW    YORK     POST-GRADUATE    MEDICAL 
SCHOOL     AND     HOSPITAL. 


VOLUME  3 


D.  APPLETON  AND   COMPANY 

NEW  YORK  ,  LONDON 

1922 


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vHY 

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■■.iC'^lfjV:^^ 

COPYRIGHT,    1922,   BY 

p.  APPLETOiSr  AND  COMPANY 


nvnvD  m  thb  united  states  op  America 


CONTRIBUTORS  TO  VOLUME  III 
Graham  Lusk,  PIlD.,  Sc.D.,  F.R.S.E. 

PROFESSOR  OF  PHYSIOLOGY,   CORNELL  UNIVERSITY    MEDICAL    COLLEGE,   SCIENTIFIC   DIRECTOR 
RUSSELL  SAGE  INSTITUTE  OF  PATHOLOGY. 


A.  I.  Ringer,  M.D. 

ASSOCIATE  PHYSICIAN,  MONTEFIORE  HOSPITAL.  NEW  YORK:  CONSULTING  PHYSICIAN,  DIS- 
EASES OF  METABOLISM,  LENOX  HILL  HOSPITAL.  NEW  YORK  CITY;  FORMERLY  ASSISTANT 
PROFESSOR  OF  PHYSIOLOGICAL  CHEMISTRY,  UNIVERSITY  OF  PENNSYLVANIA;  LECTURER  IN 
PHYSIOLOGY  AT  CORNELL  UNIVERSITY  MEDICAL  COLLEGE:  PROFESSOR  OF  CLINICAL  MEDICINE 
(DISE.VSES  OF  METABOLISM  >,  FORDHA^I  UNIVERSITY  SCHOOL  OF  MEDICINE. 

Walter  Jones,  Ph.D. 

PROFESSOR    OF    PHYSIOLOGICAL    CHEillSTRY    IN    THE    JOHNS     HOPKINS     MEDICAL    SCHOOL; 
MEMBER    OF    THE    J^ATIONAL    ACADEMY    OF    SCIENCES. 


Louis  Bauman,  M.D. 

ASSOCIATE   IN    MEDICINE,    COLUMBIA   UNIVERSITY;    ASSISTANT    VISITING    PHYSICIAN,    PRES- 
BYTERIAN HOSPITAL,  NTSW  YOB«C. 


Walter  R.  Bloor,  M.A.,  A.M.,  Ph.D. 

ASSISTANT  IN  BIOLOGICAL  CHEMISTRY,  HARVARD  MEDICAL  SCHOOL,  1008-1910;  ASSOCIATE 
IN  BIOLOGICAL  CHEMISTRY,  WASHINGTON  UNIVERSITY,  MEDICAL  SCHOOL  ( ST.  LOUIS), 
1910-1914;  ASSISTANT  PROFESSOR  OF  BIOLOGICAL  CHEMISTRY,  HARVARD  MEDICAL  SCHOOL, 
1914-1918;  PROFESSOR  of  biochemistry  and  HEAD  OF  THE  DEPARTMENT  OF  BIOCHEMISTRY 
AND   PHARMACOLOGY,    UNIVERSITY   OF   CALIFORNIA,    1918-. 


Emil  J.  Baumann,  B.S.,  Ph.D. 

IN    CHARGE  OF   DmSION  OF  CHEMISTRY  AND   LABORATORY  OF   THE  MONTEFIORE   HOSPITAL; 
FORMERLY    LECTURER    IN    BIOCHEMISTRY.    U^^^TRSITY    OF    TORONTO. 


Philip  B.  Hawk,  M.S.,  Ph.D. 

PROFESSOR  OF  PHYSIOLOGICAL  CHE3IISTRY   AND  TOXICOLOGY,   JEFFERSON    MEDICAL  COLLEGE 
AND   PHYSIOLOGICAL    CHEMIST    TO    JEFFERSON    HOSPITAL. 


Harold  L.  Higgins,  A.B.,  M.D. 

ASSISTANT   PROFESSOR  OF    PEDIATRICS,   UNIVERSITY   OF  CINCINNATI;    ATfENDINO   PEDIATRI- 
CIAN  OF   THE   CINCINNATI    GENERAL    HOSPITAL. 


HI 

/25-S3 


iv  CONTRIBUTORS  TO  VOLUME  III 

Henry  A,  Mattill,  A.M.,  Ph.D. 

JUNIOR  PROFKSSOR  OF  BIOCflFMISTI^Y,  UiMVERSlTY  OF  KOCHESTKH,  ROCHESTER,  X.  Y. ;  PRO- 
FESSOR OF  PHYSIOLOGY  AND  PHYSIOLOGICAL  CHEMISTRY,  UNIVERSITY  OF  UTAH,  SALT  LAKE 
CITY,  UTAH,  1910-1915;   ASSISTANT  PROFESSOR  OF  NUTRITION,  UNIVERSITY  OF  CALIFORNIA, 

1915-1917. 


Helen  Isham  Matill,  Ph.D. 

FORMFIBLY  ASSOCIATE  IN   CHEMISTRY.  UNIVERSITY  OF  ILLINOIS. 


Carl  Voegtlin,  M.D. 

PROFESSOR    OF    PHARMACOLOGY    AND     CHIEF     OF     DIVISION     OF     PHARMACOLOGY,    HYGIENIC 
LABORATORY,    U.    S.    PUBLIC    HEALTH    SERnCE,    WASHINGTON,    D.    C. 


Isidor  Greenwald,  Ph.D. 

CHEMIST,    HABRIMAN  RESEARCH    LABORATORY,   ROOSEVELT    HOSPITAL. 


Victor  Caryl  Myers,  B.A.,  M.A.,  Ph.D. 

PROFESSOR    OF    PATHOLOGICAL    CHEMISTRY,    NEW    YORK    POST-GRADUATE    MEDICAL    SCHOOL 
AND  HOSPITAL;    PATHOLOGICAL  CHEillST  TO  THE  POST-GRADUATE  HOSPITAL. 


John  R.  Murlin,  Ph.D.,  Sc.D, 

PROFESSOR  OF  PHYSIOLOGY   AND   DIRECTOR  OF   DEPARTMENT   OF  VIT^VL  ECONOMICS,   UNIVER- 
SITY OF  ROCHESTER,  ROCHESTER,  N.   Y.;    CHAIRMAN,  COMillTTEE  ON    FOOD   AND   NUTRITION, 

NATIONAL    RESEARCH    COUNCIL. 


Arthur  Isaac  Kendall,  B.S.,  Ph.D.,  Dr.P.H. 

PROFESSOR    OF    BACTERIOLOGY,    NORTH W?:STERN     UNIVERSITY     MEDIC^VL     SCHOOL;     DIRECTOR 
OF   THE  PATTEN  RESEARCH   FOUNDATION. 


Henry  G.  Barbour,  A.B.,  M.D. 

PROFESSOR  OF  PHARMACOLOGY,   MC  GILL  UNIVERSITY,  MONTREAL. 


Arlie  Vernon  Bock,  M.D. 

»      ASSISTANT  IN  MEDICINE,  HARVARD  UNIVERSITY ;   ASSISTANT  IN  MEDICINE,  MASSACHUSETTS 
GENERAL   HOSPITAL;    ASSISTANT    VISITING    PHYSICIAN,    COLLIS    P.    HUNTINGTON    MEMORIAL 
HOSPITAL  OF  HARVARD  UNIVERSITY. 


Herbert  S.  Carter,  A.M.,  M.D. 

ASSISTANT    PROFESSOR    OF    MEDICINE,    COLUMBIA    UNIVERSITY,    NEW    YORK;    ASSOCIATE    AT- 
TENDING PHYSICIAN  TO  THE  PRESRYTEUIAX   HOSPITAL,  NEW  YORK;    CONSULTING  PHYSICIAN 
TO    THE    LINCOLN    HOSPITAL,    NEW    YORK. 


CONTRIBUTORS  TO  VOLUME  III  v 

George  R.  Minot,  M.D. 

ASSISTANT     PROFESSOR     OF     MKDrcINE,     HARVARD     UNIVERSITY;     ASSOCIATE     IX     MEDICl^'E, 
MASSACHUSETTS    CENER.\L    HOSPITAL;    PHYSICIAN    TO    THE    COLLIS    P.    HUNTINGTON    MEMO- 
RIAL   HOSPITAL    OF    HARVARD    UNIVERSITY. 


Thomas  Ordway,  A.B.,  A.M.,  M.D.,  Sc.D. 

DEAN    AND    ASSOCIATE    PROl'ESSOR    OF    MEDICINE,    ALBANY    MEDICAL    COLLEGE;    ATTENDING 

PHYSICIAN,    ALBANY    HOSPITAL. 


Arthur  Knud;'on,  A.B.,  Ph.D. 

PROFESSOR  OF   BIOLOGICAL   CHEMISTRY,  ALBANY  MEDICAL  COLLEGE;    ACTENDINO  BIOLOGICAL 

CHEMIST,  ALBANY   HOSPIT^VL. 

E.  C.  Schneider,  B.S.,  Ph.D.,  Sc.D. 

PROFESSOR  OF  BIOLOGY,  WESLEYAN  UNIVERSITY,  MIDDLETOWN,  CONNECTICUT,  AXD  DIRECTOK 

OF  THE  DEPARTMENT  OF  PHYSIOLOGY  AT  THE  AIR  SERVICE  MEDICAL  RESEARCH  LABORATORY, 

MITCHEL  FIELD,  GARDEN  CITY,  NEW  YORK;    MEMBER  OF  THE  ANGLO-AMERICAN   PIKE'S  PEAK 

EXPEDITION  IN  1911  AND  OTHER  ALPINE  PHYSIOLOGICAL  EXPEDITIONS  TO  PIKE*S  PEAK. 


Digitized  by  the  Internet  Archive 

in  2007  with  funding  from 

IVIicrosoft  Corporation 


http://www.archive.org/details/endocrinologymet03barl<rich 


CONTENTS 

A  History  of  Metabolism 3 

SECTION  I 

DIETARY  COXSTITUEXTS  AKD  THEIR  DERIVATIVES 

The  Proteins  and  Their  Metabolism A,   I.   Ringer  81 

Nucleic  Acids Walter  Jones  135 

Urobilin  and  Urobilinogen Louis  Bauman  1G3 

Creatin  and  Creatinin Louis  Bauman  171 

Normal  Fat  Metabolism Walter  R.  Bloor  183  • 

The  Carbohydrates  and  Their  Metabolism 

A.  L  Ringer  and  Emit  J.  Bauman  213  * 

Water  as  a  Dietary  Constituent     .......     Philip  B.  Hawh  275 

The  Metabolism  of  Alcohol Harold  L.  Higgins  297 

Mineral  Metabolism Henry  A.  Matiill  and  Helen  I.  Mattill  303 

The  Metabolism  of  Vitamins Carl   Voegtlin  341 

SECTION  II 
A  Normal  Diet Isidor  Greenwald    359  • 

SECTION  III 
Body  Tissues  and  Fluids  . Victor  C.  Myers    423 

SECTION  IV 
Excretions Victor  C.  Myers    481 

SECTION  Y 
Normal  Processes  of  Energy  Metabolism     .     •     •     .    John  R.  Murlin    515  • 

SECTION  VI 

Bacterial  Metabolism,  Normal  and  Abnormal  Within  the  Body 

Arthur  Isaac  Kendall    663 

SECTION  VII 
ACTIONS  OF  DRUGS  AND  THERAPEUTIC  MEASURES 

The  Effects  of  Certain  Drugs  and  Poisons  upon  the  Metabolism 

,  Henry  G.  Barhour    747 

The  Intravenous  Injection'^of  Fluids Arlie  V.  Boch    Y87 

vii 


viii  COXTEXTS 

PAOB 

Artificial  Methods  of  Feeding Herbert    C.    Carter  805 

TiLVXSFUSioN  OF  Blood George  R.  Minot  and  Arlie  V.  Bock  821 

Mineral  Waters Henry  A.  Mattill  845 

HvDROTHERAPY Henry  A.  Mattill  855 

The  Ixfllence  of  Kokxtcex  Rays,  Radioactive    Slbstances,    Light,    and 

Electricity  upon  ^Metabolism   .  Thomas  Ordway  and  Arthur  Knudson  871 

Climate Edward  C.  Schneider  899 

Index c     o     o     c     ,     .     c 913 


LIST  OF  ILLUSTRATIONS 
A  History  of  Metabolism 

GlL\HAM   LrsK 

1.  Frontispiece  of  "De  medicina  statica  aphorismi,"  showing  Sanctorius 

seated  on  a  chair  suspended  from  a  large  steelyard 7 

2.  Priestly IG 

3.  Scheele's  apparatus  showing  bees  in   the  upper  chamber  of  a  glass 

apparatus  filled  with  oxygen IS 

4.  Lavoisier  and  his'  wife 20 

5.  The  burning  glass  of  Trudaine 21 

6.  The  closed  circuit  apparatus  of  Regnault  and  Reiset  ..•..,  41 

7.  Carl  Yoit .  66 

8.  Max  Rubner , 76 

SECTIOX  I 

DIETARY  CONSTITUENTS  AND  THEIR  DERIVATIVES 

Water  as  a  Dietary  Constituent 

Philip  B.  Hawk 

1.  Curve  showing  pronounced  stimulation  by  water  and  rapid  emptying 

of  the  stomach 282 

2.  Curve  showing  moderate  stimulation  by  water       .......  283 

3.  Curve  showing  slight  stimulation  by  water  in  the  human  stomach  .     .  283 

4.  Cunes  showing  immediate  stimulation  by  water  and  rapid  emptying 

of  the  stomach 284 

5.  Curves  showing  no  glandular  fatigue  in  human  stomach       ....     2S5 

6.  Curves  showing  comparative  stimulatory  power  of  water  and  bouillon 

in  the  human  stomach 285 

7.  Curves  showing  comparative  stimulatory  power  of  water  and  coffee 

in  the  human  stomach .     286 

8.  Curves  showing  comparative  stimulatorj*  power  of  water  and  oatmeal 

in  the  human  stomach   . 287 

9.  Chart  illustrating  the  evacuation  of  various  fluids  from  the  human 

stomach       .     .     c 289 

SECTION  II 
A  Normal  Diet 

ISIDOR   GrEEXWALD 

CHART  tAQE 

1.  Total  food  value  of  the  chief  world  foods  expressed  in  calories  .     •     .    362 

2.  Per  capita  consumption  of  meat .^     .     .     .     .     364 

3.  Neumann's  observations  on  himself  of  reduced  war  diet  .     .     .     •     .     417 

ix 


X  LIST  OF  ILLUSTRATIONS 

SECTION  V 

Normal  Processes  of  Energy  Metabolism 

Jons  Ki  Mi'RLiN 

FIOCRB  '*«« 

1.  The  smaller  respiration  apparatus  of  Pettenkofer  and  Voit  ....  517 

2.  Diagram  of  the  Jaqiiet-Grafe  respiration   apparatus  used  by  Krogh 

and  Lindhard 520 

3.  Ilaldane  respiration  apparatus .  621 

4.  Respiration  apparatus  of  Regnault  and  Reiset 522 

5.  Respiration  apparatus  of  Hoppe-Seyler .  523 

6.  Diagram  of  the  system  of  ventilation  in  the  closed  circuit  apparatus  of 

Atwater  and  Benedict     . 624 

7.  Diagram  of  the  respiration  apparatus  used  by  Benedict  and  Talbot  in 

their  study  of  the  gaseous  metabolism  of  infants 526 

8.  Respiration   incubator    ......      c      , 529 

9.  Micro-respiration  apparatus  of  Winterstein     ........  530 

10.  Mouthpiece  of  Denayrouse  with  nose  clip  attached 532 

11.  Pneumatic  nosepiece  of  Benedict     .      .      .      .      o 533 

12.  The  half  mask  as  used  by  Boothby .534 

13.  Air  valve  of  Loven 534 

14.  Metal  air  valve  of  Thiry 535 

15.  Tissot  spirometer  with  capacity  of  50  liters 536 

16.  Spirometer    of    Boothby    and    Sandiford    as    used    in    the    writer's 

laboratory    ..........      .      .......  53T 

17.  Respiration  apparatus  of  Douglas     . 538 

18.  Respiration  apparatus  of  Zuiitz  and  Geppert 539 

19.  The  Haldane  air  analyser  as  used  by  Boothby       . 540 

19-a.    Henderson  modification  of  Haldane  apparatus 541 

20.  The  air  analyser  of  Krogh 642 

21.  The   Benedict   universal    respiration   apparatus   as   employed  by   the 

writer 545 

22.  Portable  respiration  apparatus  of  Benedict  and  Collins 547 

23.  The  bomb  calorimeter  of  Riche  for  use  with  Berthelot  bomb       .     .     .  569 

24.  The  air  calorimeter  of  Lefevre * 672 

25.  Cross  section  of  chair  calorimeter  of  Benedict  and  Carpenter     .     .      .  574 

26.  The  Sage  calorimeter  at  Bellevue  Hospital 575 

27.  The  wiring  diagram  of  the  observer's  table  with  the  Sage  calorimeter  .  576 

28.  Diagram  of  the  Atwater,   Rosa,   Benedict  respiration   calorimeter  as 
prepared  by  DuBois  for  the  Sage  calorimeter 577 

29.  The  small  calorimeter  at  Cornell  University  Medical  College  shown 

in  process  of  construction 575 

30.  Richet  siphon  calorimeter 582 

31.  The  second  calorimeter  of  Rubner 583 

32.  Curves  showing  the  total  heat  output  per  minute  and  corresponding 

external  muscular  work  per  minute,  expressed  in  calories,  for  sub- 
ject riding  with  constant  load— 1.5  amperes— at  varying  speeds  .     .  589 


LIST  OF  ILLUSTRATIONS 


XI 

PAGE 


33.  Existence  d'une  loi  geometrique  tres  simple  de  la  surface  du  corps  de 

rhorame  de  dimensions  quelconques,  demontree  par  iine   nouvelle 

methode ►     .      .     596 

33-a.  Chart  for  determining  surface  area  of  man  in  square  meters  from 
weight  in  kilograms  and  height  in  centimeters  according  to  the 
formula        597 

34.  Showing  the  H.  Q.,  the  total  metabolism  determined  by  indirect  and 

direct  calorimetry  as  well  as  the  nitrogen  elimination  during  hourly 
periods  after  the  ingestion  of  1200  grams  of  meat,  by  a  dog  .      .      .     606 

35.  Variations  of  basal  metabolism  with  age 613 

36.  Cross-Section   of  bed   calorimeter    with   which   studies    on   pregnancy 

were  made  by  Carpenter  and  Murlin 623 

37.  Metabolism  during  first  year  of  life 645 

38.  Body-weight,  pulse-rate  and  basal  metabolism  per  24  hours  of  a  girl 

from  5  months  to  41  months  of  age 649 

39.  Basal  heat  production  of  boys  from  birth  to  puberty ,     650 

40.  Basal  heat  production  of  girls  from  birth  to  puberty 651 

41.  Basal  heat  production  of  boys  from  birth  to  pubertj* 651 

42.  Basal  heat  production  of  girls  from  birth  to  puberty 652 

43.  Comparison  of  basal  heat  production  of  boys  and  girls  per  24  hours 

referred  to  body-weight 653 

44.  Basal  heat  production  of  boys  from  birth  to  puberty  .      .      .      .     .     .     657 

45.  Metabolism  in  calories  per  day  of  boys  from  birth  to  15  years  of  age  .     659 

SECTION  VII 

ACTIONS  OF  DRUGS  AND  THERAPEUTIC  MEASURES 

The  Effects  of  Certain  Drugs  and  Poisons  Upon  the  Metabolism 

Henry  G.  Barbour 

1.  Influence  of  sodium  carbonate  ingestion  on  the  glycosuria  of  a  diabetic    738 

2.  Leg  bones  in  osteogenesis  imperfecta 751 

3.  Same  case  as  Fig.  2  after  two  years  of  treatment  with  1/150  grain 

phosphorus  twice  daily '^32 

4.  Effect?  of  acetyl  salicylic  acid  on  patient  with  tuberculous  abscess  .     .     769 

5.  Effect  of  thyroxin  in  cretinism «83 

Hydrotherapy 
Henry  A.  Mattill 
1.     Total  nitrogen  and  sodium  chlorid  in  tenths  of  grams,  creatinin  in 

hundredths  of  grams       . ^^^ 


Metabolism 


A  History  of  Metabolism Graham  Lusk 

Introduction — The  Dawn  of  History — The  Classical  Period — The  Dark  Ages 
"  — The  Eenaissance — The  Chemical  Eevolution — Science  After  the  French 
Eevolution — The    Beginnings    of    Calorimetr}' — The    Else    of    German 
Science — Late  French  Work — Conclusion. 


A  History  of  Metabolism 


GRAHAM  LUSK 

NEW   YOEK 

Introduction 

When  one  considers  the  history  of  the  development  of  the  science 
of  nutrition  one  is  impressed  with  the  gradual  giowth  of  knowledge  upon 
the  subject.  The  ideas  concerning  it  are  not  the  products  of  the  work 
of  supermen.  TJie  ideas  were  not  born  as  was  Minerva,  who  sprang  from 
the  head  of  Jove.  And  yet  those  who  furthered  science  were  men  pos- 
sessing much  infoiTnation  and  also  a  sense  of  appreciation  of  values. 

"Not  from   a  vain  or   shallow  thought 
His  awful  Jove  young  Phidias  brought." 

Though  vain  and  shallow  men  may  contribute  for  weal  or  woe  to 
political  Or  social  life,  they  have  no  influence  upon  science. 

This  history  has  been  composed  with  the  dominant  viewpoint  of  pre- 
senting the  subject  in  the  words  of  the  Old  Masters  themselves.  One 
would  not  desire  to  see  an  imitation  of  the  Sistine  Chapel  could  one  view 
the  reality  itself. 

The  Dawn  of  History 

It  is  interesting  to  note  that  Voit  (d)  attributes  the  higher  cultivation 
of  the  peoples  living  in  the  temperate  zones  to  the  distribution  of  food.  He 
says  in  this  regard: 

"The  ingestion  of  food  is  a  fundamental  condition  of  our  existence 
and  is  indeed  one  of  the  most  wondeiful  arrangements  of  Providence. 
To  the  blinded  eyes  of  man  it  often  appears  as  a  punishment  that  by  the 
sweat  of  his  brow  he  should  eat  bread.  Hunger  is  the  primary  and 
most  powerful  spur  to  work,  and  only  through  work  come  experience 
and  progress.  If  we  were  provided  with  sufficient  available  energy  for 
life  we  would  ever  remain  in  an  undevelopeil  state.  In  a  country  where 
nature  with  outstretched  anns  offers  excess  of  nourishment  whicb  is 
obtainable  without  effort,  one  will  seek  in  vain  for  independent,  driving 
progress.     Originally,  prehistoric  man  was  nomadic,  living  temporarily 


r 


4  GKAHAM  LUSK 

upon  the  country  where  he  settled.  He  tamed  wild  animals  for  his  ser- 
vice. ■  He  then  drifted  into  the  most  fruitful  land  areas  and  these  lie 
cultivated.     Here  came  the  dawn  of  history. 

"In  the  tropics  the  development  of  man  is  prevented  hy  an  enervating 
atmosphere.  In  the  polar  regions  where  the  greatest  exertion  results  in 
obtaining  only  a  small  amount  of  sustenance  progi-ess  is  also  limited. 
Eskimo  and  Lapp  live  as  they  did  a  thousand  years  ago  and  have  no 
history.  In  temperate  climes  the  production  of  food  is  not  so  favored 
as  in  warmer  regions,  but  the  other  conditions  for  the  maintenance  of 
an  active  life  are  more  favorable  and  therefore  civilization  will  ever  have 
her  home  there." 

The  Classical  Period 

Tho  Greeks  had  no  classical  education  but  it  has  been  said  that  they 
had  tho  two  essential  requisites  of  true  education,  the  capacity  to  express 
themselves  in  words  and  a  desire  to  understand  their  relations  with  their 
environment,  of  which  the  latter  is  science  (Prof.  E,  H.  Starling).  Epic- 
tetus  makes  the  statement  and  gives  the  advice  which  follows :  "Socrates 
in  this  way  became  perfect,  in  all  things  improving  himself,  attending  to 
nothing  except  to  reason,  but  you  who  are  not  yet  a  Socrates  ought  to  live 
as  one  who  wishes  to  be  a  Socrates.'^  This  was  the  general  attitude  of  the 
scholars  of  Greece  and  Kome. 

Socrates  (B.  C,  J^7 0-399)  held  that  the  object  of  food  was  to  replace 
the  loss  of  water  from  the  skin  and  the  loss  of  ponderable  heat. 

Hippocrates  (B.  C.  460-36 J^)y  the  Father  of  Medicine  and  a  con- 
temporary of  Socrates,  believed  that  the  loss  of  body  weight  in  fasting 
was  due  to  the  loss  of  "insensible  perspiration''  from  the  skin  and  to  a 
loss  of  heat  which  he  conceived  to  consist  of  a  fine  material.  Among  the 
writings  of  Hippocrates  may  be  found  the  following  aphorisms : 

Aphorism,  Sec.  I,  14. — Growing  bodies  have  the  most  innate  heat;  they  there- 
fore require  the  most  food,  for  otherwise  their  bodies  are  wasted.  In  old  persons 
the  heat  is  feeble  and  therefore  they  require  little  fuel  as  it  were  to  the  fiame, 
for  it  would  be  extinguished  by  much.  On  this  account,  also,  fevers  in  old  per- 
sons are  not  equally  acute,  because  their  bodies  are  cold. 

Aphorism  4,  Sec.  II. — Neither  repletion  nor  fasting  nor  anything  else  is 
good  when  more  than  natural. 

Aphorism  38.-— An  article  of  food  or  drink  which  is  slightly  worse  but  more 
palatable  is  to  be  preferred  to  such  as  are  better  but  less  palatable. 

The  Greeks  believed  that  there  were  four  elements,  fire,  air,  earth 
and  water,  and  four  elemental  properties,  hot,  cold,  moist  and  dry.  The 
broad  viewpoint  of  Hippocrates  thus  finds  expression: 

Whoever  having  undertaken  to  speak  and  write  on  medicine  have  first  laid 
down  for  themselves  some  hypothesis  to  their  argument  such  as  hot  or  cold  or 


-  A  HISTORY  OF  METABOLISM  5 

r 

moist  or  dry  or  whatever  else  they  choose  (thus  reducing?  their  subject  within 
a  narrow  compass  and  supposing  only  one  or  two  original  causes  of  disease  or 
of  death  among  mankind)  are  clearly  mistaken  in  much  that  they  say, 

Aristotle  (B.  C.  384-332)  created  the  conception  of  a  functioning 
organism  in  the  following  celebrated  passage: 

The  animal  organism  is  to  be  conceived  after  the  similitude  of  a  well  gov- 
erned commonwealth.  When  order  is  once  established  in  it  there  is  no  more 
need  of  a  separate  monarch  to  preside  over  each  separate  task.  The  individuals 
each  play  their  assigned  part  as  it  is  ordered,  and  one  thing  follows  another  in 
its  accustomed  order.  So  in  animals  there  is  the  same  orderliness — ^nature  taking 
the  place  of  custom — and  each  part  naturally  doing  his  own  work  as  nature  has 
composed  them,  There  is  no  need  of  a  soul  in  each  part,  but  she  resides  in  a 
kind  of  central  governiug  place  in  the  body  and  the  remaining  parts  live  by 
continuity  of  natural  structure  and  play  the  parts  nature  would  have  them  play. 

Galen  (A,  D,  131-200),  a  physician  from  Troy  who  practiced  in 
Rome  six  hundred  years  after  Socrates,  was  unable  to  add  anything  to 
the  ancient  doctrines  taught  by  the  Greeks.  Galen  remarks,  ''The  blood 
is  like  the  oil,  the  heart  is  like  the  wick  and  the  breathing  lungs  an 
instrument  which  conveys  external  motion." 


The  Dark  A^es 

For  thirteen  hundred  years  after  the  time  of  Galen  knowledge  of  nu- 
trition did  not  advance.  The  alchemists  were  at  work  striving  to  make 
gold  from  the  baser  metals  and  endeavoring  to  produce  infallible  medi- 
cines. But  in  the  absence  of  a  knowledge  of  the  chemistry  of  living  things 
there  could  be  iio  knowledge  of  the  function  of  food. 

Carl  Voit(<Z),  possibly  with  a  slight  national  bias,  thus  portrays  the 
events  in  the  dark  ages:  .        " 

One  usually  regards  this  period  of  the  world  as  intellectually  barren,  during 
which  only  a  blind  imitation  of  the  old  and  senseless  scholasticism  prevailed. 
However,  one  makes  a  great  mistake  to  condemn  the  human  race  as  having 
been  incapable  for  a  thousand  years.  We  should  rather  understand  why  a 
rapid  development  was  impossible.  The  conditions  for  a  continued  expan- 
sion of  scientific  knowledge  were  about  as  unfavorable  as  imaginable.  The 
Age  of  Antiquity  reached  the  highest  standard  of  cultivation  possible  from  the 
knowledge  of  the  time  and  it  needed  entirely  new  ideas  in  order  to  move 
forward,  for  the  cultivation  of  mankind  is  not  accomplished  like  a  constantly 
growing  branch,  but  rather  like  one  which  is  stimulated  anew  after  having  been 
formerly  ripe.  I  doubt  whether  the  ancient  Greeks  and  Romans  with  their  pe- 
culiar mental  temperament  had  the  power  further  to  extend  knowledge.  The 
Empires  in  which  the  old  cultivation  had  flourished  went  down,  and  younger 
races  reigned  in  their  stead.  These  rough  victors  eagerly  acquired  the  intellectual 
treasures  which  the  conquered  people  had  accumulated  in  the  days  of  their  glory ; 
they  regarded  themselves  as  pupils  and  fell  for  a  time  into  intellectual  dependence 


6  GKAHA.\r  LUSK 

as  they  devotitly  entered  into  this  great  heritage.  The  education  of  peoples  is 
like  that  of  an  individual.  It  is  some  time  after  education  in  the  schools  has 
taught  one  to  think  that  one  is  capable  of  independent  action,  and  usually  one 
seeks  first  the  wrong  way  before  one  finds  the  right.  Even  so,  the  change  from 
the  olden  to  the  modern  could  take  place  only  after  prolonged  struggle.  The 
spirit  was  gradually  sharpened  but  there  were  not  enough  new  facts  to  create 
new  ideas.  Satisfaction  was  sought  in  acute  dialectics.  This  was  only  an  indi- 
cation that  the  old  methods  brought  no  one  forward.  Finally,  the  tremendous 
events  which  took  place  in  the  fifteenth  century  changi?d  dutiful  scholars  into 
critics  and  independent  investigators  who,  through  the  revelation  of  heretofore 
unknown  methods  of  the  mind,  were  able  to  open  up  new  pathways. 


The  Renaissance 

The  xiniversities  of  Cambridge  (founded  in  1220)  and  Oxford 
(founded  in  1249)  were  established  at  a  time  when  authority  was  wor- 
shiped. After  the  revival  of  learning  in  Italy  tlie  original  versions  of 
the  ancient  classics  were  brought  into  France  and  England  and  the  for- 
gotten culture  of  a  bygone  civilization  was  revived. 

The  Greek  idea  of  medicine  persisted  after  two  thousand  years  and 
Chaucer  (1340-1400)   portrays  the  physician  as  follows: 

"He  knew  the  cause  of  every  malady, 
Were  it  of  cold  or  hot  or  moist  or  dry, 
And  where  engendei-ed  and  of  what  humour, 
He  was  a  very  perfect  practisour." 

1^0  adequate  conception  of  the  nature  of  nutrition  was  possible  with- 
out an  understanding  of  the  nature  of  air.  The  idea  that  air  was  an  ele- 
mentary substance  persisted  until  comparatively  recent  times.  The  grop- 
ing of  human  inquiry  into  the  analysis  of  the  invisible  atmosphere  con- 
stitutes a  fascinating  chapter. 

Leonardo  da  Vinci  (1452-1519),  accounted  one  of  the  greatest  paint- 
ers of  the  Renaissance  and  who  was  at  the  same  time  mathematician, 
physicist  and  naturalist,  said  at  the  end  of  the  fifteenth  century  that  no 
animal,  whether  of  the  land  or  of  .the  air,  could  live  in  an  atmosphere 
which  could  not  support  a  flame  (Milne-Edwards  I,  377).  The  broad 
mind  of  Leonardo  with  wonderful  intuition  interprets  life  as  follows: 

Hast  thou  marked  Nature's  diligence?  The  body  of  everything  that  takes 
nourishment  constantly  dies  and  is  constantly  reborn;  b€?caiise  nourishment  can 
only  enter  into  places  where  that  past  nourishment  has  expired,  and  if  it  has 
expired  it  has  no  more  life;  and  if  you  do  not  supply  nourishment  equal  to  the 
nourishment  departed  life  will  fail  in  vigor;  and  if  yow  take  away  this  nourish- 
ment life  is  utterly  destroyed.  But  if  you  restore  as  maac-h  as  is  consumed  day 
by  day,  just  so  much  of  life  is  reborn  as  is  consumed ;  as  the  flame  of  the  candle 
is  fed  by  the  nourishment  given  by  the  liquor  of  the  caiiidle,  which  flame  con- 
tinually  with   rapid    succor   restores   from   below   what   above   is   consumed   in 


A  HISTORY  OF  METABOLISIM  7 

dying;  and  from  a  brilliant  light  is  converted  into  dark  smoke;  which  death 
is  continuous  as  the  smoke  is  continuous;  and  the  continuance  of  the  smoke 
equals  the  continued  nutriment;  and  at  the  same  moment  all  the  flame  is  dead 
and  regenerated  with  the  movement  of  its  nutriment. 


Paracelsus  (Ul)'Mr>91)  recognized  the  analogy  between  the  produc- 
tion of  heat  without  Hame,  botli  in  tlie  l)ody  and  chemically  outside  the 
body,  as  had  Aristotle  and  Galen 
l>efore  him.  He  imagined  the 
existence  of  a  spirit,  t  h  e 
Archa'us,  which  lived  in  the 
stomach  and  which  there  di- 
vided the  foods  into  the  good 
and  the  bad,  the  former  being 
used  by  the  body  and  the  latter 
being  eliminated  in  the  excreta 
as  evil  and  poisonous. 

Sanctorius  (1561-1636),  a 
professor  of  Padua,  published 
in  1614  his  celebrated  '*De  medi- 
cina  statica  aphorisrai,"  which 
was  printed  in  Venice.  Sanc- 
torius kept  careful  account  of 
his  body  weight,  noted  also  the 
weight  of  food  and  drink  taken 
and  of  urine  and  excrement 
passed.  He  was  thus  able  to 
discover  that  the  major  evacua- 
tion from  the  body  was  the 
'^insensible  perspiration."  He 
determined  the  considerable  loss 
in  body  weight  during  periods 
in  which  no  urine  or  feces  were 
passed  from  the  body.  Section 
III  of  the  Aphorisms  treats  "of 
Meats  and  Drink''  and  contains 
the  following  quaint  allusions, 

as  rendered  in  a  translation  by  John  Quincy,  published  in  London  in 
1712  and  printed  for  William  Newton  in  Little  Britain. 

LXXV.  "The  Physician  who  has  the  Care  of  the  Health  of  Princes  and 
and  knows  not  what  they  daily  perspire,  deceives  them  and  will  never  be  able 
to  cure  them  except  by  Accident." 

LXXVI.  "In  the  first  four  Hours  after  Eating  a  great  many  perspire  a 
Pound  or  near;  and  after  that  to  the  ninth  two  Pound;  and  from  the  ninth  to 
the  sixteenth  scarce  a  Pound." 


Fig.  1.  Frontispiece  of  "De  medicina  statica 
aphorismi,"  showing  Sanctorius  seated  on  a 
cliair  suspended  from  a  large  steelyard. 


8  GKAHAM  LUSK 

VIII.  "Mutton  easily  digests  and  perspires;  or  it  will  waste  in  a  niglit  a 
third  part  of  a  Pound  more  than  any  other  usual  Food." 

XXIIT.  "Pork  and  Mushrooms  are  bad  both  because  they  do  not  Perspire 
themselves  and  because  they  hinder  the  Perspiration  of  other  things  eat  along 
with  them." 

LIX.  ''If  a  Supper  of  eight  Pounds  corrupts  in  the  Stomach,  the  next  Day 
the  Body  will  be  lighter  than  after  a  Supper  of  three  Pound  which  does  not  do 
so." 

These  aphorisms  summarized  signify  that  a  well  appreciated  meat, 
such  as  mutton,  increases  the  perspiration,  whereas  pork,  which  very 
likely  then  as  now  was  an  unpopular  food  in  Italy,  causes  "corruption" 
and  diarrhea  and  hence  no  increase  in  perspiration. 

This  kind  of  investigation  was  continued  by  Dodart  (died  1707)  in 
France,  who  devoted  thirty-three  years  of  exhaustive  labor  to  the  subject. 

Then  followed  the  first  discovel*y  of  carbonic  acid  gas  by  Van  Hel- 
mont  in  the  seventeenth  century. 

Van  Helmont  (1577-1644),  a  member  of  the  ancient  princely  family 
of  the  Counts  of  Merode  of  Belgium,  was  one  who  consecrated  his  life 
to  his  laboratory.  He  discovered  that  when  charcoal  burned  or  wine 
fermented  a  gas  w^as  produced  which  was  as  invisible  as  respired  air; 
that  it  is  sometimes  emitted  from  the  bowels  of  the  earth,  in  mines  or 
at  the  Grotto  del  Carno  (near  Naples — so  called  because  if  a  man 
enters  it  accompanied  by  a  dog,  the  man  lives  but  the  dog  dies,  since 
carbon  dioxid  gas  evolved  is  heavier  than  air  and  remains  near  the 
ground)  ;  that  it  is  present  in  the  waters  of  Spa  and  is  evolved  when 
vinegar  is  poured  on  chalk.  This  gaz  sylvestre  ("wood  gas")  does  not 
maintain  a  flame  nof  life  of  animals.  It  promptly  results  in  their 
asphyxiation  and  death. 

Jean  Rey,  bom  about  the  end  of  the  sixteenth  century,  died  1645,  a 
physician  of  Perigord,  found  in  1630  that  tin  and  lead  increased  in 
weight  when  calcined,  but  the  significance  of  these  facts  was  neglected 
in  the  subsequent  enthusiasm  over  phlogiston.  Key's  work,  ^^Essays  sur 
la  recherche  de  la  cause  pour  laquelle  Testain  et  le  plomb  augmentent  de 
poids  quand  on  les  calcine,"  1630,  w^as  reprinted  after  Lavoisier's  dis- 
coveries in  1777. 

Nicholas  Lefevre  (died  1674),  in  his  "Traite  de  Chimie,"  published 
about  1660,  says,  ''In  the  act  of  respiration  the  air  does  not  confine 
itself  to  refreshing  the  lungs,  but  by  means  of  the  'universal  spirit'  it 
reacts  upon  the  blood,  refining  it  and  volatilizing  all  its  superfluities." 
A  hundred  years  later  Haller  had  about  the  same  viewpoint.  Lefevre 
was.  one  of  the  founders  of  the  Academie  des  Sciences  and  was  physician- 
in-chief  to  Louis  XIY. 

Eobert  Boyle  (1621-1679)  in  1660  showed  that  the  flame  of  a  candle 
or  the  life  of  an  animal  was  extinguished  after  placing  them  in  an  air 
pump.     Between  1668  and  1678  he  made  numerous  experiments  with 


A  IITSTORY  OF  METABOLISM  9 

many  animals  of  different  species  with  a  view  of  isolating  that  part  of 
the  air  which  was  "eminently  respirahle."  Thus  he  suggests  in  a  suh- 
division  entitled  "Of  Air  in  Reference  to  Fire  and  Flame"  in  his  work 
on  "The  General  History  of  the  Air"  (1680)  the  following  experiments: 

Tho  hurning  of  candles  under  a  glass  hell. 

The  burning  of  spirits  of  wine  under  a  glass  hell. 

The  keeping  of  animals  in  the  same  instrument  whilst  the  flame  is 
burning. 

In  the  "Sceptical  Chemist,"  which  appeared  in  1661,  Boyle  thus 
voices  his  opinions: 

Now  a  man  need  not  be  very  conversant  in  the  writings  of  chemists  to  ob- 
serve in  how  lax,  indefinite  and  almost  arbitrary  senses  they  employ  the  terms 
salt,  sulphur  and  mercury.  .  .  . 

But  I  will  not  here  enlarge  upon  this  subject  nor  yet  will  I  trouble  you 
with  what  I  have  largely  discoursed  in  the  "Sceptical  Chemist,"  to  call  in  ques- 
tion the  grounds  on  which  chemists  assert  that  all  mixed  bodies  are  compounded 
of  salt,  sulphur  and  mercury. 

Boyle  lived  in  the  period  of  the  birth  of  national  scientific  societies. 
.The  Academic  des  Sciences  was  founded  in  Paris  by  Louis  XIV,  who, 
after  the  peace  of  the  Pyrenees  in  the  fullness  of  his  power,  felt  that  his 
kingdom  needed  nothing  further  than  to  he  fortified  by  science,  industry 
and  art,  and  he  instructed  his  minister  Colbert  to  carry  out  his  desires. 
The  members  were  given  stipends  from  the  state.  This  was  the  first 
example  of  state  endowTuent  of  science.  About  the  same  time  the  Royal 
Society  of  London  was  established  in  England,  which  was  the  outgrowth 
of  a  gathering  of  men  at  first  held  surreptitiously.  This  older  organiza- 
tion, of  which  Boyle  was  a  member,  is  still  perpetuated  as  the  Royal 
Society  Club. 

Among  those  influenced  by  Boyle  was  one  J'ohn  Mayow. 

John  Mayow  (1640-1679),  "descended  from  a  genteel  family  of  his 
name  living  at  Bree  in  Cornwall,  was  born  in  the  parish  of  St.  Dunstan- 
in-the-West,  in  Fleet  Street,  London,  admitted  as  a  scholar  of  Wadham 
College  the  23rd  of  September,  1659,  aged  sixteen  years,"  (Beddoes).  Ilis 
scientific  work  was  accomplished  at  All  SouTs,  Oxford.  Some  of  his  ex- 
periments may  be  thus  recounted : 

Camphor  placed  in  a  capacious  glass  vessel  inverted  over  water  is 
ignited  by  a  burning  glass.  After  cooling,  the  air  is  reduced  one-thirtieth 
in  bulk.  A  second  piece  of  camphor  will  not  burn,  "a  clear  proof  that 
the  combustion  has  deprived  the  air  of  its  fire-air  particles  so  as  to 
have  rendered  it  altogether  unfit  to  support  flame."    ^ 

A  mouse  was  put  into  a  wire  trap  and  this  was  placed  on  a  three- 
legged  stool  which  stood  in  water  and  the  whole  was  covered  with  a  bell 
jar.     The  volume  of  the  air  diminished   one-fourteenth. 


10  GRAHAM  LUSK 

If  a  burning  candle  and  an  animal  be  put  together  in  a  bell  jar 
both  will  go  out  sooner  than  one  alone  because  flame  is  extinguished  and 
an  animal  expires  for  want  of  nitro-aerial  particles. 

"Air  loses  scmewhat  of  its  elastic  force  during  its  respiration  by  ani- 
mals, as  also  in  combustion.  One  nuist  believe  that  animals,  like  fire,  re- 
move from  air  particles  of  the  same  nature." 

And  in  another  place  he  writes,  "Breathing  brings  the  air  into  contact 
with  the  blood  to  which  it  gives  up  its  nitro-aerial  constituent.  Again 
the  motion  (of  the  muscles)  results  from  the  chemical  action  in  the 
muscle  with  the  combustible  matter  contained  therein." 

Xiter  contains  the  nitro-aerial  particles  and  hence  gim powder  burns 
^^ithout  air.  Many  authoi-s  have  written  "as  if  it  had  been  ordained 
that  niter  should  make  as  much  noise  in  philosophy  as  in  war,  yet  its 
properties  are  still  concealed  from  our  knowledg^e." 

Calcined  antimony  mixed  with  niter,  when  acted  on  by  heat  from  a 
burning  glass,  increases  in  weight  through  addition  of  nitro-aerial  par- 
ticles. 

As  to  Mayow^s  death,  at  the  age  of  thirty-nine  it  was  written : 

"He  paid  his  last  debt  to  nature  in  an  apothecary^s  house  bearing 
the  sign  of  the  Anchor  in  York  Street  near  Covent-Garden,  within  the 
liberty  of  Westminster  (having  been  married  a  little  before  not  alto- 
gether to  his  content),  in  the  month  of  September,  1670,  and  was  buried 
in  the  Church  of  St.  Paul,  Covent-Garden." 

Beddoes,  his  biogi-apher,  writes:  "Mayow  .  .  .  silently  and  unper- 
ceived  in  the  obscurity  of  the  last  century  discovered  if  not  the  whole 
sum  and  substance,  yet  certainly  many  of  those  splendid  truths  which 
adorn  the  writings  of  Priestley,  Scheele,  Lavoisier,  Crawford,  Goodwyn 
and  other  philosophers  of  this  day." 

"Should  I  ask  you  who  of  all  your  acquaintance  is  the  person  least 
likely  to  be  overtaken  by  surprise  you  would,  T  think,  name  a  certain 
Xorthern  Professor.  .  .  .  Yet  at  the  sight  of  the  annexed  representation 
of  Mayow's  pneumatic  apparatus,  this  sedate  philosopher  lifted  up  his 
hands  in  compleat  astonishment" 

The  "sedate  philosopher"  was  undoubtedly  Black.  Writing  in  1790, 
however,  Beddoes  cannot  escape  from  the  absurd  statement,  "He  (Mayow) 
has  clearly  presented  the  notion  of  phlogiston  which  rendered  the  name 
of  Stahl  so  celebrated." 

Mayow's  "Treatise  on  Respiration"  was  published  in  hi»  twenty-eighth 
year.  INewton  invented  the  calculus  when  twenty  years  old;  Black  found 
"fixed  air^'  at  twenty-four;  li.  ^[ayer  formulated  the  Law  of  the  Con- 
servation of  Energy  at  twenty-six. 

flayer's  paper  containing  the  last-named  doctrine  was  refused  pul> 
lication  in  Liebig's  AnnaJcn!  These  facts  shonhl  afFord  a  stimulus  to 
the  youn<?  and  food  for  the  thouicht  of  the  more  mature. 


A  HISTORY  OF  METABOLISM  11 

Willis  (1621-1()75),  a  conteiiiporary  of  Boyle,  and  his  pupil  Lower, 
a  colleague  of  Majow  at  Oxford,  demonstrated  the  reddening  of  blood 
by  the  respiration  by  admitting  and  excluding  air  from  an  animal. 

Stephen  Hales  (1677-1761)  was  a  parish  priest  described  by  Horace 
Walpole  as  "a  jX)or,  good,  primitive  creature."  And  yet  this  apparently 
unimportant  man  writes  in  his  "Statical  Essays,"  published  in  1727, 
"A  part  of  the  inspired  air  is  lost  in  the  blood,  but  it  is  as  yet  entirely 
dark  what  its  use  may  be." 

Boerhaave  (1668-1738),  when  he  published  his  great  work,  the 
*^Element3  of  Chemistry,"  in  172-1,  is  believed  to  have  had  the  work  of 
Mayow  in  mind  when  he  wrote:  *'Who  can  say  whether  an  air  of  spe- 
cial virtue  for  the  maintenance  of  the  lives  of  animals  and  plants  does 
not  exist ;  whether  it  may  not  become  exhausted ;  whether  its  consump- 
tion is  not  the  cause  of  the  death  of  animals  who  can  no  longer  possess 
it?  Many  chemists  have  announced  the  existence  of  a  vital  element  in 
the  air,  but  they  have  never  told  what  it  is  or  how  it  acts.  Happy  the 
man  who  discovers  it!" 

Stahl  (1660-1734),  the  German  chemist  who  in  1716  moved  to  Berlin 
as  physician  to  the  King  of  Prussia,  was  the  originator  of  the  phlogiston 
theory  of  combustion  which  enthralled  the  minds  of  men  for  nearly  a 
hundred  years.  According  to  this  theory  all  combustible  substances  con- 
tained phlogiston  \yhich  passed  from  them  when  they  were  burned.  What 
we  now  know  as  oxids  of  iron  or  lead  were  those  metals  ^vhich  through 
burning  had  lost  their  phlogiston.  Such  substances,  if  calcined  wdth 
carbon,  a  material  supposed  to  be  rich  in  phlogiston,  absorbed  phlogiston 
and  became  metals  once  more.  This  simple  theory  availed  to  explain  all 
the  plienomena  of  combustion  and  was  generally  accepted  by  the  scientific 
world. 

When  one  halts  to  consider  the  general  knowledge  of  nutrition  in 
the  middle  of  the  eighteenth  century  one  finds  little  to  distinguish  be- 
tween the  statements  of  Sanctorius,  150  years  earlier,  and  Benjamin 
Franklin.  Sanctorius  writes,  "]\Ieats  wdiich  promote  Perspiration  bring 
Joy,  but  those  which  obstruct  it  Sorrow";  and  Franklin  in  1742,  "If 
thou  art  dull  and  heavy  after  Meat  it  is  a  sign  that  thou  hast  exceeded 
due  measure;  for  Meat  and  Drink  ought  to  refresh  the  Body  and  make 
it  cheei-ful  and  not  to  dull  or  oppress  it." 

The  general  opinion  of  high  authorities  in  the  eighteenth  century  was 
voiced  by  Haller. 

Albrecht  von  Haller  (1708-1777),  the  great  physiologist,  published 
his  *'EIementa  Physiologica"  between  1757  and  1765.  He  asserts  "that 
fire  is  contained  in  the  blood  is  proved  by  its  heat,"  and  he  has  this 
rather  hazy  conception  of  the  process  of  respiration:  "The  secondary 
uses  of  respiration  are  very  numerous.  It  exhales  copiously  and  removes 
from  the  blood  something  highly  noxious;  for  by  remaining  in  the  air 


12  '  GRAHAM  LUSK 

it  will  cause  suffocation;  and  the  breath  of  many  people  crowded  in  a 
close  and  small  place  impregnates  the  air  with  a  suffocating  quality.  On 
the  other  hand,  it  absorbs  from  the  air  a  thin  vapor,  of  which  the  use 
is  not  sufficiently  known.'^ 

And  Benjamin  Franklin  in  **Poor  Richard,"  1746,  thus  poetically 
popularizes  the  ideas  of  his  time: 

"Like  cats  in  air  pumps  to  subsist  we  strive, 
On  joys  too  thin  to  keep  the  soul  alive.'^ 

The  dawn  of  the  modern  era  has  been  reached,  but  there  is  little 
to  indicate  the  impending  clarification  of  thought.  Before  considering 
the  events  which  led  to  the  Chemical  Revolution  one  must  stop  to  learn 
of  a  case  of  self-inflicted  human  scurvy. 

William  Stark,  M.D.  (1740-1770).— The  work  of  Stark  was  edited 
after  his  death  by  J.  C.  Smyth. 

In  the  editor's  preface  one  reads,  "His  experiments  on  diet  are 
the  first  and  will  probably  long  remain  the  only  experiments  of  the 
kind.'' 

It  is  stated  that  he  began  his  experiments  on  diet  in  1769,  greatly 
encouraged  by  Dr.  Franklin,  "from  whom  he  received  many  hints." 

Stark  thus  describes  himself:  "The  person  upon  whom  these  ex- 
periments are  tried  is  a  healthy  man  about  twenty-nine  years  of  age,  six 
•feet  high,  stoutly  made  but  not  corpulent,  of  a  florid  complexion,  with 
red  hair." 

He  reached  the  following  general  conclusions:  "A  very  spare  and 
simple  diet  has  commonly  been  recommended  as  most  conducive  to  health, 
but  it  would*  be  more  beneficial  to  mankind  if  we  could  shew  them  that  a 
pleasant  and  varied  diet  w^as  equally  consistent  with  health  as  the  very 
strict  regimen  of  Cornaro  or  the  Miller  of  Essex.  These  and  other  ab- 
stemious people,  who  having  experienced  the  great  extremities  of  bad 
health,  were  driven  to  temperance  as  their  last  resource,  may  run  out  in 
praises  of  a  simple  diet,  but  the  probability  is  tliat  nothing  but  the  dread 
of  former  sufferings  could  have  given  them  resolution  to  persevere  in  so 
strict  a  course  of  abstinence." 

He  gives  the  following  reasons  for  undertaking  the  investigation: 
"Dr.  B.  Franklin  of  Philadelphia  informed  me  that  he  himself  when  a 
journeyman  printer  lived  a  fortnight  on  bread  and  water  at  the  rate  of 
ten  pounds,  of  bread  per  week  and  found  himself  stout  and  hearty  on 
this  diet."  ... 

"I  learned  from  Dr.  Mackenzie  that  many  of  the  poor  people  near 
Inverness  never  took  any  kind  of  animal  food,  not  even  eggs,  cheese, 
butter  or  milk." 

Mr.  Hjewson  told  him  that  a  ship^s  crew,  having  consumed  the  pro- 
visions, lived  one  part  on  tobacco^  the  other  part  on  sugar.     The  latter 


A  HISTORY  OF  METABOLISM 


13 


generally  died  of  scurvy,  while  the  former  remained  free  from  the  disease 
or  soon  recovered. 

Dr.  Cirelli  informed  him  that  Neapolitan  physicians  frequently  gave 
for  periods  of  forty  days  no  food  to  patients  suffering  from  fever. 

Mr.  Slingshy  has  lived  many  years  on  bread,  milk  and  vegetables  with- 
out animal  food  or  wine  and  has  been  free  from  gout  ever  since  he  began 
this  regimen. 

Stark's  experiments  of  taking  bread  and  water  alone  may  thus  be  sum- 
marized : 


Daily  diet 


weight 


oz. 


Body 
at  start 
lbs. 


Period 


Period  I 

Bread,  20 

171 

2  weeks 

"        II 

Bread,  30 

163 

3       " 

"        III 

Bread,  30 

161 

5  days 

"       IV 

Bread,  38 

158 
IGO 

(at 
en( 

1  week 
^1) 

"During  the  third  period  I  was  one  day  irregular,  having  ate  about 
four  ounces  of  meat  and  drank  two  or  three  glasses  of  wine.  At  the  con- 
clusion of  it  I  was  perfectly  hearty,  my  head  clear,  often  hungi-y." 

After  this,  from  July  26  to  August  24,  he  took  a  diet  of  bread,  water 
and  sugar.  On  August  11,  "I  now  perceived  smallmlcers  on  the  inside 
of  my  cheeks,  particularly  near  a  bad  tooth ;  the  giuns  of  the  upper  jaw 
of  the  same  side  were  swelled  and  red  and  bled  when  pressed  with  the 
finger;  the  right  nostril  was  also  internally  red  or  purple  and  very 
painful." 

On  August  13,  having  been  extremely  ill,  he  took  a  few  ounces  of 
meat  and  two  or  three  glasses  of  wine  with  his  bread.  This  caused 
marked  improvement  in  his  condition.  On  Augiist  22  he  dined  heartily 
on  meat  and  fruit  and  drank  some  wane. 

From  August  24  to  September  13,  a  diet  of  bread,  water  and  olive 
oil.  On  September  8  he  was  so  weak  that  he  almost  fainted  when  walking 
across  the  floor.  The  gums  were  swollen  and  he  "spat  in  considerable 
quantity  a  very  disagreeable,  fetid,  yellowish  fluid."  On  September  9 
he  took  "a  basin  of  mutton  broth"  and  thereafter  lived  freely  on  animal 
food,  milk  and  wine  until  September  18,  when  "I  felt  myself  quite  re- 
covered." 

On  September  18  to  October  2,  a  diet  of  bread,  water  and  milk.  IJpon 
this  diet  the  gums  improved  and  the  offensive  smell  disappeared. 

From  October  2  to  October  14  the  diet  consisted  of  bread,  water  and 
roast  goose.    He  became  "hearty  and  vigorous,  both  in  mind  and  body." 


14  GKAIIA^L  LUSK 

October  14-  to  10  lived  fredy  on  aiiiraal  food. 

October  21  to  28,  bread,  water  and  boiled  beef.  ^*]Sever  the  least 
heavy  or  dull,  .  .  .  but  had  a  keenness  for  studj.''  * 

October  28  to  Xovember  1,  diet  of  bread,  water  and  sugar.  The  gums 
were  not  affected  by  the  sugar. 

Xovember  17  to  20,  lean  beef,  20  oz.     Upon  this  diet  he  felt  hungry. 
Xovember  21  to  25,  lean  beef,  20  oz.,  and  suet,  7  oz.     ^^I  slept  longer 
and  more  quietly  than  formerly  and  was  more  disposed  to  be  drowsy 
than  when  I  lived   on  meat  alone." 

Xovember  26  to  December  8,  flour,  20  oz. ;  suet,  4  to  6  oz.  This  diet 
Avas  arranged  in  order  to  compare  its  value  with  that  of  meat.  It  was 
taken  in  the  form  of  a  pudding.  He  notes  an  extraordinary  gain  in 
body  weight  of  8  lbs.,  in  five  days  after  changing  the  dietary  from  meat 
to  flour,  (vide  later  experiments  of  Voit,  p.  70). 

December  0  to  13,  flour,  24  oz.  Upon  this  diet  he  became  extremely 
hungry. 

He  finds  that  flour  and  beef  suet  disagi-ee  with  him,  tries  to  substitute 
butter  fat  for  beef  suet,  but  does  not  return  to  a  normal  appetite  until 
he  has  enjcyed  eating  two  pounds  of  figs.  In  another  experiment  he  has 
indigestion  after  taking  for  four  days  puddings  made  of  flour  and  butter. 
February.  4  to  15.  Bread  and  flour  with  honey.  Scorbutic  symp- 
toms developed  on  February  12.  Honey  pudding  had  a  remarkable  diu- 
retic effect  and  provoked  diarrhea. 

On  February  15  he  w^as  feeble  and  took  an  infusion  of  rosemary. 
February  16  and  17.    Diet — bread  with  Cheshire  cheese  to  check  the 
diarrhea,  which  it  did. 

February  IS  he  omits  cheese  but  continues  with  the  infusion  of  rose- 
mary.    His  mouth  is  sore,  there  are  pimples  at  the  corner  of  his  mouth 
and  many  large  ones  on  his  body. 
This  closes  his  diary. 

On  February  18  he  was  bled,  but  died  on  February  23,  1770,  evi- 
dently of  acute  intestinal  infection,  the  victim  of  his  scientific  curiosity. 
John  Hunter  made  a  report  of  the  findings  at  the  autopsy. 


The  Chemical  Revolution 

Out  of  the  misty  conclusions  of  the  middle  of  the  eighteenth  century 
before  its  close  modern  chemistry  developed.  The  work  of  ^^L'ayow  was 
forgotten  in  the  enthusiasm  over  tlie  phlogiston  doctrine  of  Stahl.  The 
pioneer  discoverer  was  again  an  Englishman,  Joseph  Black.  It  is  quite 
probable  that  had  ^Fayow  known  c£  Black's  "fixed  air"  he  might  have 
solved  the  problem  of  respiration.  And  also  had  Black  known  of  the 
existence  of  ^Mayow's  experiments  without  having  learned  of  them  to  his 


A  HISTORY  OF  :A[ETABOLIS:Nr  15 

^'compleat  astonishment'',  he  too  might  have  had  the  honor  reserved  for 
Lavoisier. 

Black  (  1Tl^S-1T(>1>)  in  1754  puhlished  a  Latin  essay  which,  in  its 
English  form,  is  entitled  ^'Experiments  on  ^lagnesia  Alba,  Quicklime 
and  other  Alkaline  Substances."  In  this  Black  describes  the  discoverv 
of  ^'fixed  air''  or  carbonic  acid.     Black  writes  of  himself  as  follows: 

In  the  early  days  of  my  chymioal  studies  the  author  whose  works  made  the 
most  agreeable  impression  on  my  mind  was  Markgraaf  (1709-1782)  of  Berlin;  he 
contrived  and  executed  his  experiments  with  so  nnich  chymical  skill  that  they 
were  uncommonly  instructive  and  satisfactory;  and  he  described  them  with  so 
much  modesty  and  simplicity,  avoiding  entirely  the  parade  of  erudition  and 
self-importance,  with  which  many  other  authors  encumber  their  works,  that  I 
was  quite  charmed  with  Markgraaf  and  said  to  Dr.  Culleii  that  I  would  gather 
be  the  author  of  Markgraaf  s  Essays  than  of  all  the  chymical  works  in  the  library. 
The  celebrated  ReaumuFs  method  of  writing  appeared  to  me  also  uncommonly 
pleasing.  After  three  years  spent  with  Dr.  Cullen  I  came  to  Edinburgh  to  finish 
my  education  in  medicine.  Here  I  attended  the  lectures  of  Dr.  ^Monroe,  senior, 
and  the  other  medical  professors  until  the  sununer  of  1754  when  I  received  the 
degree  of  Doctor  of  Medicine  and  printed  my  inaugural  dissertation,  "De  Humore 
Acido  a  Cibis  Orto,  ct  Magnesia  Alba." 

Black  finds  that  the  carbonates  yield  "fixed  air"  on  ignition  and  that 
caustic  alkalis  absorb  the  same  air.  Magnesia  alba  loses  half  its  weight 
when  heated  and  gives  oif  "fixed  air"  when  treated  with  acids.  Lime 
water  does  not  combine  with  ordinary  air  but  does  combine  with  "fixed 
air."  Black  describes  the  new  found  kind  of  air  as  one  "which  is  dis- 
persed through  the  atmosphere  either  in  the  state  of  a  very  subtle  powder, 
or  more  probably  in  that  of  an  elastic  fluid.  To  this  I  have  given  the 
name  of  fixed  air,  and  perhaps  very  improperly;  but  I  thought  it  better 
to  use  a  word  already  familiar  in  philosophy  than  to  invent  a  new  name, 
before  we  are. There  fully  acquainted  with  the  nature  and  properties  of 
this  substance." 

This  was  the  pioneer  discovery  in  the  field  long  known  as  pneumatic 
chemistry.  "Fixed  air"  was  produced  in  fermentation,  in  the  cordbus- 
tion  of  carbon,  and  was  eliminated  in  the  respiration.  The  next  gas  to 
be  discovered  w^as  hydrogen. 

Cavendish  (1731-1810)  was  a  nephew  of  the  third  Duke  of  Devon- 
shire. He  was  a  man  of  wealth  and  of  extremely  eccentric  character.  It 
was  he  who  discovered  hydrogen  in  1766  and  gave  it  the  name  of  "in- 
flammable air."  He  considered  hydrogen  to  be  phlogiston.  Later,  in 
1781,  he  found  that  when  two  volumes  of  "inflammable  air"  and  one 
volume  of  Priestley's  "dephlogisticated  air"  (oxygen)  were  united  by  an 
electric  spark  the  airs  disappeared  and  water  resulted.  Cavendish  con- 
cluded that  dephlogisticated  air  was  water  deprived  of  its  phlogiston. 

The  French  have  ahvavs  claimed  that  Lavoisier  was  the  first  to  dis- 


10 


GRAHAM  LUSK 


cover  the  composition  of  water.     A  discussion  of  the  Water  Controversy 
is  given  by  Thorpe. 

DankS  Eutherford  (1749-1819)  was  a  pupil  of  Black's  and  tlie  uncle 
of  Sir  Walter  Scott.  Kuthorford  in  1772  described  ^^a  residual  air/'  or 
nitrogen  gais,  as  it  is  now  called.  He  f(jund  that  when  a  candle  burned 
in  an  inchj«ed  i)lace  until  it  went  out  and  the  ^'fixed  air"  was  then  ab- 
sorhed  by  ;i^kali,  there  remained  a  huge  volume  of  air  which  extinguished 

life  and  iiame  in  an  instant. 
Priestley  (1733-1804)  in 
1771,  a  year  before  Ruther- 
ford's discovery  of  nitrogen, 
introduced  a  growing  sprig  of 
mint  into  an  atmosphere  in 
which  a  candle  had  burned  out 
and  after  a  lapse  of  several  days 
found  that  another  candle 
burned  in  it  perfectly.  Evi- 
dently the  burning  candle  filled 
the  space  with  phlogiston;  the 
growing  plant  absorbed  the  phlo- 
giston and  produced  ^'dephlo- 
gisticated  air."  This  could  again 
receive  phlogiston  when  the 
second  candle  burned. 

Shortly  after  this  discovery 
(1774)  Priestley  submitted  red 
oxid  of  mercury  to  the  heat  of 
a  burning  glass  and  foimd  that 
an  air  was  evolved  in  which  a 
candle  burned  very  vigorously. 
Priestley  assumed  that  this  air  w^as  pure  dephlogisticated  air,  while  com- 
mon air  was  only  pai-tly  dephlogisticated. 

And  Priestley  writes,  *']My  reader  will  not  wonder  that,  after  having 
ascertained  the  superior  goodness  of  dephlogisticated  air  by  mice  living 
in  it  and  the  other  tests  above  mentioned,  I  should  have  the  curiosity  to 
taste  it  myself.  I  have  gratified  that  curiosity  by  breathing  it,  drawing 
it  through  a  glass  siphon,  and  by  this  means  1  retluced  a  large  jar  full 
of  it  to  the  standard  of  connnon  air.  The  feeling  of  it  to  my  lungs  was 
not  sensibly  difierent  from  that  of  common  air;  but  I  fancied  that  my 
breath  felt  j>ecnliarly  light  and  easy  for  some  time  afterward.  Who 
can  tell  but  that  in  time  this  pure  air  may  become  a  fashionable  article 
in  luxury?  Hitherto  only  two  mice  and  myself  have  had  the  privilege 
of  breathing'  it." 

Priestley   explained  the  presence  of  Black's   "fixed  air"  in   the  ex- 


Fig.   2.    Pri«!«tNy.     From   an   engraving  of 
a  portrait  by  Gilbert  Stuart. 


•  A  HISTORY  OF  METABOLISM  '  -     17 

pired  air  thus :  "It  will  follow  that  in  the  precipitation  of  lime  bj  breath- 
ing into  lime  water  the  fixed  air  which  incorporates  with  lime  comes  not 
from  the  lungs  but  from  the  common  air,  decomposed  by  the  phlogiston 
exhaled  from  them.''  And  Priestley,  who  was  one  of  the  discoverers  of 
oxygen,  was  gathered  to  his  fathers  at  Northumberland,  Pennsylvania,  in 
1804,  still  believing  the  phlogiston  theory  of  combustion. 

Crawford  (1748-1795)  was  the  first  individual  to  publish  experiments 
on  animal  calorimetry.  In  1777  he  found,  after  burning  wax  and  carbon 
or  on  leaving  a  live  giiinea-pig  in  his  water  calorimeter,  that  for  evei-y 
100  oz.  of  oxygen  used  the  water  was  raised  the  following  number  of 
degrees  Fahrenheit: 

Wax  2.1 

Carbon  1.03 

Guinea-pig  1.73 

Crawford  states,  "Animal  heat  seems  to  depend  upon  a  process  similar 
to  a  chemical  elective  attraction."  However,  the  theory  of  phlogiston 
renders  Crawford's  work  quite  unintelligible  and  in  the  second  edition 
of  his  "Experiments  and  Observations — Animal  Heat,"  published  in  17SS, 
one  still  finds  statements  like  this,  "Now  it  has  been  proved  that  when 
an  animal  is  surrounded  by  a  medium  at  a  low  temperature  it  phlogisti- 
cates  a  greater  quantity  of  air  in  a  given  time  than  when  it  is  surro^^  a.ded 
by  a  warm  medium." 

Scheele  (1742-1786). — Independent  of  Priestley  and  before  him, 
Scheele,  a  Swedish  apothecary  and  eminent  chemist,  discovered  oxygen 
by  decomposing  dioxid  of  manganese  and  other  substances.  Scheele  be- 
lieved that  the  atmosphere  was  composed  of  "spoiled  air"  and  "fire  air." 
AYhen  a  body  burned  in  air  it  lost  its  phlogiston,  which  united  with  "fire 
air."  Heat  consisted  of  "fire  air"  united  with  phlogiston.  It  passed 
through  glass.    In  this  way  a  portion  of  air  could  pass  through  glass. 

In  1771  Scheele  (Scheele,  1793)  had  found  that  when  silver  carbonate 
was  heated  in  a  retort,  "fixed  air"  was  liberated  as  well  as  "fire  air," 
while  a  residue  of  metallic  silver  remained.  In  1775  he  placed  silver 
carbonate  in  a  small  retort  connected  with  a  collapsed  bladder  and  then 
heated  the  substance.  Two  airs  were  evolved,  **fixed  air"  which  he  re- 
moved with  lime  water,  and  "fire  air"  in  which  a  flame  burned  brightly. 
In  the  interim  between  these  two  experiments  he  wrote  Lavoisier  in 
Paris  a  letter  dated  September  30,  1774,  asking  him  to  use  his  powei-ful 
burning  glass  upon  silver  carbonate,  then  to  absorb  the  "fixed  air"  in 
lime  water  and  observe  whether  a  candle  would  burn  and  an  animal  live 
in  the  remaining  air,  and  he  beggeil  Lavoisier  to  infonn  him  of  the 
results. 

Scheele  performed  another  striking  experiment  (Scheele,  1777).  He 
placed  two  large  bees  together  with  a  little  honey  in  a  small  up^wr  chamber 


18 


GUAIiA.M  LI'SK 


Fig.  3.  Scheele's  apparatus 
showing  bees  in  the  upper  chamber 
oi  a  glass  apparatus  filled  with 
oxvgen. 


of  a  glass  apparatus  which  he  had  devised.  This  upper  chamber  was  in 
communication  with  a  glass  cylinder.  The  glass  cylinder  he  filled  with 
"fire  air"  and  immersed  its  lower  end  in  lime  water.  The  volume  of  the 
air  Vvithin  the  receptacle  diminished  day  by  day  and  the  lime  water  whicli 
absorbed  the  carbonic  acid  rose  in  the  tube.  After  eight  days  the  bees 
were  both  dead  and  the  lime  water  almost  completely  filled  the  space. 

It  is  evident  that  Scheele  had  intro- 
^  duced  bees  into  pure  or  nearly  pure  oxygen 

gas  and  that  the  carbon  dioxid  whicli  they 
produced  had  been  completely  absorbed  by 
the  lime  water. 

Scheele  made  no  direct  comment  upon 
this  truly  beautiful  experiment  but  in  the 
general  criticism  of  several  experiments 
one  may  read  the  following  hazy  general- 
ization : 

Why  do  not  the  blood  and  lungs  change 
"fire  air"  into  "acid  air"?  I  take  the  liberty 
to  express  my  opinion  concerning  this,  for 
what  would  such  exacting  experiments  profit 
unless  through  them  I  had  the  hope  to  more 
nearly  approach  my  ultimate  aim,  the  truth. 
Phlogiston,  which  combines  with  most  sub- 
stances causing  them  to  become  more  fluid, 
more  mobile  and  more  elastic,  must  have  the  same  influence,  upon  the  blood. 
The  blood  corpuscles  must  absorb  it  from  the  air  through  delicate  openings  in 
the  lungs.  Through  this  combination  they  are  expanded  and  in  consequence 
become  more  fluid.  In  some  part  of  the  circulation  they  must  give  oflf  this 
absorbed  phlogiston  and  consequently  be  able  to  again  absorb  this  fine  principle 
when  they  next"  reach  the  lungs.  Whither  the  phlogiston  goes  during  the  circu- 
lation I  will  leave  to  others  to  find  out.  The  affinity  of  blood  for  phlogiston 
caimot  be  as  great  as  in  the  instance  of  plants  and  insects  which  take  it  from 
the  air  and  ah?rr-the^ood  cannet-convert  it  into  "acid  air,"  but  it  is  changed 
into  a  kind  of  air  which  is  midway  between  "fire  air"  and  "acid  air'*;  it  is 
"spoiled  air."  For  it  does  not  unite  with  lime  water  or  water  as  does  "fire  air," 
though  it  extinguishes  fire  as  does  "acid  air." 

Scheele's  ""spoiled  air"  was  nitrogen.  The  poor  struggling  apothecary 
who  had  made  so  many  careful  and  accurate  experiments  and  who  was 
one  of  the  greatest  chemists  of  his  time,  was  unable  to  interpret  his  results 
without  adherence  to  the  dominant  fetisli  of  phlogiston. 

We  have  here  the  picture  of  two  earnest  men,  Priestley  and  Scheele, 
both  absorbingly  interested  in  chemistry,  both  contributing  important 
knowledge  and  ranking  among  the  gi-eatest  scientists  of  their  day,  and 
yet  neither  had  the  philosophical  acumen  to  understand  the  meaning  ol" 
his  experiments.  Priestley  was  a  Dissenting  cloi-gyman,  earning  his  living 
by  preaching,  but  in  his  old  age  his  house  was  burned  by  Loyalists  and  he 


■   }  ■      ■      ^     ^ 

;  /  A  HISTORY  OF  METABOLTS]\[  19 

shprtly  afterward  fled  to  America.     Scheele,  though  honored  by  scientific 

'i        men  the  workl  over,  remained  a  poor  apothecary  to  the  end  of  his  days. 

,        In  the  current  parlance  of  to-day  these  two  p:reat  contributors  to  human 

knowledge  would  undoubtedly  have  been  known  outside  their  own  circles 

as  ^'narrow-minded  scientists." 

This,  however,  could  never  have  been  said  of  Lavoisier,  who  repeated 
and  extended  their  experiments,  overthrew  the  phlosriston  theory  and 
established  modern  chemistry. 

Lavoisier  (1743-1794). — The  family  of  Antoine  Laurent  Lavoisier 
traced  its  ancestry  back  seven  generations  to  Antoine  Lavoisier,  who  was  a 
post-boy*  in  the  stables  of  the  king  and  who  died  in  1620.  Successive 
generations  raised  the  position  of  the  family  name  to  ever  higher  levels 
until  it  was  said  of  the  great  Lavoisier  that  it  would  require  perhaps  a 
hundred  years  for  the  appearance  of  his  equal.  Xative  intelligence,  a 
fine  education,  great  wealth,  combined  wath  the  environment  of  the 
searchingly  critical  atmosphere  of  the  Paris  of  his  day,  allowed  of  the 
vivid  inspiration  which  filled  his  life. 

Lavoisier  was  elected  a  member  of  the  Academie  des  Sciences  in  17G8 
at  the  age  of  twenty-four.  About  the  same  time,  desirous  of  promoting 
his  personal  fortune,  he  became  associated  with  Ja  ferme  generale,  through 
whose  activities  the  taxes  were  collected  in  France.  Some  of  his  fellow 
academicians  looked  askance  at  this  undertaking,  but  the  mathematician 
Fontaine  is  reported  to  have  remarked,  "Never  mind,  he. will  be  able  to 
give  us  better  dinners."     (Grimaux,  (A;)  1896.) 

In.  the  ferme  gene  rale  the  young  man  was  the  subordinate  of  one 
Paulze,  a  nephew  of  the  then  all-powerful  Terray,  Minister  of  State  and 
Controller  of  Finance.  At  the  age  of  twenty-eight  Lavoisier  married  the 
fourteen-year-old  daughter  of  Paulze.  His  own  position  and  his  marriage 
brought  him  gTeat  wealth  but  in  no  way  diminished  his  tireless  activity. 
He  congratulated  himself  that  his  patronage  of  the  instrument  makers 
of  Paris  had  rendered  France  independent  of  Great  Britain  in  the  manu- 
facture of  scientific  instruments. 

Lavoisier's  first  paper  before  the  Academie  was  "On  the  Nature  of 
Water  and  on  Those  Experiments  Which  Pretend  to  Prove  Its  Trans- 
formation Into  Earth."  In  this  experiment  he  placed  rain  water  in  a 
flask  and  boiled  it  for  101  days.  Mineral  matter  appeared  in  the  flask 
but  the  whole  did  not  change  in  weight  and  the  mineral  material  which 
appeared  was  shown  to  be  derived  from  the  disintegi*ation  of  the  flask 
itself,  which  lost  in  weight.  Lavoisier  used  an  extremely  sensitive  (fres 
exact e)  balance,  made  by  the  official  who  was  charged  with  the  weighing 
of  gold. 

Hero  wo  witness  the  overthrow  of  a  dogma  more  than  two  thousand 
years  old,  a(»complished  by  the  introduction  of  the  quantitative  method  into 


,• 


20 


GH.VIIA.\r  LFSK 


chemistrj.     One  maj  recall  the  words  of  Lavoisier  written  in  his  "Ele- 
ments of  Chemistry"  (Kobert  Kerr,  (m)  17DIJ)  :  ' 

As  the  usefulness  and  accuracy  of  chemistry  depend  entirely  upon  the  de- 
termination of  the  weig-hts  of  the  in^rredients  and  products  both  before  and  after 
experiments,  too  much  precision  cannot  be  employed  in  this  part  of  the  subject 
and  for  this  purpose  we  must  be  provided  with  good  instruments.  ...  I  have 
three  sets  (of  balances)  of  different  sizes  made  by  M.  Fontin  with  the  utmost 
nicety ;  and  excepting  thase  made  by  Mr.  Ilamsden  of  London  I  do  not  think  that 
any  compare  with  them  in  precision  and  sensibility. 


Lavoisier  had  a  bal- 
ance which  could  weigh 
600  gm.  within  five  mg. 
and  another  which  was 
sensitive  to  within  a 
tenth  of  a  milligram, 
which  were  quite  up  to 
modem  standards  of  ac- 
curacy.  One  may  visit 
the  Conservatoire  des 
Arts  et  Metiers  in  Paris 
and  see  there  a  notable 
collection  of  Lavoisier ^s 
apparatus.  One  sees  a 
gasometer  for  the  accu- 
rate measurement  of 
gases;  there  is  the  cele- 
brated ice  calorimeter  of 
Lavoisier  and  La  Place ; 
there  also  are  barom- 
eters of  finest  workman- 
ship, set  in  mahogany 
sup}X)rts  decorated  with 
gilded  Qlagree  work,  re- 
minding one  of  the 
choicest  furniture. 
These    treasures    were 

placed  in  the  cellar  of  the  Consei-vatoire  during  the  bombardment  of  Paj-is 

by  the  Germans  in  the  late  war. 

Concerning  the  gasometers,  Lavoisier  wrote  (Lavoisier,  (m)  1799)  : 

It  becomes  expensive  because  in  many  experiments,  such  as  the  formation 
of  water  and  of  nitric  acid,  it  is  absolutely  necessary  to  employ  two  of  the  same 
machines.  In  the  present  advanced  state  of  chemistry  very  expensive  and  com- 
plicated instruments  are  become  indispensably  necessary  for  ascertaining  the 
analysis  and  synthesis  of  bodies  with  the  requisite  precision  as  to  quantity  and 
proportion. 


Fig.  4.     Lavoisier  and  his  wife, 
of  a  portrait  by  David. 


From  an  engraving 


A  HISTORY  OF  METABOLISM 

It  is  strange  that  Lavoisier's  insistence  upon  the  use  of  ac     '■ 
quantitative  measurements  through   the  application  of  which  nea 
lunidred  and  tiftj  years  ago  he  brought  about  the  "Chemical  Revoluti.       * 
.sli(nild  appear  as  new  truth  when  enunciated  by  some  of  our  ultra  mode 
scientists. 

In  the  heart  of  France  near  Puy-du-Dom,  at  Chateau  de  la  Carriere, 
now  (nvned  by  ^Fonsicur  de  Chazelles,  there  is  a  veritable  museum  of 
scientific  apparatus  which  fonnerly  belonged  to  Lavoisier  (Tiiichot,  (s) 
1879).     There  are  several  thermometers  of  jn-eat  accuracy  and  a  fine 


,  -  <^       •*    Jf  Hi.  t  .'It  linit.u\f  II  ^*^,   J,      u    t^i 


Fig.  5.     The  burning  glass  of  Tnidaine.     From  "CEuvres  de  Lavoisier,"  VoL  Jl.r, 


balance,  and  there  are  three  large  glass  globes,  one  capable  of  holding  15 
liters  of  air,  another  12  liters  and  a  third  7  liters;  also  many  another 
treasure  of  great  historic  value.  Lavoisier  made  his  experiments  btfore 
the  days  when  rubber  and  cork  reduced  laboratory  expenses.  His  gL^ss 
tuljes  and  receptacles  were  united  with  finely  polished  brass  joints. 

"We  may  imagine  this  accomplished  Frenchman  at  work  in  his  labora- 
tory, or  his  library,  or  receiving  information  from  visitors  to  the  fashion 
able  and  brilliant  capital  of  France.  It  is  related  (Thorpe,  (r)  1908)  that 
Priestley  dined  with  Lavoisier  in  Paris  in  October,  1774,  and  informed 
him  concerning  the  production  of  "pure  dephlogisticated  air''  from  oxid 
of  mercury,  and  we  may  also  recall  that  Scheele,  on  September  30  of  the 
same  year,  w^rote  to  Lavoisier,  asking  him  to  expose  silver  carbonate  to 


J- 

GFLVHAM  LUSK     '  ^ 

.  Axoat  rays  of  a  large  burning  glass  and  produce  "fixed  air''  and  "fire  air" 
from  them.  Ten  days  after  his  conversation  with  Priestley,  and  again 
during  the  month  of  the  following  March,  Lavoisier  went  to  Montigny  to 
visit  his  friend  Trudaiiie,  who  was  the  owner  of  an  immense  burning 
glass  42  ins.  in  diameter,  which  had  cost  15,000  livres  (about  $3,000), 
and  lie  here  repeated  Priestley's  experiments.  In  the  paper  read  before 
the  Academic  des  Sciences  at  Easter,  1775,  Lavoisier  (a)  stated  that  he 
took  the  red  mercury  calx  and  heated  it  w'ith  carbon  and  obtained  "fixed 
air,"  and  wlien  he  heated  the  same  without  carbon  a  gas  was  evolved  in 
which  a  flame  burned  with  the  splendor  of  phosphorus  in  air,  and  that  this 
gas  was  the  "air  eminently  respirable."  The  loss  in  weight  of  the  mercury 
calx  was  equal  to  the  weight  of  the  "air  eminently  respirable"  given  off. 
He  concluded  that  "fixed  air"  was  the  result  of  the  union  of  carbon  with 
"air  eminently  respirable."  In  a  subsequent  paper  he  reported  that  it  was 
this  "air  eminently  respirable"  which  was  absorbed  by  phosphorus  and 
siilphur  when  they  burn  with  the  production  of  phosphoric  and  sulphuric 
acids  (ft). 

Having  discovered  these  facts,  Lavoisier  (c)  proceeded  to  determine  the 
effect  of  a  sparrow  upon  the  content  of  air  in  a  confined  space.  In  a 
,  brief  memoir  published  in  1777  he  enunciated  the  principles  that  during 
respiration  it  was  only  "air  eminently  respirable"  (oxygen)  which  dis- 
appeared from  the  atmosphere  when  an  animal  was  put  into  a  confined 
space  and  that  this  air  was  supplanted  by  expired  "aeriform  calcic  acid" 
(carbon  dioxid)  ;  that  when  metals  were  calcined  in  air  oxygen  was 
absorbed  until  its  supply  was  exhausted;  that  if  after  an  animal  had 
perished  in  a  confined  space  and  the  carbon  dioxid  in  the  atmosphere  was 
absorbed  by  alkali  the  "foul  air"  remaining  was  the  same  kind  of  air  as 
that  found  after  metals  had  been  calcined  in  air  in  an  inclosed  space. 
All  the  former  qualities  of  this  air  could  be  restored  by  adding  to  it  "air 
eminently  respirable." 

Three  years  later  Lavoisier  and  La  Place  made  another  step  in  ad- 
vance. (Lavoisier  and  La  Place,  {n)  1780.)  They  noticed  that  a  guinea- 
pig  produced  224  grains  of  carbonic  acid  in  ten  hours,  and  that  what  would 
now  hx5  called  the  respiratory  quotient  was  0.84.  Then  they  put  another 
guinea-pig  in  their  recently  constructed  ice  calorimeter  and  found  that 
the  heat  given  off  by  the  animal  melted  13  oz.  of  ice  in  a  period  of  10 
hours.  Kext  they  calculated  that  if  carbon  was  oxidized  so  that  224 
grains  of  carbonic  acid  were  produced,  10.4  oz.  of  ice  would  have  been 
melted.  They  realized  that  in  the  case  of  the  guinea-pig  allowances  would 
have  to  be  made  (1)  because  the  legs  of  the  animal  became  chilled  during 
the  experiment;  (2)  because  the  water  of  respiration  was  added  to  that  of 
the  melted  ice;  and  (3)  because  the  influence  of  cold  increased  the  heat 
production  of  the  animal.  But  they  nevertheless  stated  that  "Since  w^e 
have  found  in  the  preceding  experiments  that  the  two  qualities  of  lieat 


A  IirSTORV  OF  :METAF>0LISM  23 

obtained  are  nearly  the  same,  we  can  conclude  directly  and  without 
hypothesis  that  the  conservation  of  animal  heat  in  the  animal  body  is  due, 
at  least  in  greater  part,  to  the  transformation  of  ^air  pur'  (oxygen)  into 
^air  fixe'  (carbonic  acid)  during  the  process  of  respiration."  Here 
bo  it  noted  that  Lavoisier  refers  to  the  conservation  of  animal  heat  more 
than  fifty  years  before  the  general  law  of  the  conservation  of  energy  was 
enunciated.  He  also  observed  that  two  sparrows  produced  about  the 
same  quantity  of  carbonic  acid  in  the  unit  of  time  as  did  a  guinea-pig. 

About  a  year  after  these  experiments  (ITSl)  Cavendish  in  England 
found  that  when  'inflammable  air''  (or  hydrogen)  and  Priestley's  "dc- 
plilogisticate-l  air''  were  united  by  an  electric  spark  the  airs  disappeared 
and  water  resulted. 

It  is  said  that  Lavoisier,  hearing  of  these  experiments  from  Blagden, 
secretary  of  the  Royal  Society  of  London,  repeated  them.  ;he  im- 

])ortant  point  is  that  Lavoisier  {d)  was  the  first  really  to  understand  the 
phenomenon.  In  a  memoir  presented  to  the  Academie  des  Sciences  in 
1783  he  stated  that  water  is  merely  a  combination  of  ^'inflammable  air" 
and  oxygen  and  that  any  heat  or  light  produced  by  their  union  is 
imponderable. 

In  the  same  year  Lavoisier  (e)  completely  demolished  the  phlogiston 
hypothesis  and  concluded  his  memoir  "Reflections  upon  Phlogiston"  with 
these  w^ords :  " 

My  object  in  preparing  this  memoir  has  been  to  record  the  new  developments 
of  the  theory  of  combustion  which  I  published  in  1TT7,  to  show  that  the  phlogiston 
of  Stalil,  which  he  gratuitously  supposed  existed  in  metals,  sulphur,  phosphorus 
and  all  combustible  substances,  is  an  imaginary  creation.  All  the  phenomena 
of  combustion  and  calcination  are  much  more  readily  explained  without  phlogis- 
ton than  with  phlogiston.  I  understand  that  my  ideas  will  not  be  suddenly 
adopted.  The  human  mind  conforms  to  a  certain  manner  of  vision  and  those 
who  during  a  portion  of  their  lives  comprehend  nature  from  a  given  point  of 
view  have  difBculty  in  acquiring  new  ideas.  In  good  time  the  opinions  I  have 
set  forth  will  be  confirmed  or  destroyed.  In  the  interim,  it  is  a  great  satisfaction 
for  me  to  see  that  young,  unprejudiced  minds  among  those  who  are  commencing 
to  study  science,  such  as  mathematicians  and  physicists  who  have  a  new  sense 
of  chemical  truths,  no  longer  believe  in  phlogiston  as  presented  by  Stahl  but 
regard  the  whole  doctrine  as  scaffolding  which  is  more  embarrassing  than  it  is 
useful  for  the  continuance  of  the  structure  of  the  science  of  chemistiy. 

And  the  wonder  of  it  all  is  that  the  great  chemists  of  his  time  outside 
of  his  own  country  persisted  in  their  narrow  viewpoint.  Priestley  and 
Cavendish  refused  to  be  converted.  Scheele  wrote  in  1783,  ''Is  it  im- 
possible to  convince  Lavoisier  that  his  system  will  not  find  universal 
acceptance?  The  idea  of  nitric  acid  from  nitrous  air  and  pure  air,  of 
carbonic  acid  from  carbon  and  ])ure  air,  of  sulphuric  acid  from  sulphur 
and  pure  air,  of  lactic  acid  from  sugar  and  pure  air!!  Can  one  believe 
such  things?    Rather  will  I  support  the  English." 


24  GKAHA^E  l.USK 

Only  Black,  professor  of  chemistry  at  Edinburgh  and  the  discoverer 
of  "fixed  air/'  saw  the  truth.  Lavoisier  wrote  to  Black  on  Xovemhcr  13, 
17C>0,  a  letter  (Richet,  (p)  1887)  composed  six  months  after  the  reading  of 
his  last  memoir  to  the  Academie  ^les  Sciences,  lie  concluded  the  letter 
with  the  truest  French  courtesy:  *Mt  is  only  right  that  you  should  be  the 
first  to  be  informed  of  progress  in  a  field  which  you  ojx?ncd  and  in  which 
we  all  regard  ourselves  as  your  disciples.  We  do  the  same  kind  of 
experiments  and  I  have  the  honour  to  connnunicate  to  you  the  results  of 
our  recent  discoveries.  I  have  the  honour  to  remain,  with  respectful 
attachment,  etc.'" 

And  to  this  Black  replied  in  1701,  '^The  numerous  experiments  which 
you  have  made  on  a  large  scale  and  which  you  have  so  well  devised  have 
been  persued  with  so  much  care  and  with  such  scrupulous  attention  to 
details  that  nothing  can  be  more  satisfactory  than  the  proofs  you  have 
obtained.  The  system  which  you  have  based  on  the  facts  is  so  intimately 
connected  with  them,  is  so  simple  and  so  intelligible,  that  it  must  become 
more  and  more  generally  approved  and  adopted  by  a  great  number  of 
chemists  who  have  long  been  accustomed  to  the  old  system.  .  .  .  Having 
for  thirty  years  believed  and  taught  the  df^ctrine  of  phlogiston  as  it  was 
understood  before  the  discovery  of  your  system,  I  for  a  long  time  felt 
inimical  to  the  new  system  which  represented  as  absurd  that  which  I  had 
hitherto  regarded  as  sound  doctrine,  but  this  enmity  which  springs  only 
from  force  of  habit  has  gradually  diminished,  subdued  by  the  clcarneafs 
of  your  proofs  and  the  soundness  of  your  plan." 

In  reading  of  the  overthrow  of  the  old  doctrine  of  the  fire  principle 
phlogiston  one  must  feel  a  throb  of  the  impending  horror  of  the  Fi-ench 
Kevolution  when  one  considers  the  statements  of  ^farat  written  in  3  701. 
Ararat  at  one  time  had  declared  that  a  flimie,  when  placed  in  a  confined 
vessel,  went  out  because  the  heat  of  the  flame  suddenly  expanded  the  air, 
causing  such  a  pressure  on  the  flame  that  it  was  extinguished.  Lavoisier 
refuted  this  doctrine.  Marat,  "L'Ami  du  People,'^  under  the  title  ''Mod- 
ern  Charlatans,-'  published  the  following:  *^Lavoisier,  the  putative 
father  of  all  the  discoveries  that  are  noised  about,  having  no  ideas  of  his 
own,  snatches  at  those  of  others,  but  having  no  ability  to  appreciate 
them,  he  quickly  abandons  them  and  changes  his  theories  as  he  doe&  his 
shoes."    Certainly  words  of  unqualified,  contemporaneous  disapproval ! 

Lavoisier's  new  system  of  salts  and  oxids  led  him  to  forecast  the 
discovery  of  sodium  and  potassium,  for  in  his  "Elements  of  Chemistry" 
(Lavoisier,  (m)  1700)  he  wrote,  "It  is  quite  possible  that  all  the  substances 
we  call  earths  may  be  only  metallic  oxids  irreducible  by  any  hitherto 
known  process."  A  eulogist  of  Lavoisier  has  likened  this  to  the  vision  of 
Copernicus  before  Galileo's  invention  of  the  telescope. 

Lavoisier  had  now  progressed  so  that  he  was  able  to  lay  the  funda- 
mental basis  of  njodem  chemical  physiolog;^'.     Thus,  in  1785,  he  stated 


A  HISTORY  OF  METABOLTSllit 


25 


tliat  the  discrepancy  between  the  quantity  of  expired  carbonic  acid  and 
inspired  oxygen,  wliich  lie  had  observed  in  1780,  was  accounted  for  by  the 
fact  that  a  part  of  the  absorbed  oxy^^en  was  utilized  to  oxidize  hydrogen 
in  the  hini»s.  This  oxi(hition  woidd  produce  additional  heat  and  account 
for  the  discrepancy  between  the  heat  direotly  measured  from  a  guinea-pig 
and  the  heat  calculated  as  being  derivable  from  the  oxidation  of  carbon  by 
oxygen.  It  is  interesting  to  recall  that  eighty  years  later,  in  18G0, 
Eischoff  and  Voit  still  calculated  the  heat  value  of  the  metabolism  from 
the  heat  which  would  be  produced  in  burning  the  carbon  and  hydrogen 
dements  of  the  metabolism. 

Respiration  experiments  on  a  human  being  constituted  the  final  con- 
tribution in  the  culmination  of  this  gi-eat  career.  The  w^ork  is  presented 
l)y  Scguin  and  Lavoisier  (t)  in  the  memoirs  of  the  Academie  des  Sciences 
during  the  year  1780.  In  this  paper  the  authors  remark:  ''This  analogy 
between  combustion  and  respiration  did  not  escape  the  attention  of  the 
poets  and  philosophers  of  antiquity,  of  which  they  were  the  interpreters 
and  spokesmen.  Fire  taken  from  the  heavens,  this  flame  of  Prometheus, 
not  only  represents  an  idea  that  is  ingenious  and  poetical  but  it  is  a  true 
picture  of  the  operations  of  nature  on  behalf  of  animals  who  respire;  one 
can  say  with  the  ancients  that  the  fire  is  lighted  the  moment  a  baby  takes 
its  first  respiration  and  is  not  extinguished  until  its  death." 

Before  giving  the  details  of  the  experiments  on  man  the  authors 
state  that  a  guinea-pig  respired  in  pui'e  oxygen  and  in  a  mixture  of  oxygen 
and  hydrogen  gas  just  as  it  did  in  ordinary  air;  respiration,  circulation 
and  the  intensity  of  combustion  were  uninfluenced.  Nitrogen  had  nothing 
to  do  with  respiration. 

In  the  experiments  on  man  Segiiin  himself  was  the  subject.  The 
results  are  given  in  the  accompanying  table: 

RESUT.TS  OF  EXPERIMENTS  ON  ^VIAN 


Condition 


{ 1 )  Without  food    

(2)  Without  food     

(3)  With  food    

(4)  Work   (n,195  foot  pounds)   without  food.. 
(.">)  Work  (9,750  foot  pounds)  with  food 


Environ- 
mental 

Tempera- 
ture 
Degrees 


26 
12 


Oxygen    Absorbed   per 
Hour 


Pouces 


1210 

1344 

1800-1900 

3200 

4600 


Liters 


24 
27 
38 
65 
91 


Here  are  the  basic  facts  regarding  metabolism.  The  basal  metabolism 
was  increased  10  per  cent  after  exposure  to  cold ;  50  per  cent  after  taking 
food;  200  per  cent  by  exercise;  and  300  per  cent  on  combining  the  influ- 
ences of  food  and  exercise.  We  now  know  more  details  and  w^e  may  also 
calculate  that  Lavoisier's  determination  of  24  liters  of  oxygen  absorbed 


26  GRAHAM   LFSK 

per  hour  in  this  first  historical  experiment  on  the  hasal  niotaholism  was  25 
per  cent  too  high.  As  for  tlie  experimental  plan,  it  is  as  moilcrn  as  the 
work  of  to-day,  and  yet  it  was  executed  140  years  ago  by  the  first  man 
who  really  understood  the  sigiiiiicanc-e  of  oxygen.  It  is  only  in  the  last 
decade  that  the  summation  of  the  individual  stimuli  caused  by  food  and 
muscular  work  and  noted  by  Lavoisier  has  been  verified.  Lavoisier  (/>) 
also  observed  a  constant  i-elation  between  the  quantity  of  oxygen  consumed 
and  the  rate  of  the  pulse  multiplied  by  the  number  of  respirations. 

How  Lavoisier  achieved  these  remarkable  results  is  not  known,  for 
the  times  iu  which  he  lived  became  too  troubled  to  allow  further  work  in 
pure  science.  We  find,  however,  the  following  statement  in  the  original 
memoir:  ^'It  would  have  been  impossible  to  accomplish  these  exact 
experiments  upon  respiration  before  the  introduction  of  a  simple,  easy 
and  rapid  method  of  gas  analysis.  This  service  ^l.  Segiiin  has  rendered 
to  chemistry." 

If,  now,  one  turns  to  the  report  of  Seguin  (Seguin  (q),  1791)  one  finds 
that  he  states  that  in  his  work  with  Lavoisier  he  used  eudiometers  8  to  10 
inches  high  and  an  inch  in  diameter  in  order  to  determine  the  "vital  air" 
or  oxygen  in  the  respired  air.  The  tube  was  first  filled  with  mercury  and 
inverted  over  mercur}',  a  little  of  the  gas  to  be  analyzed  was  introduced 
and  then  a  bit  of  phosphorus,  which  phosphorus  was  later  ignited  by 
bringing  a  burning  ember  in  the  vicinity  of  the  glass.  The  rest  of  the 
air  to  be  analyzed  was  gi-adually  admitted  and  when  the  tube  cooled  the 
voliune  of  the  air  remaining  could  be  measured.  The  loss  in  volume 
represented  the  quantity  of  oxygen  absorbed.  Carbonic  acid  could  then  be 
absorbed  by  potash.  Seguin  stated  that  the  older  method,  as  originally 
introduced  bv  Priestley,  had  twenty  sources  of  error  but  that  his  method 
merited  attention  on  account  of  the  very  great  exactitude  with  which  he 
could  determine  the  gases  which  are  contained  in  respired  air. 

He  furthermore  truly  stated  that  "if  we  enter  into  a  room  containing  a 
large  number  of  people  we  immediately  smell  a  strong,  suffocating  odor, 
but  if  we  use  eudiometers  to  analyze  this  foul  air  and  compare  it  with 
ordinary  atmospheric  air  we  find  hardly  any  difference  in  the  proportions 
of  gases  which  are  contained  in  them." 

After  Lavoisier's  death  Madame  Lavoisier  drew  from  meniorj^  the 
apparatus  used  by  her  husband.  The  drawings  were  retouched  by  J3avid, 
Madame  Lavoisier's  instructor  in  art.  There  are  two  pictures  quite  dis- 
similar. Good  reproductions  are  to  be  found  in  Grimaux's  "Lavoisier." 
In  both  pictures  Seguin  sits  naked  in  a  chair,  breathing  througli  a  mask 
into  a  series  of  globes  or  bell  jars.  In  both  pictures  ^Madame  Lavoisier  is 
shown  seated  at  a  table,  taking  notes  of  the  experiment.  In  both  pictures 
the  pulse  is  being  counted.  In  one  experiment  a  weight  is  placed  on 
Seguin^s  instep.  The  arrangement  of  the  apparatus  is  quite  different  in 
the  two  pictures.    In  the  experiment  showing  Seguin  at  work  it  seems  as 


A  IIISTOEY  OF  METABOLISM  27 

though  valves  were  indicated  through  wliich  inspired  air  was  received 
from  the  atmosphere  while  the  expired  air  was  driven  through  a  tube 
into  a  hell  jar  under  water.  Nysten  (Xysten,  (o)  1817),  working  in  Paris 
in  1811,  described  the  method  by  which  he  caused  tuberculous  and  other 
patients  to  respire  through  valves  into  a  previously  collapsed  bag  for 
half  a  minute  and  then  analyzed  the  expired  air  by  a  method  similar  to 
that  of  Seguin. 

These  are  the  knowTi  historical  facts  about  the  apparatus  used  in  the 
first  respiration  experiments  on  man,  but  the  exact  details  of  the  method 
hv  which  results  were  established  and  which  still  are  the  basis  of  metab- 
olism studies  are  unknown. 

In  contemplating  his  results  Lavoisier  (/)  said:  ^'This  kind  of  obser- 
vation suggests  a  comparison  of  forces  concerning  which  no  other  repoi^t 
exists.  One  can  learn,  for  example,  how  many  pounds  of  weight  lifting 
correspond  to  the  effort  of  one  who  reads  aloud  or  of  a  musician  who  plays 
a  musical  instrument.  One  might  even  value  in  mechanistic  terms  the 
work  of  a  philosopher  who  thinks,  the  man  of  letters  who  writes,  the 
musician  who  composes.  These  factors,  which  have  been  considered 
purely  moral,  have  Boraething  of  the  physical  and  material  which  this 
report  allows  us  to  compare  with  the  activities  of  a  man  who  labors  with 
his  hands.  It  is  not  without  justice  that  the  French  language  has  united 
under  the  common  expression  worh  the  effort  of  the  mind  with  that  of 
the  body,  the  work  at  the  desk  with  the  work  at  the  shop.  .  i  , 

Thus  far  we  have  considered  respiration  only  as  a  consumption  of  air,  the 
same  kind  for  the  rich  as  for  the  poor,  for  air  belongs  equally  to  all  and  costs 
nothing.  The  laborer  who  works  enjoys  indeed  in  great  measure  this  gift  of 
nature.  But  now  that  experiment  has  taught  us  that  respiration  is  a  true  process 
of  combustion  which  every  instant  consumes  a  portion  of  an  individual,  that  this 
combustion  is  greater  when  the  circulation  and  respiration  are  accelerated  and 
is  augmented  in  proportion  to  the  activity  of  the  individual  life,  a  host  of  moral 
considerations  suggest  themselves  from  these  determinations  of  physical  science. 

What  fatality  ordains  that  a  poor  man»  who  works  with  his  arms  and  who 
is  forced  to  employ  for  his  subsistence  all  the  power  given  him  by  nature,  con- 
sumes more  of  himself  than  does  an  idler,  while  the  latter  has  less  need 
of  repair?  Why  the  shocking  contrast  of  a  rich  man  enjoying  in  abundance 
that  which  is  not  physically  necessary  for  him  and  which  is  apparently  destined 
for  the  laboring  man?  Let  us  take  care,  however,  not  to  calumniate  nature  and 
accuse  her  of  faults  undoubtedly  a  part  of  our  social  institutions  and  perhaps 
inseparable  from  them.  Let  us  be  content  to  bless  the  philosophy  and  humanity 
which  unite  to  promote  wise  institutions  which  tend  to  bring  about  equality  of 
fortune,  to  increase  the  price  of  labor,  to  assure  to  it  just  recompense,  to  offer 
to  all  classes  of  society  and  especially  to  the  poor  more  pleasures  and  greater 
happiness.  Let  us  trust,  however,  that  the  enthusiasm  and  exaggeration  which 
so  readily  seize  men  united  in  large  assemblies,  that  the  human  passions  which 
sway  the  multitude,  often  against  their  own  interest,  and  sweep  the  sage  and  the 
philosopher  like  other  men  into  their  whirlpool,  do  not  reverse  an  outlook  with 
such  beautiful  vistas  and  do  not  destroy  the  hope  of  the  country.  ... 


28  GRAHA;]^!  LITSK 

We  end  this  memoir  with  a  consoling  reflection.  To  merit  well  of  liumanity 
and  to  pay  tribute  to  one's  country  it  is  not  necessary  to  take  part  in  brilliant 
public  functions  that  have  to  do  with  the  organization  and  rej-Tcneration  of  em- 
pires. The  naturalist  may  also  perform  patriotic  functions  in  the  silence  of  his 
laboratory  and  at  his  desk;  he  can  hope  through  his  labors  to  diminish  the  mass 
of  ills  which  afflict  the  human  race  or  to  increase  its  happiness  and  pleasure;  and 
should  he  by  some  new  methods  which  he  has  opened  up  prolong  the  average  life 
of  men  by  years  or  even  by  days  he  can  also  aspire  to  the  glorious  title  of  bene- 
factor of  humanity. 

These  are  words  written  by  the  greatest  scientist  of  his  day  under  the 
spell  of  the  French  Revolution.  They  are  words  of  an  educated,  culti- 
vated man  of  middle  age  spoken  in  the  Academic  des  Sciences  in  the 
year  of  the  fall  of  the  Bastile  and  at  a  time  when  Edmund  Burke  from 
the  other  side  of  the  Channel  said.  '*In  the  groves  of  their  Academy  at 
the  end  of  every  vista  you  see  nothing  but  the  gallows." 

Lavoisier  and  Franklin  had  been  intimate  friends,  living  near  each 
other  in  Paris  and  Franklin  dining  frequently  with  the  great  French 
chemist  and  his  wife.  In  a  letter  written  to  Franklin,  then  in  America,  on 
February  5,  1790,  during  the  early  days  of  the  French  Revolution, 
Lavoisier  says:  "After  having  recited  what  has  transpired  in  chemistry 
it  is  well  to  speak  of  our  political  revolution.  We  regard  it  as  accom- 
plished, well  accomplished  and  beyond  recall.  There  still  exists,  howeverj 
an  aristocratic  party  which  is  making  vain  efforts  but  is  evidently 
feeble.  .  .  .  We  greatly  regi-et  at  this  moment  your  absence  from  France. 
You  could  be  our  guide  and  mark  the  limits  beyond  which  we  ought  not 
to  pass."    . 

And  in  1790  Lavoisier  (g)  concluded  his  last  scientific  communication 
to  the  xVcademie  with  these  words.  "Up  to  the  present  time  we  have  learned 
only  to  conjecture  as  to  the  cause  of  a  great  number  of  diseases  and  as  to 
the  means  of  their  cure.  Before  hazarding  a  theory  we  propose  to  multiply 
our  observations,  to  investigate  the  phenomena  of  digestion  and  to  analyze 
the  blood  both  in  health  and  in  disease.  We  will  draw  ujwn  medical 
records  and  the  light  and  experience  of  learned  physicians  who  are  our 
contemporaries  and  it  will  be  only  when  we  are  thus  completely  ai'med 
that  we  will  dare  to  attack  a  revered  and  antique  colossus  of  pi'ejudice 
and  of  error." 

No  person  of  understanding  can  escape  a  thrill  at  this  vision  of  modern 
medicine  expressed  by  him  who  had  overthrown  phlogiston,  discovered  the 
composition  of  the  air  and  its  relation  to  combustion  and  to  life,  wl)o 
had  created  calorlmetry  and  revolutionized  the  whole  of  chemical  thought. 

True  to  his  enthusiasm  we  find  him  drawing  up  the  conditions  for  an 
international  prize  of  5,000  livres  offered  by  tlie  Academic  des  Sciences 
in  1792  to  the  author  of  the  best  experimental  treatise  on  the  livei"  and 
the  bile  (t). 

Lavoisier's   life  outside  his  laboratory   had   been   that   of   a   public 


A  HISTORY  OF  METABOLISM  29 

official,  a  tax  gatherer,  and  lie  had  also  been  associated  with  the  national 
iiiaiiufactiu'o  of  iiunpowder,  the  finality  of  which  he  had  greatly  improved. 
He  piuchased  a  large  landed  estate  and  made  experiments  in  scientific 
agricnltiiro,  doubling  the  wheat  crop,  (piintupting  the  number  of  beasts 
en  the  land  anxl  earning  thereby  the  enduring  gratitude  of  the  peasants. 
However,  as  before  remarked,  he  liad  ineurj-ed  the  bitter  hatred  of  ^Marat 
and  he  was  a  tax  gatherer.  In  iSTovember,  1703,  he  was  arrested  at  the 
Arsenal  in  his  lal)oratory  there,  npon  which  he  had  spent  a  large  portion 
of  his  fortune.  Just  a  little  while  before,  in  August  of  the  same  year, 
the  Acadomie  des  Sciences  had  been  closed  as  inimical  to  the  welfare 
of  the  state.  Les  amis  du  peupJe  are  notoriously  suspicious  of  the  "intelli- 
genzia,''  and  the  Academic  was  abolished. 

Just  prior  to  his  execution  Lavoisier  wrote  to  a  friend,  "I  have  had  a 
sufficiently  long  career,  always  a  very  happy  one,  and  I  believe  that  my 
memory  will  be  thought  of  with  some  regret  and  perhaps  as  having  some- 
thing of  glory.  What  more  could  I  desire?  The  circumstances  which 
surround  me  would  probably  lead  to  an  uncomfortable  old  age.  ...  It  is 
certainly  true  that  all  the  social  vii-tues,  important  services  to  the  country, 
a  useful  career  employed  in  promoting  ai*t  and  human  knowledge,  have 
not  sufficed  to  save  me  from  a  sinister  end  or  to  prevent  me  from  perish- 
ing as  a  criminal," 

One  of  the  charges  against  Lavoisier  was  that  he  had  allowed  tho 
collection  of  taxes  upon  the  water  contained  in  tobacco.  On  May  8,  1794, 
at  the  age  of  fifty  years,  he  was  tried  and  found  gliilty.  Twenty-eight 
fenmers-generaux  were  executed  in  the  Place  de  la  Rcpublique  at  the 
same  time.  He  witnessed  the  execution  of  his  father-in-law,  Paulze,  who 
was  fourth  on  the  list,  and  he  was  the  fifth  upon  whom  the  ax  of  the 
guillotine  fell. 

Such  was  the  Terror. 

His  friend  Lagi*ange  whispered  that  night  to  an  intimate,  "It  took 
but  an  instant  to  cut  off  his  head ;  a  hundred  years  will,  not  suffice  to 
produce  one  like  it!'' 

Writing  a  hundred  years  later,  Berthelot  (y)  (1890)  exclaimed,  "It  is 
our  right  to  admire  the  positive  work  which  he  accomplished.  The  uni- 
versal jiulgment  of  the  civilized  world  increasingly  reveres  his  establish- 
ment of  chemistry,  one  of  the  fundamental  sciences,  upon  a  fixed  and 
definite  basis.  There  is  no  gi-ander  accomplishment  in  the  history  of 
civilization  and  hence  the  name  of  Lavoisier  will  live  forever  in  the 
memory  of  humanity." 

It  is  interesting  to  consider  the  difl^erences  in  the  lives  of  the  men 
concerned  in  the  great  discoveries  of  the  last  quarter  of  the  eighteenth 
century.  Priestley,  an  indigent  clergyman ;  Cavendish,  of  whom  it  was 
said  that  he  was  the  most  wealthy  of  learned  men  and  the  most  learned  of 
the  wealthy ;  Scheele,  a  poor  Swedish  apothecary ;  and  Lavoisier,  a  man  of 


30  graha:m  lusk 

affairs,  a  noble  of  high  social  jxisitioii,  in  receipt  of  huge  pergonal  i-cvennes. 
What  is  it,  then,  that  makes  for  greatness  in  science  ?  Would  l^avoisier 
have  accomplished  more  had  lie  been  on  a  "full-time'^  basis  willi  a 
restricted  income  ?  It  is  a  question  of  individual  opinion,  but  to  most 
people  it  would  appear  that  scicnlilic  greatness  depends  primarily  upon 
the  quality  of  the  intellectual  piotoplasm  of  the  brain,  npon  the  advantages 
offered  to  the  functioning  of  that  brain  l\v  a  favoring  mental  environment, 
and  on  the  }X)Ssession  of  a  good  conscience. 

Olio  may  well  understand  that  the  clarification  of  the  work  of  Black, 
Rutherford,  Cavendish,  Priestley  and  Scheele  by  the  brilliant  mind  of 
Lavoisier  might  lead  others  than  they  to  tlie  expression  of  national 
scientific  self-consciousness.  Thus,  \Vurtz*s  ''Histoirc  des  doctrines 
chimiques,"  published  in  Paris  in  18G1,  begins  with  the  proud  statement, 
"La  chimie  est  une  science  fran^aise;  elle  fut  constituee  par  Lavoisier." 
It  is  needless  to  state  that  this  caused  reverberations  of  disapproval  from 
England.  The  personal  opinion  of  national  worth  finds  still  more  intense 
modern  expression  in  the  Manifesto  of  the  Intellectuals  (1915),  ^^Thc 
German  Mind  is,  in  our  opinion,  beyond  all  doubt  our  one  supremely 
valuable- asset.  It  is  the  one  priceless  }X)Ssession  amongst  all  our  posses- 
sions. It  alone  justifies  our  people's  existence  and  their  impulse  to  main- 
tain and  assert  themselves  in  the  world;  and  to  it  they  owe  their  supei-iority 
over  all  other  peoples.'' 

A  historic  case  in  which  a  generous  attitude  was  taken  occurred  Avhen 
the  French  Academy  in  1806,  just  prior  to  a  declaration  of  war  between 
France  and  ITngland,  conferred  its  newly  established  Volta  medal  upon 
Humphrey  Davy.  A  French  delegation  went  to  London  to  deliver  the 
medal  while  the  war  was  in  progTess  and  Davy,  in  acknowledging  it,  said, 
"Science  knows  no  country.  If  the  two  countries  or  governments  are  at 
war,  the  men  of  science  are  not.  That  would,  indeed,  be  a  civil  war  of  the 
worst  description.  We  should  rather  through  the  instrumentality  of  men 
of  science  soften  the  asperities  of  national  hostility." 

Perhaps  this  "old-fashioned''  courtesy  was  a  relic  of  the  days  of  a 
bygone  chivalry.  At  any  rate,  it  affords  a  delightful  example  of  human 
behavior. 

Science  after  the  French  Revolution 

Kapoleon,  during  the  winter  of  1707-1 703,  attended  the  regular  course 
of  chemical  lectures  delivered  by  Berthollet,  who  had  been  an  associate 
of  Lavoisier.  At  a  later  date  Berthollet  and  Monge,  the  mathematician, 
organized  a  company  of  one  hundred  scientists  to  accompany  JSTapoleon  to 
Egypt.  At  least  the  scientific  men  of  France  had  no  cause  to  complain  of 
lack  of  recognition.  And  perhaps  partly  in  consequence  of  this  one  finds 
living  in  Paris  in  1823,  the  year  Liebig  studied  there,  such  men  as  La 


A  HISTORY  OF  3IETAB0LISM  31 

Place,  Berthollet,  Gay-Liissac,  Tlicnard,  Ciivier,  Ampere,  Laennec  and. 
]\rai^pn(lie. 

Thori>e  writes  of  them  (1D08)  : 

"That  constellation  has  set — 

'The  world  in  vain 
Will  hope  to  look  ii],x>n  their  like  again.'" 

The  atmosphere  for  the  development  of  French  science  reached  at 
this  time  a  maximum  of  power  to  stimulate.  One  of  the  few  mistakes 
(;f  Lavoisier  was  his  conception  that  oxidation  took  place  in  the  lungs. 
Lagrange,  the  illustrious  mathematician,  a  friend  and  associate  of  La- 
voisier, reflecting  that  if  the  heat  production  took  place  in  the  lungs  their 
temperature  must  be  higher  than  elsewhere  in  the  body,  concluded  that 
heat  was  generated  wherever  the  blood  circulated,  that  oxygen  dissolved  in 
the  blood,  combined  with  hydrogen  and  carbon  there,  and  that  carbonic 
acid  was  eliminated.  This  interpretation  of  Lagi'ange  w^as  published  in 
171)1  before  Lavoisier's  death  by  Lavoisier's  pupil  Ilassenfranz  (I),  who 
agrees  that  the  caloric  necessary  to  maintain  animal  heat  is  liberated  in  the 
blood  by  the  combination  of  carlx)n  and  hydrogen  wath  oxygen,  with  which 
the  blood  is  mixed. 

Humphrey  Davy  (1778-1829)  was  the  first  to  obtain  oxygen  from 
arterial  blood  by  warming  it  to  93°  C.  and  carbonic  acid  from  the  venous 
blood  by  warming  it  to  45°  C.  He  was  apparently  not  well  acquainted 
with  Lavoisier's  work,  and  his  own  work,  published  in  1799,  remained  long 
forgotten.  To  him  oxygen  occurred  as  "pliosoxygcn,"  a  combination  of 
heat  and  light.  In  his  experiment  XVII  he  shows  that  "phosoxygen''  can 
be  absorbed  by  venous  blood  in  the  dark  without  the  liberation  of  light, 
but  with  the  result  that  the  color  of  the  blood  changes  from  dark  red  to 
bright  vermilion. 

Experiment  XVIII. — 

A  phial  containing-  about  12  inches,  havinjr  a  pneumatic  apparatus  affixed  to 
it,  was  filled  with  arterial  blood  from  the  carotid  arterj'  of  a  calf.  The  phial  was 
placed  in  a  sand  bath  at  a  temperature  ol  90"  and  the  heat  gradually  and  slowly 
raised.  In  about  ten  minutes  the  temperature  of  the  bath  was  108°  and  the  blood 
began  to  coagulate.  At  this  moment  some  globules  of  gas  were  perceived  passing 
through  the  tube.  Gas  continued  to  pass  in  very  small  quantities  for  about  half 
an  hour  when  the  temperature  of  the  sand  was  about  200° ;  the  blood  had  coagu- 
lated perfectly  and  was  now  almost  black.  About  1.8  cu.  in.  of  gas  \vere  collected 
in  the  mercurial  apparatus;  of  this  LI  cu.  in.  were  carbonic  acid  and  the  re- 
maining 0.7  phosoxygen. 

From  this  experiment  it  is  evident  that  the  arterial  blood  contains  phosoxy- 
gen, and  we  have  proved  before  by  synthesis  that  it  is  capable  of  combining  with 
it  directly.  We  are  possessed  of  a  number  of  experiments  which  prove  that 
phosoxj'gon  is  consumed  in  respiration.  It  has  been  likewise  proved  that  gases 
can  penetrate  through  moist  membranes  like  those  of  which  the  vessels  of  the 
lungs   arc  composed.     We   may   therefore  conclude  that   phosoxygen  combines 


32  GRAIIA:\[  Ll'SK 

with  the  venous  blood  of  the  system  in  the  pulmonary  vessels.  As  no  light 
was  liberated  in  Experiment  XVII  there  cannot  be  even  a  partial  decompo- 
sition of  phosoxygen  in  respiration, 

Davy's  iiiferpretatioiis  are  far  from  clear,  as  will  be  seen  in  the 
followinc:  paragraph:  ''Jtespirali»;n  ihon  is  a  chemical  process,  the  com- 
bination of  phosoxygen  with  tlie  venous  blood  of  the  Inngs  and  liberation 
of  carbonic  acid  and  acpicous  gas  from  it.  From  the  combination  and 
decomposition  ai'ises  an  i'.icrease  of  repulsive  motion  which,  combined 
with  that  pi'oduced  by  the  other  chemical  processes  taking  place  in  the 
system  and  that  generated  by  the  reciprocal  action  of  the  solids  and 
flnids,  is  the  cause  of  animal  heat;  a  heat  which  the  other  systems  have 
supposed  to  arise  chiefly  from  the  decomposition  of  phosoxygen  (oxygen 
and  caloric)." 

About  the  same  time  that  Davy  was  experimenting  in  England  Spal- 
lanzani  in  Italy  was  inquiring  into  the  validity  of  Lavoisier's  ideas. 

Spallanzani  (1729-1799). — The  experiments  of  Spallanzani  were 
published  in  1804  after  his  death.  Ilis  biogi-apher  states:  ^'When  the 
Empress  Maria  Theresa  had  reestablished  the  University  of  Pavia  on  a 
more  extensive  plan  she  w^ished  to  render  it  at  once  celebrated  by  the 
attainments  of  its  professors;  she  empowered  Count  Firmian  to  invite 
Spallanzani  to  give  lectures  on  natural  history." 

Spallanzani  says  that  ox\'gen  is  transported  by  the  blood  to  the  heart 
and  is  necessary  for  the  heart  beat,  but  he  is  not  convinced  that  oxygen  is 
necessary  for  the  production  of  carbonic  acid.  He  put  snails  into  two 
tubes  filled,  respectively,  with  atmospheric  air  and  with  nitrogen.  "On 
removing  them  from  the  tubes  at  the  end  of  twelve  hours  I  found  the 
animals  still  alive;  I  examined  the  two  aerifonn  fluids  and  was  astonished 
to  discover  that  the  quantify  of  carbonic  acid  gas  was  gieater  in  the 
azotic  gas  (nitrogen)  than  in  the  common  air.''  He  obtained  the  same 
result  when  he  used  hydrogen  gas  and  says,  *T  shall  only  conclude  from 
these  experiments  that  it  is  clearly  proved  that  the  carbonic  acid  gas 
produced  by  the  living  and  dead  snails  in  common  air  resulted  not  from 
atmospheric  oxygen,  since  an  equal  or  even  a  greater  quantity  of  it  was 
obtained  in  azotic  and  hydrogen  gas." 

This  is  very  nearly  the  same  as  Davy's  conclusion.  Of  his  method 
of  work  Spallanzani  says:  ''Being  engaged  in  similar  experiments,  it  was 
natural  for  me  to  attend  to  this  part  of  the  subject  uninfluenced  by  the 
opinion  of  those  celebrated  men,  in  order  that  I  might  obsei-ve  only 
nature  herself.  This  is  at  least  the  mode  T  have  always  pui'sued,  when 
it  was  possible,  with  respect  to  the  most  universally  received  opinions, 
however  respectable  the  quarter  whence  they  proctx'ded;  I  have  always 
myself  examined  the  facts  on  which  they  were  built." 

William  F.  Edwards  (1776-1842)  confirmed  the  work  of  Spallanzani, 
finding  that  frogs  when  placed  in  hydrogen  gas  eliminated  in  a  few  houj-s  a 


A  HISTORY  OF  :\rETABOLTSM  33 

volume  of  carl)OTiic  noid  equal  to  tlicir  own  vohuuc  and  larger  ill  quantity 
rhun  they  would  have  expired  Jiad  they  hrcatlied  in  air.  lie  concluded 
rhat  eiirhon  dioxid  was  not  foiined  hy  oxidation  in  the  lungs  but  must 
have  1  ('cn  exen^ted  from  the  hhxid,  and  he  supports  this  conclusion  by 
ritini:-  unpuhli8he<l  ex}>eriment&  hy  Vau(pielin  in  which  bh)od  was  exposed 
r..  a  ]ivdr<»iivii   atmo.si)here  with  the  result  that  carbonic  acid  was  eriven 

Magnus  (1802-1870)  repeated  the  experiments  of  Vauquelin,  shaking 
]il.;«)d  in  hydrogen  gas,  and  he  also  placed  blood  in  a  complete  vacuum 
iiiid  n»)ticed  the  elimination  of  a  great  volume  of  gases.  There  was  more 
•  arlionic  acid  eliminated  than  could  be  accounred  for  by  the  bicarbonate 
]>re^f'nt. 

Gay-Lussac  (1778-18.50)  criticized  these  results  and  stated  that  the 
.|uanrity  of  oxygen  found  in  the  bh)od  was  sixteen  times  larger  than  could 
1  e  dissolved  by  water  and  that  no  differences  api>eared  in  the  analyses  of 
arterial  and  venous  bloods.  ^FagnTis  (1845)  replied  that  100  parts  of  gas 
extracted  from  blood  contained: 

Arterial  Blood  Venous  Blood 

Carl)onic  acid C2.3  71.6 

Oxygen 23.2  15.3 

Xitrogen 14.5  13.1 

100  100 

He  found  also  that  when  blood  was  pumpeil  out  it  could  again  al^orb 
sixteen  volumes  per  cent  of  oxygen. 

Berzelius  (1779-1848)  announced  in  1838  that  little  oxygen  could  be 
a<]ded  to  blood  serum  freed  from  corpuscles,  but  when  the  serum  was  mixed 
with  the  coloring  matter  of  the  blood  it  was  absorbed  in  large  volume. 
Berzelius  attributed  the  affinity  of  ^'hematin'-  for  oxygen  to  its  content 
'.tf  iron. 

Dumas  in  1840  found  that  on  replacing  blood  serum  with  a  solution 
"f  sudium  sulphate  the  blood  corpuscles  suspended  therein  still  changed  in 
'•"liir  after  shaking  with  oxygen. 

It  was  Liebig  in  1851  who  gave  expressit;n  to  modem  thought  iijxjn 
the  sulfject  of  the  respiration  in  saying,  "The  absorption  of  a  gas  by  a 
liquid  is  due  to  two  causes,  an  external  consisting  in  the  pressure  exerted 
1  y  the  gas  u|K)n  the  liquid,  and  a  chemical,  an  attraction  manifested  by  the 
f^-onstituent  particles  of  the  liquid;" 

F>»r  complete  references  to  this  story,  consult  "Lecons  sur  la  physiolo- 
liie."  by  II.  .Milne-Edwards,  Volume  1,  printed  in  1857.  Tiiese  volumes 
treat  the  subject  of  physiology  with  a  thoroughness  lately  thought  to  be 
♦•xelusivelv  German, 


34  GKAnA:\[  LUSK 


The  Be^innin^s  of  Calorimetry 

The  work  of  Lavoisier  concerning  the  source  of  animal  heat  was  in- 
STifficicntly  convincing,  and  so  the  French  Academy  of  Science  offered  a 
pfiw  to  any  one  wlio  w«.n]d  produce  the  hest  tliesis  on  the  subject.  Tl)e 
prize  was  compered  for  by  Despretz  and  hy  Dulong.  It  was  awarded  in 
1823  to  the  former^  although  in  the  light  of  modern  knowledge  it  would 
seem  that  the  latter  had  a  greater  insight  into  the  problem. 

Despretz  (17U2-1803)  gives  the  following  account  (1824):  "Xo 
phenomenon  in  physiology  is  more  capable  of  attracting  attention  than 
the  singidar  property  enjoyed  by  man  and  warm-blooded  animals  of  pre- 
serving an  almost  constant  temperature*,  although  the  tem|>erature  with 
which  they  are  surrounded  is  subject  to  continual  variations.  All  bodies 
tend  constantly  to  seek  heat  equilibrium;  reciprocal  exchange  tends  to 
establish  a  uniform  temperature  between  dilferent  bodies. 

*' Warm-blooded  animals,  en  the  contrary,  though  they  are  e<]ually 
exjK^sed  to  heat  loss  occasioned  by  contact,  radiation  and  the  evaporation 
of  water,  possess  within  themselves  a  power  to  produce  heat  wdiich  main- 
tains their  temperature  as  a  rule  at  about  30°  above  the  melting  point 
of  ice.'' 

The  resources  of  modern  science  were  lacking  in  the  days  of  Galen, 
Boerhaave  and  Ilaller.  The  author  cites  Lavoisier  (n)  (1780)  and  criti- 
cizes Crawford's  (1779)  very  imperfect  method.  He  states  tbat  Brodie 
(1812  Philosophical  Transactions)  thought  the  brain  proiluced  heat  through 
the  nerves,  citing  the  heat  loss  after  decapitation.  This  was  denienl  by  Le 
Gallois,  who  maintained  artificial  respiration  in  a  decapitated  animal. 

Type  of  experiment  by  Despretz: 

Subjects,  three  guinea-pigs. 

Ventilation,  55  to  60  liters  per  2  hours,  the  air  being  purified  by- 
passing through  potash. 

Condition  of  the  environmental  air,  0  j>er  cent  CO2  and  water 
saturation. 

Experiment  1 : 

CO2  formed,  2,587  liters. 

Oo  unaccounted  (i.  e.,  not  in  COg),  0.700  liter. 

The  three  animals  raised  the  temperature  of  23310.5  g. 

water  0.03  . 
Animal  beat  as  measured,         100   per  cent. 
Heat  due  to  formation  CO2     60.0  per  cent. 
Heat  due  to  formation  water,  19.4  per  cent 
Total  heat  as  calculated,  89.3  per  cent. 


A  IIISTOKY  OF  ]\IETAB0LIS:M  35 

The  modern  calculation  would  be: 

0-2  CO2  E.  Q.  Calories  Calories 

indirect  direct 

liters         liters 
3.30  2..>1>  0.78  15.86  14.68 

Or  8  j>er  cent  too  much  calculated  heat  instead  of  11  per  cent  too 
little. 

The  conclusions  of  Despretz  were : 

1.  That  the  respiration  is  the  principal  cause  of  the  development  of 
animal  heat;  that  assimihition,  movement  of  the  blood,  friction  in  different 
parts,  can  easily  produce  the  small  residual  amount. 

2.  Although  oxyoen  is  employed  in  forming  carbonic  acid,  a  certain 
quantity,  sometimes  considerable  in  amount,  disapi>ears;  it  is  generally 
thought  that  it  is  used  in  the  combustion  of  hydrogen. 

3.  There  is  an  exhalation  of  nitrogen  in  the  respiration  of  both 
carnivorous  and  herbivorous  animals. 

The  following  animals  were  used:  Ducks,  chickens,  cocks,  young  and 
old  pigeons,  gulls,  buzzards,  owls,  magpies,  dogs,  cats,  rabbits  and  guinea- 
pigs. 

•/'Dulong  (1785-1838)   presented  the  second  paper  in  competition  for 
the  prize  of  the  Academy,  of  which  a  resume  follows : 

The  author,  who  is  both  physicist  and  chemist,  proposes  to  determine 
if  the  quantity  of  oxygen  intake  is  sufficient  (in  health)  to  repair  the 
heat  loss  by  animals  under  natural  conditions  of  life;  in  other  words, 
whether  animal  heat  is  entirely  due  to  combustion  which  takes  place 
within  the  animal  through  respiration. 

He  calls  attention  to  the  fact  that  Lavoisier  used  two  different  guinea- 
pigs,  one  in  the  calorimeter  and  another  for  the  determination  of  the 
gaseous  exchange.  He  uses  the  water  calorimeter  of  Rumford,  The 
temperature  of  the  water  is  the  same  as  that  of  surrounding  air  at  the 
start ;  at  the  end,  higher.  The  animals  can  move  at  will.  Cat,  dog,  kestrel, 
capibara  (water-hog),  rabbit,  and  pigeon  are  used.  He  finds  that  in 
the  cat,  dog  and  kestrel  the  volume  of  oxygen  inspired  is  one-third  more 
than  that  of  the  carbonic  acid  expired,  whereas  in  rabbits,  capibara  and 
pigeons  the  oxygen  is  only  one-tenth  more  than  the  carbonic  acid.  There- 
fore he  thinks  this  difference  is  due  to  food  or  to  a  difference  of  animal 
organization  thrrugh  food.  He  finds  that  nitrogen  is  exhaled.  The  heat 
from  carbonic  acid  in  carnivora  is  40  to  55  per  cent  of  the  total  heat 
measured;  in  herbivora,  65  to  75  per  cent.  Calculated  inclusive  of  the 
heat  produced  from  the  oxidation  of  hydrogen,  it  equaled  69  to  80  per 
cent.    The  experiments  were  repeated  many  times. 

One  source  of  error  in  the  calculations  of  Despretz  and  of  Dulong 


3G 


GKAHAAL  LUSK 


lay  in  the  fact  that  the  ealori','  values  attributed  to  the  oxidation  of  carbon 
and  hydro«ion  were  wronir.  Ouo  may  compare  the  values  used  nt  different 
I)eriods  as  follows : 


Favre  and 

Lavoisier 

Despretz 

Silberuiann 

1780 

1823 

1852-53 

calories 

calories 

calones 

yields .  . 

.   22.170 

23.G40 

34.402 

viehJs.  . 

.     7.237 

7.014 

8.080 

1  gnu  IT  oxidized 
1  gm.  C  oxidized 

The  agreement  berweeii  Despretz  and  Dulong  that  nitrogen  was 
present  in  the  expired  air  in  an  amount  larger  than  that  inspired  Avas 
accepted  for  many  years  ]»y  many  wTiters.  ]\Iagendie,  in  his  ^'Elements  of 
Physiology,"  in  1830,  thus  expresses  the  thoughts  of  his  time:  ^"^Accord- 
ing to  the  experiments  of  M.  Despretz  upon  herbivora,  the  respiration 
furnishes  only  80  per  cent  of  the  animal  heat,  and  in  carnivora  only  80  per 
cent.  Therefore,  other  sources  of  animal  heat  must  exist  in  the  economy. 
It  is  probable  that  these  occur  in  the  friction  of  various  parts,  in  the 
movement  of  the  blood,  the  friction  of  the  blood  corpuscles  u}X)n  one 
another  and  finally  in  nutritive  phenomena.  This  supposition  is  not 
forced,  for  it  is  known  that  most  chemical  combinations  give  rise  to  heat, 
and  it  is  doubtless  true  that  combinations  of  this  nature  take  place  in  the 
organs,  both  during  secretion  and  digestion.'^ 

It  is  evident  that  ignorance  of  the  Law  of  the  Conservation  of  Energy 
hampered  progress  at  this  time. 

Dumas  (1800-1884). — In  the  year  1823  a  paper  was  published  by 
Prevost  and  Dumas  pjiiiting  out  the  fact  that  if  the  kidneys  were  ex- 
tirpated in  cats  and  rabbits,  urea  rose  to  high  concentration  in  the  blood. 
This  experiment  proved  that  urea  was  not  formed  in  the  kidney.  Rouelle 
in  1773  had  found  urea  in  the  urine.    • 

It  was  the  year  1S23.  the  year  of  the  publication  of  the  work  of 
Despretz,  of  Dulong  and  <'.f  Dumas,  that  Liebig,  at  the  age  of  twenty, 
came  to  Paris  to  study.  This  should  be  remembered  as  the  story  of  the 
deveh'pmcnr  of  the  French  school  is  unfolded.  The  part  Liebig  played 
will  be  tohl  later. 

Diunas  was  an  organic  cheinist  of  high  repute.  Concerning  his  influ- 
ence, the  words  of  Pasteur,  spoken  in  1882,  may  be  recalled:  "^ly  dear 
^fastei-,  it  is  indeed  forty  years  since  I  first  had  the  happiness  of  knowing 
you  and  since  you  first  taught  me  to  love  science. 

**I  was  fresh  from  the  country:  after  each  of  your  classes  I  would 
leave  the  Sorbonne  tran?|X)rted,  often  niove^l  to  tears.  Fro;n.  that  moment 
your  talent  as  a  professor,  your  immortal  labors  and  your  noble  character 
have  inspired  me  with  an  admiration  which  has  gTOwna  with  the  maturity 
of  my  mind," 


A  HISTORY  OF  METABOLISM  37 

Dumas  came  into  freqiiciit  intellectual  conflict  with  Liebig  and 
Wohler  in  Germany  and  Berzeliiis  in  Sweden.  In  1828  Wohler  produced 
uiea  synthetically  from  ammonium  cyanaie,  delivering  the  final  death 
Mow  to  the  doctrine  that  organic  compounds  arise  only  through  the  inter- 
vention of  living  things. 

JVIagendie  (178:5-185;-))  was  among  the  first  to  differentiate  between 
various  kinds  cf  foods.  This  distinguish**!  physiologist  fed  dogs  cane 
sugar  or  olive  oil  or  butter  and  fouuil  tlwit  death  occurred  in  31  days 
(  Magendie,  1830).  He  rightly  coneluilcd  that  the  nitrogien  of  the  organs 
of  the  body  arose  only  from  the  nitrogen  «;f  tlie  food,  that  the  nitrogen-free 
food-stuffs  were  not  transformable  into  nitrogen-containing  food-stuffs. 
He  rendered  great  service  in  i>ointing  out  the  nitrogen  content  of  rice, 
maize  and  potatoes,  foods  upon  which  jjeoplc  live. 

Magendie  also  found  that  dogs  fe^l  with  bread  alone  lived  only  a 
month.  The  second  gelatin  commission  of  tlie  French  Academy  (Magen- 
die,  1841),  sitting  in  1811  under  the  pi-esitlency  of  Magendie,  determined 
that  bread  and  gelatin  given  together  to  eitlker  dog  or  man  constituted  an 
insufficient  diet. 

Boussingault  (1802-1887). — Organic  analysis,  which  was  founded  by 
Lavoisier,  was  further  advanced  by  Gay-I-ussac  and  Thenard  (1810-15), 
by  Berzelius  in  1814,  and  was  perfected  l>j  Liebig  in  1830.  This  work 
led  to  that  of  Boussingault,  who  curioii:s!y  eiicugh  had  been  previously  for 
several  years  in  the  employ  of  an  English  mining  company  in  equatorial 
South  America. 

The  experirnents  of  Boussingault  in  1839  may  be  considered  to  be 
[U'ophetic  of  the  future  evohition  of  metabolism  studies.  Boussingault 
compares  the  quantities  of  carbon,  hydiX)g€^n,  nitrogen  and  oxygen  in  the 
fodder  constituting  a  maintenance  ration  of  a  milch  cow,  with  the  quan- 
tities of  the  same  elements  eliminated  in  the  urine,  feces  and  milk.  The 
difference  between  these  quantities  wciuhl  he  available  for  the  respiration. 
He  gives  the  following  account  (Boussingault,  (h)  1839)  : 

'Tt  is  generally  recognized  to-day  that  the  food  of  animals  must  con- 
rain  a  certain  amount  of  nitrogen.  The  j>resence  of  nitrogen  in  a  larg-o 
number  of  vegetable  foods  forces  thr*  coHclusion  that  herbivora  receive 
nitrogen  in  their  food,  which  enters  into  tlieir  constitution. 

^*In  ordinary  alimentation  an  individwid  does  not  change  his  average 
weight ;  this  state  of  affairs  exists  wlien  an  animal  takes  a  maintenancG 
ration  {ration  d'entretlen).^^ 

Lender  these  conditions  the  food  of  the  animal  should  be  found  in  his 
excretions.  During  gi'owth,  or  the  jnx3cess  of  fattening  the  conditions 
would  be  different. 

Cows  were  given  a  maintenance  ration  of  known  elementary  com- 
position and  the  elements  recovered  \n  tlie  urine,  feces  and  milk  were 
.-subtracted  from  those  in  the  fodder,  with  the  following  results: 


H 

0 

N 

Salts 

lAiC) 

1035 

201.5 

8S9 

M2 

20S3 

174.5 

021 

38  GK.VllAxM   LUSK 

C 

Elements  in  the  fodder 4813 

Elements  in  tlie  urine,  feces  and  milk.  20(^3 

—2211 —203 —1052    --27       +32 

Unitinir  the  oxyiren  of  the  food  with  the  livdrogen  in  such  a  proportion 
as  to  form  water,  there*  would  remain  10.8  «ni.  of  hydrogen  requiring 
inspired  atmo.-pheric  oxyiren  for  its  conversion  into  water.  The  loss  of 
carbon  equaling  2211  pn.,  it  would  require  4052  liters  to  convert  it  into 
7000  gin.  of  carbonic  acid.  A  cow  would  therefore  deprive  10  square 
meters  of  air  of  its  oxy^rc-n. 

Boussingault  states  that  one  nitrogen  determination  is  not  sufficient 
to  decide  whether  nitrogen  as  a  gas  enters  into  the  metabolism  of 
protein. 

The  same  kind  of  work  is  done  with  a  horse  (Boussingault,  (a)  1S30). 
It.  is  concluded  tliat  45S4  liters  of  oxygen  would  be  required  to  form,  the 
carbonic  acid  produced.  There  were  24  gm.  less  of  nitrogen  in  the 
excreta  than  in  the  food.  It  seems  clear  that  atmospheric  nitrogen  is  not 
assimilable  by  the  body. 

In  a  subseqtieiit  experiment  published  in  1843  Boussingault  (c)  gives 
food  to  a  turtle-dove  and  estimates  the  carbonic  acid  elimination  as  he 
had  done  with  the  horse,  but  he  also  determines  directly  the  carbonic  acid 
given  off.  By  the  first  method  0.211  gm.  of  carbon  were  estimated  to 
have  been  expired  and  by  the  second  method  an  average  of  0.198  gm. 
were  actually  found.     This  closely  approaches  modern  technic. 

Boussingault  and  Le  Bel  (1830)  made  the  first  complete  analyses 
of  cow's  milk.  They  conclude  from  their  work  that  the  nature  of  the 
fodder  does  not  aiTect  the  quantity  or  the  chemical  composition  of  the 
milk,  provided  the  cow  receives  the  same  relative  nutritive  equivalents  in 
the  fodder. 

The  nutritive  equivalents,  however,  were  based  on  the  nitrogen  content 
of  the  fodders,  thu^  13.5  kg.  of  hay  Avere  accounted  the  nutritive  equiva- 
lents of  54  kg.  of  beets  or  27  kg.  of  potatoes.  It  is  evident  that  at  this 
date  there  was  no  real  understanding  of  the  nature  of  the  different  food- 
stuffs. 

Barral  (I81D-l>iS4)  in  1840  applied  the  principles  of  Boussingaidt's 
method  to  the  analysis  of  the  nietal>olism  of  human  beings.  He  thus 
presents  his  problem:  ^'Knowing  the  amount  and  the  eleinentary  com- 
position of  the  food,  both  solid  and  liquid,  taken  each  day,  determining 
the  elementary  comjx)sition  of  the  excreta  and  perspiration,  one  may 
calculate  the  gains  and  losses  of  the  human  body.'' 

His  experiment  on  himself  lasted  five  days,  with  the  following  results 
per  day: 


A  HISTORY  OF  METABOLISM  39 

Water        Salts        CI  C  H  N  O  Total 

In   the  food lOOS.G         31.3         7.8         300.2         57.3         28.0         205.7         2754  9 

In  the  excreta. .. .     1177.8         15.4         5.0  30.5  5.4         13.7  10.0         1204.7 

Differences     —  820.8    — 15.0    —  2.8    —33.5.7    —  5L0    —14.3    —248.8    —1490  2 

248.8  g.   O,  -f-   31.1  g.  IT,  =  279.0  g.  H,0 

20.8  g.  Hj  -f.  1G0.:J  g.  inap.  0,  =  187.1  g.  II^O 
335.7  g.  G  -1-  805.2  g.  insp.  O,  =  1230.9  g.  CO, 

It  is  evident  that  1001  inn.  of  oxygen  would  have  been  inspired  and 
1231  gin.  of  carbonic  acid  expire<l,  according  to  this  calculation.  He 
finds  that  his  figures  for  carbonic  acid  elimination  accord  with  those  of 
Andral  and  Gavarret  (see  below).  He  calculates  the  heat  production  as 
follows: 

335.7  g.  C   X     7.200  calories  =  2417,040  calories  from  0 
20.8  g.  H  X  34.000        "        =     719.080        "         "    H 

Total    313G.720 

These  calories  were  calculated  for  a  man  from  the  food  partaken 
during  the  winter  months. 

Barral  makes  the  further  analysis  of  the  heat  produced  by  vai'ious 
individuals  in  24  hours: 

Total  Calories 

Subject.  calories  perkgm. 

Barral,  in  winter  (age  29  yrs. ;  wgt.  47.5  kgm.)  .  . .  3,136.720  60.030 

Barral,   in  summer 2,312.000  48.673 

BarraFs  son  (age  6  yrs. ;  wgt.  15  kgm.) 1,223.960  81.597 

Laboratory  servant  (age  59  yrs. ;  wgt.  58.7  kgni.)  .  2,559.080  43.595 

Woman  (ag-e  32 ;  wgt.  61.2  kgm.) 2,541.100  41.521 

The  quantity  of  nitrogen  in  the  food  was  always  greater  than  that 
found  in  the  evacuation,  so  much  so  that  a  part  must  have  been  eliminated 
in  the  respiration.  This  portion  was  one-third  or  one-quarter  of  the 
nitrogen  taken  in  the  food  but  was  not  more  than  the  hundredth  part  of 
the  volume  of  carbonic  acid  eliminated.  The  loss  of  food  nitrogen  was 
estimated  as  not  more  than  six  ten-thousandths  of  the  total  volume  of  air 
expired. 

Barral  did  not  know  that  his  urinary  nitrogen  analyses  were  faulty. 

Barral  criticizes  the  contemporary  work  of  Liebig  as  follows:  "Liebig 
has  attempted  the  solution  of  the  question  which  occupies  us  by  the  same 
method  and  as  concerns  man.  This  skilful  chemist  was  content  to  measure 
the  ptincipal  foods  of  a  company  of  the  grand  ducal  guard  of  Hesse- 
Darmstadt  and  to  regard  the  minor  food-stuifs  as  the  approximate  equiva- 
lent of  the  material  found  in  the  feces  and  urine  so  far  as  carbon  content 
was  concerned.  He  also  made  similar  valuations  of  the  food-stuiYs  of 
prisoners  at  Giessen  and  at  jMarienbad  and  of  a  family  composed  of  five 


40  gkaiia:\i  lusk 

persons.     But  this  applic«atlon  of  tlic  metliod  ai  Bonssingault  is  too  im- 
perfect to  establish  tkfinitely  iiufontiovertihle  results  in  science." 

It  niiiiht  hv  athlinl  at  this  j)oiiit  tliat  Liebiii'  in  1815  found  that  ninc- 
tenths  and  more  of  the  heat  measured  hy  the  eah)iimelers  of  J)uU>ni^  and 
of  Despretz  could  I>e  sieeounted  for  fiom  the  oxidation  of  carhon  and 
hydrogxm  calculated  a«.*c<;rdin<^'  to  the  method  of  Lavoisier.  The  more 
modern  cah)ric  values  fwr  hydrogen  were  liere  employed  as  later  in  lSr>^ 
hy  Gavarret. 

Liehiii'  jdso  points  out  that  if  one  of  the  dog\s  exj)erimeided  upon  hy 
DuloniT  ha<l  really  eliminated  the  quantity  of  nitrogen  gas  Dulong  had 
reported,  the  animal  in  seven  days  would  have  expired  as  nitrogen  gas 
The  amount  of  that  elcoient  contained  in  its  hair,  skin,  flesh  and  blood,  and 
at  the  end  of  the  perio*]  would  have  been  merely  a  mass  of  mineral  ash. 

Regnault  ( ISlD-lSTSj. — Henri  Victor  Regnault  was  born  in  Aix-la- 
chapelle,  and  in  1810  lecame  professor  of  physics  and  chemistry  at  the 
Univei*sity  of  Paris.  In  1847  he  became  also  chief  engineer  of  mines; 
in  18r>4  was  director  of  the  Sevres  porcelain  manufactory.  He  Avas  a 
strict  disciplinarian  of  students  and  up  to  the  outbreak  of  the  war  in 
1014  his  memory  w^as  held  in  tradition  as  representative  of  the  highest 
pedagogical  severity. 

In  1841)  JlegmmU  and  Beiset  published  their  celebrated  monograph 
upon  the  respiration  of  animals.  The  apparatus  which  they  used  consisted 
of  a  closed  system,  from  which  the  carbonic  acid  produced  by  an  animal 
placed  within  the  system  could  be  absorbed,  and  into  which  oxygen  could 
be  admitted  as  the  atmcvspheric  air  was  consumed  by  the  animal.  This  is 
the  ^'closed  system  af  Regiiault  and  Heiset,"  the  principle  of  which  is 
employed  in  modem  calorimeter  work  (vide  Atwater  and  Benedict, 
1005)1 

'^     The  i-esults  obtained  were  usually  accurate  and  their  interpretations 
were  within  the  compjiss  of  the  knowledge  of  the  time. 

Their  main  conclur^ions  as  they  enumerated  tliem,  together  with  some 
of  their  experimental  data,  are  presented  in  the  following  abstract: 

For  anitnals  tf  Winrm  blood,  mammals  and  birds: 

1.  Xormally  nourished  animals  constantly  expire  nitrogen  but  the 
quantity  eliminated  is  very  small,  never  exceeding  two  per  cent  and  often 
being  less  than  one  pin  cent  of  the  total  oxygen  consumption. 

2.  If  animals  fast  they  fre(]uently  absorb  nitrogen.  The  proportion 
of  nitrogen  al)?orbed  varies  within  the  same  limits  as  the  exhalation  of 
nitrogen  by  animals  regularly  fed.  This  absorption  of  nitrogen  takes 
place  in  almost  every  instance  in  the  case  of  birds  but  scarcely  ever  in 
manmials.  ... 

(In  experiment  10  performed  on  a  rabbit  the  quantity  of  nitrogen 
absorbed  was  0.08  per  cent  of  the  quantity  of  oxygen  absorbed.  In  the 
text  of  the  article  they  remark  that  the  enormous  elimination  of  nitrogen 


A  HISTORY  OF  METABOLISM 


41 


rrpoilf'(]  by  Diilong-  is  inipossihle  and  that  Liebig  had  pointed  out  [p.  40] 
that  when  one  considered  rlie  loss  of  nitrogen  in  tl»e  urine  and  feces,  an 
animal  expiring  in  addition  the  amount  of  nitrogen  found  hv  Dulono- 
would  tlnis  in  a  few  days  liheiate  all  the  nitrogen  contained  in  the  organic 
iiiafcMial  of  its  own  body.  They  also  state  that  the  respiration  cannot 
contain  rnoi-e  than  extremely  .-mal}  quantities  of  ammonia. ) 

4.     ...  'J'ho  alternating  elimination  and  absorption  of  nitrogen  found 
in  the  same  animal  under  various  conditions  is  favorable  to  the  opinions 


_^, — J — 3- 


/■/' *.^— ^  -  /  a.;,,. 


i 


^r--i=^ 


I  in 


Fig.  6.  The  closed  circuit  apparatus  of  Rofrnaiilt  and  Reiset.  From  **Annales  de 
Cliimie  et  de  Physique/'  Series  "i.  Vol.  XXVI.  PI.  ITT.  Water  rising  in  the  glass  recep- 
tacle drives  oxygen  into  the  glass  bell  jar.  A  pump  alternately  raises  and  lo\v»'rs  two 
cylinders.  The  lower  cylinder  fills  with  alkali  at  the  expen&e  of  the  upper  one,  and 
this  movement  of  the  liquid  forces  air  from  one  cylinder  into  the  bell  jar  and  draws 
a  corresponding  amount  from  the  bell  jar  into  the  other  cylinder. 


of  Edwards,  who  believes  tlnit  an  elimination  and  an  absorption  of  nitro- 
gen constantly  takes  place  during  respiration,  and  what  one  finds  is  the 
resultant  of  these  two  contrary  processes. 

5.  The  relation  between  the  quantity  of  oxygen  exlialed  as  carbon 
dioxid  and  the  quantity  of  total  oxygen  consumed  appears  to  dejX'ud  more 
on  the  nature- of  the  food  than  on  the  si)ecies  of  the  animal.  This  ratio  is 
higher  in  the  animals  whicli  live  upon  grain  and  in  them  it  may  exceed 
unity.  When  they  are  given  meat,  the  ratio  is  less  and  varies  between 
0.02  and  0.80.  TJ^>on  a  diet  of  legumes  the  ratio  is  between  that  found 
after  giving  meat  and  that  after  giving  bread. 

0.  This  ratio  is  nearly  constant  in  animals  of  the  same  race,  such  as 
dogs  when  they  are  given  the  same  diet. 


42  GKAIIAM    LUSK 

7.  Fasting  animals  show  about  the  .same  ratio  (R.  Q.)  as  they  do 
when  fed  with  lueat,  though  usually  a  little  less  than  under  latter  con- 
ditions. Durin**:  inanition  fastina:  animals  live  off  their  own  flesh,  which 
is  of  the  same  nature  as  the  flesh  whicli  they  eat.  All  fasting  animals 
present  the  picture  of  carnivora. 

8.  The  fact  that  the  relation  betweei)  the  volumes  of  oxygon  absorbed 
and  carbonic  acid  exhaled  varies  between  0.02  and  1.04  according  to  the 
kind  of  food  whicli  the  animal  takes  in,  destroys  the  validity  of  the 
hypothesis  of  IJrimner  and  Valentin  (1840),  attributing  the  respiration 
to  the  simple  ditfiision  of  gases  through  membranes  according  to  the  laws 
of  Grahaiii  (which  calls  for  a  constant  ratio  of  0.85).  Tu  the  text  they 
describe  how  they  placed  the  bodies  of  animals  (fowls,  dogs,  i-abbits)  in 
an  impermeable  robber  sack  and  found  in  mammals,  as  well  as  in  birds, 
that  the  total  quantity  of  carbon  dioxid  eliminated  from  the  skin  and 
intestine  of  these  animals  was  practically  negligible,  rarely  exceeding  two 
per  cent  of  that  found  in  the  pulmonary  respiration. 

9.  Lavoisier  tiried  to  prove  that  the  heat  of  the  body  came  from  the 
oxidation  of  cailjon  and  hydrogen.  RegTiault  and  Ileiset  do  not  doubt 
that  the  heat  is  in  fact  derived  entirely  from  chemical  reactions  in  the 
body.  But  they  tMnk  the  reactions  are  too  complex  to  be  compiled  on  the 
basis  of  the  oxygen  intake.  ^'The  substances  which  are  oxidized  are 
composed  of  earlKWi,  nitrogen,  hydrogen,  and  often  contain  a  considerable 
amount  of  oxygen.  Though  they  be  completely  oxidized  in  the  lespiration 
process,  their  own  c^xygen  content  contributes  to  the  production  of  water 
and  carbonic  acid,  and  the  heat  which  is  liberated  is  necessarily  different 
from  that  whieli  would  have  been  evolved  by  the  oxidation  of  carbon  and 
hydrogen  supposedly  liberated.  ^Moreover,  the  food  substances  are  not 
completely  destvoyed,  for  portions  are  converted  into  other  materials 
which  play  a  special  part  in  the  body's  economy  and  portions  are  trans- 
formed into  urea  and  uric  acid.  In  all  the  transformation  and  assimilative 
processes  which  tla'se  substances  undergo  in  the  organism  there  is  either 
liberation  or  absorption  of  lieat ;  but  the  proi'esses  are  evidently  so  complex 
that  it  is  very  \inlikely  that  one  will  ever  be  able  to  calculate  them.'' 

(They  found  in  fowls  that  the  volume  of  carbon  dioxid  was  often 
greater  than  the  volume  of  oxygen,  which  rendered  the  proposition  of 
estimating  the  heat  production  from  the  oxygen  impossible.) 

10.  The  quantity  of  oxygen  varies  during  different  periods  of  diges- 
tion bec*auso  of  muscle  work,  and  numerous  other  circumstances.  In  ani- 
mals of  the  same  species  and  the  same  weight  the  quantity  of  oxygen  is 
larger  in  young  individuals  than  in  adults.  It  is  greater  in  healthy,  thin 
animals  than  in  fat  ones. 

11.  The  consiuiiption  of  oxygen  absorbed  varies  greatly  in  different 
animals  per  unit  of  body  weight.  It  is  ten  times  greater  in  sparrows  than 
in  chickens.     Since  the  diffei'cnt  species  have  the  same  body  temperature 


A  HISTORY  OF  METABOLISM  43 

aiul  the  smaller  animals  present  a  relatively  larger  area  to  the  environ- 
mental air.  they  experience  a  substantial  cooling  effect,  and  it  becomes 
necessary  that  the  sources  of  heat  production  operate  more  energetically 
and  that  the  respiration  increases. 

11.  Awakening  marmots  consume  oxygen  in  very  largely  increased 
quantity. 

1 7.  Reptiles  consume  much  less  oxygen  per  unit  of  body  weight  than 
do  warm-blooded  animals,  but  do  not  differ  from  them  in  the  relative 
quantities  of  oxygen  and  carbon  dioxid. 

18.  Frogs  without  lungs  respire  just  as  well  as  frogs  with  lungs. 

19.  Frogs  and  earthworms  show  nearly  the  same  metabolism  per 
kilogi'am  of  body  substances. 

20.  The  respiration  of  insects,  such  as  beetles  and  silkworms,  is  very 
much  more  active  than  that  of  reptiles.  For  equal  body  weights  they 
consume  as  much  oxygen  as  mammals,  and  a  proportionately  large  amount 
of  nourishment.  We  are  comparing  insects  with  animals  two  to  ten 
thousand  times  heavier  than  they. 

A  thermometer  placed  in  the  midst  of  a  mass  of  active  beetles  inclosed 
in  a  sack  show^ed  a  temperature  of  two  degrees  higher  than  the  sur- 
rounding air. 

The  results  of  the  work  on  these  low^er  forms  of  life  may  be  tlius 
summarized: 


Temp. 


37  Beetles    .  .  . 

Weight 
gm. 
.     37. 

R.Q. 
0.82 

Oxygen  per 

kg.  per  hr. 

0.1)62 

18  Silkworms  . 

.     42.5 

0.79 

0.840 

25  Chrysalides.. 
—  Earthworms, 

21. 
.    112. 

0.64 
0.78 

0.240 
0.101 

2  Frogs     

.    127.5 

0.75 

0.105 

21.  Animals  of  different  species  respire  just  the  same  in  air  con- 
taining two  to  three  times  the  usual  quantity  of  oxygen,  and  do  not  per- 
ceive the  difference  in  oxygen  content.  (The  air  contained  72.6  per  cent 
of  oxygen.) 

22.  If  hydrogen  replaces  nitrogen  of  atmospheric  air  there  is  very 
little  difference  in  the  respiration  process.  (The  air  contained  77  per 
cent  of  hydrogen  and  21.0  per  cent  of  oxygen.) 

There  were  104  experiments  in  all. 

Reg-nault  and  Reiset  exemplify  their  natural  instincts  of  friendsliip 
and  courtesy  when  they  write  that  experiment  26,  in  which  they  varnished 
a  dog  with  gelatin,  was  done  at  the  suggestion  of  "cet  habile  physiologiste 
-^^agendie,"  and  that  M.  Bernard  **dont  Phabilite  est  hi  en  connue  de  tons 
les  physiologistes''  had  extirpated  the  limgs  of  the  frogs  about  half  an 
hour  before  placing  them  in  their  apparatus. 


44  GPixVIIA:M  LUSK 

In  the  closin*^  -words  of  tliis  masterpiece  the  authors  write: 

We  are  far  from  conckulini^  that  our  work  presents  a  complete  study  of 
respiration.  Wc  consider  ourselves  happy  if  we  have  established  the  principal 
facts  and  if  our  methods  are  useful  to  ijhy.riologisti>  who,  through  their  special 
learning,  may  he  able  to  extend  them. 

Tlie  animals  were  never  inconvenienced  in  any  wa}^  in  the  apparatus. 
Thouiih  sin^iile  animals  were  often  ii-cd  in  mafiy  exjK^riments,  there  was 
never  any  deleterious  effect  upon  their  liealtli. 

It  will  be  noticed  that  there  are  two  regrettable  omissions  in  our  work,  ex- 
periments on  the  respiration  of  fish  and  of  man.  We  have  not  made  experiments 
on  fish  because  we  knew  that  Valenciennes  was  doing  this.  Eegarding  the  res- 
piration of  man  it  was  our  intention  to  accomplish  this  in  a  special  research. 
We  proposed  to  study  not  only  healthy  men  under  various  conditions  of  diet 
and  at  rest  or  at  work,  but  also  patient^  affected  with  different  diseases  and  we 
hoped  to  associate  ourselves  in  this  important  work  with  one  of  the  skilled  physi- 
cians of  the  large  Paris  hospitals.  Unfortunately,  the  new  apparatus  which  was 
to  have  served  for  this  investigation,  on  account  of  the  special  conditions  it  had 
to  satisfy,  cost  more  money  than  we  had  at  our  disposal  and  we  had  to  renounce 
our  project. 

The  study  of  the  respiration  in  man  in  its  various  pathological  phases  ap- 
pears to  us  to  be  one  of  the  most  important  subjects  that  could  occupy  those 
who  follow  the  art  of  healing  the  sick;  it  can  give  a  precious  means  of  diagnosis 
in  a  grertt  number  of  diseases  and  render  more  evident  the  transformations 
which  take  place  in  the  organism.  .  .  .  Our  desires  will  be  fulfilled  if  our  work 
provokes  study  that  will  be  of  such  great  importance  to  humanity. 


The  Rise  of  German  Science 

^  Justus  von  Liebig  (1S03-1873). — It  has  already  been  stated  that 
Liebig  was  in  Paris  during  the  greatest  period  of  French  scientific  achieve- 
ment. Liebig  had  been  a  dunce  at  school  and  was  laughed  at  by  hig 
teacher^  when,  as  a  boy,  he  expressed  his  determination  to  become  a 
chemist.  Liebig  attended  the  university  of  Erlangen,  where  he  Avas  duly 
educated  in  the  spirit  of  the  phlogiston  hypothesis.  lie  heard  witli  im- 
patience the  lectures,  of  the  renowned  philosopher  Schelling,  and  fonnd 
no  satisfaction  until,  in  the  autimin  of  1822,  he  went  to  study  in  Paris 
(see  p.  3G).  Both  Liebig  and  Dumas  were  introduced  into  the  scientific 
circles  of  Paris  by  Alexander  von  Humboldt.  Liebig,  dedicating  a  French 
edition  of  one  of  his  books  to  Thenard,  a  former  master,  thus  expresses 
his  appreciation: 

"To  Monsieur  le  Baron  Thenard, 

Member  of  the  Academic  des  Sciences. 
Monsieur : 

"In  1823  when  you  presided  over  the  Academic  des  Sciences  a  young  foreign 
student  came  to  you  and  begged  you  to  advise  him  concerning  the  fulminates 
which  he  was  then  investigating. 


A  IITSTOIIY  OF  METABOLISM  45 

"Attracted  to  Paris  by  the  immense  reputation  of  those  celebrated  masters 
wliose  glorious  researches  established  the  foundations  of  the  sciences  and  elevated 
tliem  into  an  admirable  edifice,  he  had  no  other  introduction  to  you  except  his 
love  of  study  and  his  fixed  desire  to  profit  from  your  teachinjrs. 

''You  bestowed  on  him  a  most  encourasinjr  and  flattering  welcome,  you 
dirc^'ted  his  first  researches,  and  through  your  influence  he  had  the  honor  to 
communicate  them  to  the  Academie. 

"It  was  the  session  of  the  28th  of  July  which  decided  his  future  and  opened 
a  career  in  which  for  seventeen  years  he  has  labored  to  justify  your  benevolent 
patronage, 

"If  his  labors  have  been  useful,  it  is  to  you  that  science  is  indebted  for 
them,  and  he  feels  obliged  to  express  publicly  to  you  his  ineffaceable  sentiments 
of  gratitude,  esteem  and  veneration." 

Justus  Liebig. 
Giessen,  1  January,  1841. 

Through  the  influence  of  Alexander  von  Humboldt,  Liebig  was  ap- 
pointed professor  of  clieniistry  at  Giessen  in  1S24  at  the  age  of  twenty- 
one.  Wilhelni  Ostwald  writes  in  his  '^Grosse  Miinner''  that  this  gave 
him  free  water  to  swim  in.  Here  lie  built  the  first  nioilem  chemical  re- 
search laboratory  and  attracted  to  it  men,  many  of  whom  afterward  became 
distinguished.  J.iebig's  "Thierchemie  in  Ihrer  Anwendung  auf  Physiol- 
ogie  und  Pathologie''  was  first  published  in  1840  and  jxissed  through  nine 
editions.  Comparison  should  be  made  between  it  and  the  publications 
of  Boussingault  already  described. 

Liebig  divided  the  foodstuffs  into  protein,  fat  and  carbohydrate,  and 
stated  that  protein  could  take  the  place  of  body  protein,  while  carbo- 
hydrate and  fat  could  spare  body  fat.  He  believed  that  muscular  work 
caused  the  metabolism  of  protein,  while  oxygen  destroyed  fat  and  car- 
bohydrate. 

In  the  introduction  he  states  tbat  in  fifty  years  it  will  be  as  impossible 
to  separate  chemistry  from  physiology  as  it  was  then  to  separate  cbemistry 
from  physics ;  that  he  had  endeavored  to  bring  chemistry  and  physiology 
together  in  a  single  book. 

In  one  of  his  writings  Liebig  says  that  the  acceptance  of  principles, 
like  the  application  of  chemistry  to  physiology,  all  dei)eiids  on  the  mental 
development,  that  the  great  Leibnitz  refused  to  accept  Xewton's  doctrine 
of  gravitation,  which  is  now  understood  by  every  schoolboy. 

The  time  w^s  propitious  for  the  writing  of  Liebig's  book.  He  himself 
had  been  more  largely  the  creator  of  organic  chemistry  than  any  man  then 
living.  Chemical  compounds  of  carbon  were  becoming  known,  Sclieele 
had  discovered  uric  acid  and  lactic  acid  in  1776  and  glycerin  as  a  com- 
ponent of  fat  in  1778;  Fourcroy  and  Vauquelin  in  1779  and  Prout  in 
l>^i)?j  had  analyzed  urea;  Clievreul  announced  the  chemical  constitution  of 
fat  in  1S23  and  Thenard  investigated  the  composition  of  bile;  Berzelius, 
the  composition  of  the  secretions  in  general.     In  1828  Wohler  prepared 


46  GIfAIIAAE  LUSK 

urea  synthetically,  and  in  1837  Liebig  and  Wolilcr,  working  togctlier, 
described  the  dcconiixjsition  products  of  uric  acid. 

Carl  Voit,  writing  in  1865^  thus  describes  Liebig's  services: 

AH  these  chemical  discoveries,  to  which  Liebig  so  largely  contributed,  gave 
him  his  fruitful  conceptions  concerning  the  processes  in  the  animal  body.  Be- 
fore him  the  ob.^erviitions.  were  like  single  building-stones  without  interrelation, 
and  it  required  a  mind  like  his  to  bring  them  iulo  ordered  relation.  It  is  a 
service  which  the  physiologists  of  our  own  day  do  not  sufficiently  recognize.  In 
order  to  appreciate  tlii<  one  has  only  to  read  physiulogical  papers  written  before 
the  publication  of  his  books  and  afterward  in  order  to  witness  how  his  writing 
changed  the  mental  attitude  toward  the  processes  in  the  organism.  The  chemical 
discoveries  on  Avhich  he  based  his  conclusions  were,  in  fact,  matters  of  general 
knowledge,  but  it  was  he  who  applied  them  to  the  jjroctcsscs  of  living  things. 
Scientific  progress  is  determined  by  the  establishment  of  correct  interpretations 
and  the  creation  llierehy  of  new  pathways  and  problems.  A  school-boy  has  a 
better  knowledge  of  many  things  than  the  wisest  man  had  formerly;  and  he 
laughs  at  the  ignorance  of  his  forefathers  because  he  does  not  understand  the 
history  of  the  human  mind. 

The  m^m  of  science  ought  to  realize  the  factors  which  have  given  him  the 
vantage  which  he  holds.  But  there  are  textbooks  on  physiology  in  which  the 
chapters  on  the  animal  mechanism  do  not  even  mention  the  name  of  Liebig. 
This  anomaly  is  possible  only  for  those  who  do  not  understand  history,  and  who 
hold  onlj'  the  new  to  be  worthy  of  consideration.  Liebig  was  the  first  to  establish 
the  importance  of  chemical  transformations  in  the  body.  He  stated  that  the 
phenomena  of  motion  and  activity  which  we  call  life  arise  from  the  interaction 
of  oxygen,  food  and  the  components  of  the  body.  He  clearly  saw  the  relation 
between  metabolism  and  activity-  and  that  not  only  heat  but  all  movement  was 
derived  from  metabolism.  He  investigated  the  chemical  processes  of  life  and 
followed  them  step  by  step  to  their  excretion  products. 

The  following  quotations  from  Liebig's  (b)  ^^Thierchemie"  appear  to  be 
significant  cf  his  attitude  (Cambridge,  1842;  Braunschweig.  IS-lrG) : 

It  is  clear  that  the  number  of  heat  units  liberated  increases  or  decreases  with 
the  quantity  of  oxygen  giveii  to  the  body  in  a  given  time  through  the  respiratory 
process.  Animals  whi«.'h  respire  rapidly  and  are  therefore  able  to  absorb  a  great 
deal  of  oxygen  can  eliniinate  a  larger  number  of  heat  units  than  those  which 
have  the  same  volume  but  absorb  less  oxygen. 

Of  metabolism  in  fasting    -rewrites: 

The  first  action  of  hunger  is  a  disappearance  of  fat.  This  fat  is  present 
neither  in  the  scanty  feces  nor  in  the  urine,  its  carbon  and  hydrogen  must 
have  been  eliminated  through  the  lungs  in  the  form  of  oxygen-compouuds.  It 
is  clear  that  these  ''onstituents  are  related  to  the  respiration. 

Oxygen  enters  every  day  and  takes  away  a  part  of  the  body  of  the  fasting 
person  with  it. 

^[artell  found  that  a  fat  pig  lived  160  days  without  food  and  lost 
120  pounds. 


A  HISTOKY  OF  METABOLISM  47 

In  herbivora  tun  volumes  of  oxygen  absorbed  result  in  nine  volumes' 
of  carbon  clioxid  eliniinate<l.  In  carnivora  only  six  or  five  volumes  carbon 
(Uoxid  are  eliminated  (l)nlong'  and  Despretz). 

With  the  exception  of  a  small  amount  of  sulphur,  hydrogen  is  the  only 
other  combustible  substance  with  which  oxygen  could  combine  and  it  can  be 
regarded  as  settled  that,  whereas  in  the  body  of  an  herbivorous  animal  one- 
tenth  of  the  oxygen  is  used  to  form  water,  in  the  body  of  the  carnivorous  animal 
four  or  five  times  that  quantity  are  so  employed. 

In  the  exact  analysis  of  the  process  of  respiration  it  is  evident  that  the 
rbou  dioxid  production  is  related  to  water  formation  and  the  two  cannot  be 
dissociated.  It  is  therefore  self-evident  that  the  determination  of  the.  quantity 
of  carbon  dioxid  expired  by  an  animal  within  a  given  time  is  not  a  measure 
of  tlie  respiratory  process  and  that  all  experiments  in  whicli  the  relation  of  the 
food  to  the  total  oxygen  intake  is  not  considered  have  only  a  relative  value. 

In  starvation  it  is  not  alone  fat  which  disappears  but  also  all  solids  wliich 
are  capable  of  solution.  In  the  completely  wasted  body  of  the  fasting  man  the 
muscles  become  thin  and  soft,  lose  their  contractility;  all  parts  of  the  body  which 
were  capable  of  producing  movement  have  served  to  protect  the  rest  of  the  organs 
of  tlie  body  from  the  destroying  influence  of  the  atmosphere.  Finally  the  par- 
ticles of  the  brain  become  involved  in  the  oxidation  process,  delirium,  madness 
and  death  follow;  resistance  completely  ceases,  chemical  putrefaction  ensues, 
and  all  parts  of  the  body  unite  with  the  oxygen  of  the  air. 

Liebig  speaks  of  the  cleavage  of  sugar  into  lactic  acid,  into  alcoliol 
and  carbonic  acid,  and  later  into  but;yTic  acid,  hydrogen  and  carbonic  acid. 
He  then  remarks: 

Xo  one  will  deny  that  such  influences  are  at  work  not  only  in  the  respiratory 
I>rocess  but  also  have  a  part  in  the  processes  which  take  place  iii  the  animal  body, 
and  if  further  investigations  demonstrate  that  the  cause  of  the  decomposition 
of  sugar  into  alcohol  and  carbonic  acid  in  alcoholic  fermentation  is  dependent 
'•n  the  development  of  a  lower  order  of  vegetation,  and  that  the  metabolism 
of  complex  molecules  with  the  production  of  new  substances  can  be  caused  by 
•  Miitact  with  certain  particles  which  are  in  the  state  of  vital  movement,  it  is 
rl*  ar  that  a  pathway  has  been  constructed  which  leads  to  a  vision  of  the  mysteri- 
'•u>  processes  of  nutrition  and  secretion. 

As  to  tbe  energy  production,  he  says : 

The  lack  of  a  correct  viewTpoint  regarding  energy  and  activity  and  their 
rtlation  to  natural  phenomena,  has  led  people  to  ascribe  the  production  of  animal 
h»  at  to  the  nervous  system.  If  one  excludes  tha  metabolism  within  the  active 
nenes.  the  above  proposition  would  be  merely  s  j^ing  that  movement  would  arise 
i'roni  nothing.    But  out  of  nothing  no  power  or  activity  can  arise. 

Liebig  asks: 

What  is  the  use  of  fat,  butter,  milk-sugar,  starch,  cane-sugar  in  the  diet? 
Through  these  non-nitrogenous  food-stuffs  a  certain  amount  of  carbon  and  in 
^}m'  case  of  butter  a  certain  amount  of  carbon  and  hydrogen  are  added  to  the 
Jiitrogen-containing  materials  and  form  an  excess  of  elementary  substances  which 
••aiinot  be  used  to  generate  nitrogen-  and  sulphur-containing  substances,  which 
latter  are  contaiiKxl  preformed  in  the  food.    Hardly  a  doubt  can  be  entertained 


48  GRAHAM  LUSK 

that  this  excess  of  carbon  or  of  carbon  and  hydrogen  is  expended  in  the  pro- 
duction of  animal  b(^at  and  serves  to  protect  tlio  orp:nnisni  fr-tjn  hcing  attiickcd 
by  atmospheric  oxyg,en. 

Fiirthei-  on  he  remarks: 

In  their  final  forms  meat  and  blood  which  are  consumed  yield  the  greater 
part  of  their  carbon  to  tlic  respiration,  their  nitrogen  is  recovered  as  urea,  and 
their  sulphur  as  sidphuric  acid.  Before  this  occurs  the  dead  meat  and  blood 
must  be  converted  into  living  flesh  and  blood.  The  food  of  carnivora  is  con- 
verted into  blood  which  is  destined  for  the  reproduction  of  organized  tissue. 

We  know  that  the  nitrogen-containing  products  of  metabolism  are  not  sus- 
ceptible of  further  change  and  are  eliminated  from  the  blood  by  the  kidney. 

Differences  in  the  quantity  of  urea  secreted  in  these  and  similar  experiments 
are  explained  by  the  condition  of  the  animal  in  regard  to  the  amount  of  the 
natural  movement  permitted.  Every  movement  increases  the  amount  of  organ- 
ized tissue  which  undergoes  metamorphosis.  Thus,  after  a  walk,  the  secretion 
of  urine  in  man  is  invariably  increased. 

In  the  animal  body  the  comi)onents  of  fat  are  used  for  the  respiration 
process  and  hence  for  the  production  of  animal  heat. 

If  the  condition  and  the  weight  of  all  parts  of  a  carnivorous  animal  are 
to  be  maintained  it  must  daily  receive  a  certain  definite  measure  of  sulphur  and 
nitrogen-containing  food  substances  as  well  as  of  fat. 

The  difficulties  of  calculating  the  metabolism  are  discussed. 

The  weight  of  the  ingested  materials  must  be  the  same  as  those  eliminated 
in  the  forms  of  uric  acid,  urea,  carbonic  acid  and  water.  The  weight  of  the 
ingested  fat  must  be  the  equivalent  of  the  fat  eliminated  in  the  form  of  carbonic 
acid  and  water.  From  this  it  follows  that  the  quantity  of  oxygen  absorbed 
cannot  be  a  measure  of  the  amount  of  the  living  substance  destroyed  in  a  given 
time. 

The  oxygen  absoi-ption  expresses  the  sum  of  two  factors;  one  the  destruction 
of  nitrogen-free  substances  and  the  other  the  destruction  of  nitrogen-containing 
substances.  It  has  already  been  frequently  stated  that  the  measure  of  the  latter 
can  be  determined  from  the  nitrogen  content  of  the  urine. 

He  later  consider^  die  metabolism  of  a  horse:  "A  horse  preserves 
itself  in  a  state  of  healrii  if  he  be  given  Ti/^  kg.  hay  and  2(^4  kg.  oats. 
Hay  contains  1.5  per  cent  and  oats  2.2  per  cent  of  nitrogen.  Assuming 
that  all  the  protein  in  the  food  is  transformed  into  the  lil)rin  and  seriini 
albumin  of  the  blood,  there  would  be  produced  daily  4  kg,  of  blood,  con- 
taining 20  per  cent  of  water  and  140  gin.  of  nitrogen.  The  quantity  of 
carbon  combined  with  tlie  protein  and  ingested  at  the  same  time  would 
have  been  448  gm.  Of  this  only  24G  gin.  could  have  served  for  the  respira- 
tion, for  05  gm.  are  eliminated  in  the  form  of  urea  and  109  gm.  in  the 
forai  of  hippuric  acid.  .  .  .  The  experiment  of  Boussingault  which  shows 
that  a  horse  expires  2450  gm.  of  carbon  in  a  day  cannot  be  very  far 
from  the  truth.'* 

The  nitrogen-containing  substances  of  the  fodder  of  the  horse  do  not  con- 
tain more  than  one-fifth  of  the  carbon  necessary  for  the  nuiintenance  of  the 


A  HISTORY  OF  :^i:E:TABOLIS^r  49 

respiration,  and  wc  see  that  the  wisdom  of  the  Creator  has  added  to  all  the 
foods  tho  remainder  of  the  carbon  in  tlie  form  of  sugar,  starch,  etc.,  which  is 
necessary  for  the  renewal  and  maintenance  of  animal  heat  and  for  the  conversion 
of  inspired  oxygen  into  carbonic  acid.  If  these  substances  had  not  been  present 
in  the  food  and  th(M'e  had  been  the  same  intake  of  oxygen,  then  the  materials 
of  the  animal's  own  body  would  have  been  used  instead. 

J.iebi«i:  says  that  only  a  small  fraction  of  the  bile  is  unabsort)cd  and 
cannot  contribute  ji^reatly  to  the  formation  of  tlie  feces. 
As  to  tho  formation  of  fat,  Liebig  argues  as  follows: 

A  spider,  fierce  with  hunger,  sucks  the  blood  of  the  first  fly,  but  is  not  to 
be  disturbed  by  a  second  or  third  fly.  A  cat  eats  the  first  and  perhaps  a  second 
mouse,  and  will  kill  but  not  eat  a  third.  Lions  and  tigers  react  the  same  way, 
driven  by  hunger  to  devour  their  prey. 

IIow  different  with  a  sheep  and  a  cow  in  the  pasture,  which  eat  almost 
without  intermission  as  long  as  the  sun  in  the  heavens  shines  upon  them. 

The  herbivorous  animals  eat  in  such  excess  that  the  ingestion  of  starch  is 
greater  than  is  necessary  for  union  with  oxygen,  and  hence  the  animals  fatten 
through  conversion  of  starch  into  fat. 

Concerning  alcohol,  he  makes  the  following  comments:  "Alcohol  is 
oxidized  in  the  body,  the  carbon  dioxid  elimination  decreases  after  alcohol 
(Vierordt)  because  relatively  more  oxygen  unites  with  hydrogen." 

Liebig  has  been  informed  that  in  England  all  servants  are  given  beer, 
or  where  the  Temperance  Society  is  influential  the  money  equivalent  of 
beer.  Under  the  latter  conditions  more  bread  is  eaten,  so  that  the  beer 
is  paid  for  twice,  once  in  money  and  once  in  extra  food  containing  the 
?amo  carbon  and  hydrogen  equivalents  as  the  beer. 

Liebig  enters  into  the  calculation  of  the  oxidation  of  various  foods 
in  the  body  and  gives  the  following  values  (p.  lOG)  : 

100  Liters  of  O^  And  they  warm  liters  of 

combine  with  water  from  0°  to  37° 

120.2  gm.  starch  28.356 


48.8  iiin.  fat  27.04 


Liebig  also  calculates  the  caloric  value  of  meat.  lie  prepares  a  table 
•  >f  isodynamic  equivalents  which  are  given  below,  contrasted  with  the 
\alu('s  given  by  Rubner  (r/)  later  in  1S85  (p.  75). 

Liebig  writes: 

Since  the  capacity  of  these  substances  (the  respiratory  materials)  to  develop 
luat  through  union  with  oxygen  is  dependent  on  the  amount  of  combustible 
t'loiuents  which  equal  weights  contain,  and  since  the  amount  of  oxygen  neces- 
sary for  their  combustion  increases  in  the  same  proportion,  therefore  it  is  pos- 
>il>le  to  calculate  approximately  their  relative  heat  producing  power  or  respira- 
tory value.  The  following  table  contains  the  respiratory  materials  arranged  in 
'•no  possible  order.  The  figures  express  the  relative  amount  of  each  substance 
uhich  a  given  amount  of  oxygen  would  convert  into  carbonic  acid  and  water  or 


50  GILVIIAM  LirSK 

approximately  how  inuch  one  must  eat  in  order  to  maintain  the  body  tempera- 
ture at  a  given  lev(;l  of  metabolism  during  a  given  time: 

Table  of  Isodijmimic  Values 

Liebig  Eiibner 

in  1846  in  1885 

Fat     .300  100 

Starch 242  232 

Cane-sugar     .....* 249  234 

Dried  meat    300  243 

This,  surely,  i$  a  divination  of  Itiibner's  su])scquc'ntly  enunciated  isodj- 
namic  law. 

As  regards  the  oxygen  requirement  for  the  combustion  of  different 
foods,  comparisons  may  be  made  between  the  findings  of  Liebig  in  1846 
and  those  of  Loewy  in  1011: 

To  oxidize     .  requires  Oo  m  c.c. 

I^iebig  Loewy 

Fat,  1  gm .T~2050  2019 

Starch,  1  gm 832  828 

It  is  evident  that  Liebig  clearly  understood  that  it  was  protein,  car- 
bohydrate and  fat  which  were  oxidized  in  the  body  and  thai  they  were 
the  source  of  energ;^'  and  not  carbon  and  hydrogen  supposed  to  be  pro- 
duced from  them, 

Liebig  divides  the  foodstuffs  of  man  into  two  classes,  the  nitrogenous 
and  the  non-nitrogenous.  The  first  class  can  be  converted  into  blood;  the 
other  cannot  be.  The  constituents  of  organs  of  the  body  are  built  up 
from  those  foods  which  are  conveitible  into  blood.  In  the  state  of  normal 
health  the  other  foodstuffs  are  used  merely  for  maintaining  the  respira- 
tion process.  He  calls  the  nitrogen-containing  foods  the  plastic  food- 
stuffs and  the  non-nitrogenous,  the  respiratory  foodstuffs.  They  are  as 
follows : 

Plastic  Foods  Bespindonj  Foods 

Plant  fibrin  Fat    . 

Vegetable  albumin  Starch 

Vegetable  casein  Gum 

Meat  and  blood  of  animals  Sugars 

Pectin 

Bassorin. 

Beer 

Wino 

Brandv 


A  HISTORY  OF  METABOLISM  61 

"It  is  a  fimdamental  fact,  so  far  without  a  contradictory  experiment, 
that  the  sulphur-  and  nitrogen-containing  constituents  of  plants  have  tlie 
same  cheinical  cumposition  as  the  principal  comj)onents  of  the  blood.  We 
know  of  no  nitrogen-containing  material  of  a  comjx>sition  different  from 
tihrin,  alhumin  and  casein  which  is  able  to  sustain  life. 

''The  animal  organism  is  certainly  able  to  construct  its  membranes  and 
cells,  nerves  and  brain,  the  organic  materials  of  ribs,  cartilages  and  bones 
nut  of  the  constituents  of  its  own  blood,  but  these  constituents  must  be 
already  constructed  in  proper  form  or  the  production  of  blood  and  life 
itself  is  brought  to  an  end. 

''Looking  at  the  matter  from  this  standpoint,  it  is  easily  understood 
wliv  gelatin  is  not  a  builder  of  blood  or  a  supjxjrter  of  life,  for  its  com- 
position is  different  from  that  of  the  fibrin  and  albumin,  of  the  blood." 

Concerning  the  ultimate  disposal  of  the  products  of  metabolism,  Liebig 
writes : 

The  kidneys,  skin  and  lungs  cannot  be  the  only  ways  tbrougli  which  products 
of  the  metabolism  are  eliminated  from  the  body.  The  intestinal  canal  functions 
also  as  an  organ  of  excretion  and  its  relation  to  the  respiration  process  must 
not  be  misunderstood. 

If  the  quantity  of  oxygen  absorbed  in  a  given  unit  of  time  is  that  which 
is  exactly  nece3sa:y  to  convert  the  products  of  metabolism  present  during  the 
same  period  into  carbonic  acid,  urea  and  water,  then  the  intestinal  canal  will 
contain  only  indigestible  substances. 

...  In  general  it  must  be  assumed  that  all  of  the  nitrogen-  and  sulphur- 
containing  constituents  of  the  food  of  man  are  completely  digestible,  are  brought 
into  solution  and  absorbed  into  the  circulating  blood,  for  a  property  belonging 
to  some  pa.rts.must  belong  to  all.  In  such  cases  it  is  undoubtedly  true  that  the 
discover^'  of  nitrogen-containing  materials  in  the  feces  signifies  that  they  can 
•  •nly  be  the  products  of  the  metabolism  of  the  intestinal  canal  itself  or  products 
which  have  escaped  normal  metabolism  and  have  been  excreted  from  the  blood 
by  the  intestinal  wall. 

Just  before  the  publication  of  Liebig's  gi-eat  work  Dumas,  in  glowing 
language,  pictured  similar  interpretations  without  giving  Liebig  credit 
tV)r  the  ideas.  He  utilized  a  formula  similar  to  tbat  given  by  Liebig 
without  stating  its  derivation.  Thus,  in  1842,  Dumas  and  Cahours  pre- 
M  iited  the  following  penetrating  conception:     • 

The  food  of  an  ordinary  nraintenance  ration  contains  16  to  21  gm.  nitrogen. 
This  nitrogen  is  almost  entirely  recoverable  in  the  urine  in  the  form  of  urea. 
Ignoring  the  intermediary^  phases,  protein  breaks  up  as  follows: 

^^sHg A^O,^  +  100  O  =  C,  ll,J^,,0,    urea 

^42  ^84  carbon  dioxid 

Hog       O25  water 


C,,-K,,-N,fi,,, 


llie  only  object  in  giving  this  formula  is  to  enable  one  to  calculate  the  heat  of 
c«.>iiihustion  of  protein.    Allowing  for  the  daily  production  of  urea  from  protein, 


52  GRAHAM  LUSK 

there  would  remain  50  gin.  of  carbon  and  6  gm.  of  hydrogen  suitable  for  oxida- 
tion; this  would  yield  575  calorics.  Since  calculations  based  on  the  carbonic 
acid  elimination  and  oxygen  absorption  show  that  a  man  produces  between  2,500 
and  3,000  calories  daily,  it  follows  that  he  needs  an  additional  200  gin.  of  carbon 
and  10  gm.  of  hydrogen  to  complete  the  required  quantity  of  heat. 

The  writings  of  Dumas  brought  Liehig  (h)  to  the  defense  of  his  priority 
in  an  article  entitled,  '^Antwort  anf  llerrn  Dumas'  Eechtfertiginig  wegen 
eines  Plagiati*/'  published  in  1842.  He  recited  "how,  in  the  winter  of 
184CM1,  he  Lad  lectured  to  his  students  upon:  (1)  the  respiration  process 
in  its  relation  to  the  bile,  (2)  the  nitrogen-containing  substances  of  the 
vegetable  kingdom  are  identical  with  those  of  the  blood;  and  (3)  sugar 
and  starch  are  not  food  materials  but  serve  for  respiration  and  for  fat 
production.  A  young  Swiss  student  of  Geneva  came  to  Liobig  with  a 
letter  from  Dumas,  attended  the  lectures,  and  afterward  carried  the  in- 
formation to  Dumas  in  Paris.  With  volume  41  of  Liebitr's  Annalen  the 
name  of  Dumas  as  collaborator  disapj)ears  from  the  front  page.  Berzclius 
sided  with  Dumas  in  this  historic  controversy^  greatly  increasing  the  bit- 
terness of  Liebig.  The  feeling  between  the  two  men,  however,  must  have 
died  down,  for  in  a  dedication  to  Dumas  of  his  "^ouvelles  lettres  sur 
la  chimie,"  dated  Giessen,  1851,  Liebig  speaks  in  the  most  flattering  terms 
of  his  old  associate  and  brilliant  antagonist. 

Charges  of  plagiarism  are  contemporaneous  with  the  progress  of  hu- 
man thought.  Wlien  two  people  work  together  they  may  find  it  possible  to 
make  the  pleasing  statement  of  Bidder  and  Schmidt,  "As  the  result  of 
mutual  exchange  of  ideas  and  through  intellectual  metabolism,  we  find 
ourselves  in  entire  agreement.''  But  as  regards  the  controversies  regarding 
the  priority  of  discoveries,  such  as  grouped  themselves  around  the  person 
of  Lavoisier  and  the  person  of  Liebig,  no  such  self-abnegation  was  pos- 
sible. 

Wohler  writes  to  Liebig  regarding  another  matter  in  the  following 
words  (Moore,  1018)  : 

To  make  war  upon  Marchand  (or  any  one  else  for  that  matter)  is  of  no  use. 
You  merely  consume  yourself,  get  angry,  and  ruin  your  liver  and  your  nerves — 
finally  with  Morrison's  Pills.  Imagine  yourself  in  the  year  1900,  when  we  shall 
both  have  been  decomposed  again  into  carbonic  acid,  water  and  ammonia,  and 
the  lime  of  our  bones  belongs  perhaps  to  the  very  dog  who  then  dishonors  our 
grave.  Who  then  will  care  whether  we  lived  at  peace  or  in  strife?  Who  then 
will  know  anything  about  your  scientific  controversies — of  your  sacrifices  of 
health  and  peace  for  science?  No  one:  but  your  good  ideas,  the  new  facts  you 
have  discovered,  these,  purified  from  all  that  is  unessential,  will  be  known  and 
recognized  in  the  remotest  times.  But  how  do  I  come  to  counsel  llie  lion  to 
eat  sugar  1 

This  is  the  correct  interpretation  to  be  placed  upon  rights  of  priority. 
The  influence  of  an  individual  is  evidently  the  result  of  the  sum  total 
of  all  activities  of  his  life.     If  he  contributes  to  the  ideas  of  others,  the 


A  HTSTOPcY  OF  METABOLISM  53 

results  may  be  of  three  kinds:  (1)  the  donor  may  be  publicly  acknowl- 
edged; (2)  the  donor  may  be  honestly  forgotten  and  the  recipient  may 
honestly  believe  that  he  has  for  years  held  the  same  views;  or  (3)  the 
(h)nor  may  be  well  known  to  the  recipient  but  be  deliberately  and  sys- 
tematically ignored.  The  last-named  reaction  is  the  one  most  difficult  to 
k^ar  with  l)ecoming  humility  of  spirit,  but,  interpreted  in  the  light  of 
history,  it  signifies  but  little.  It  matters  little  to  the  world  at  large 
whether  Hacon  wrote  Shakespeare  or  Shakespeare  wrote  it  himself.  The 
heritage  of  the  masterpieces  is  what  matters. 

Before  Licbig's  deatli  he  wrote  to  Wohler  concerning  the  publication 
of  their  correspondence  as  follows:  "When  we  are  dead  and  gone  these 
letters  which  united  us  in  life  will  be  as  a  token  for  the  memory  of  man 
of  a  not  frequent  example  of  two  men  who,  without  jealousy  or  envy, 
strove  in  the  same  field  and  always  remained  intimatelv  united  in  friend- 
ship.^' 

-  Liebig's  Munich  Period. — In  1852,  at  the  age  of  forty-nine,  Liebig 
moved  to  ^[unich  to  become  professor  of  chemistry  there.  His  creative 
work  ceased  and  a  period  of  literary  activity  set  in.  He  engaged  in 
violent  polemics  with  Pasteur,  maintaining  that  alcoholic  fennentation 
was  a  purely  chemical  phenomenon  and  not  one  of  biological  origin.  He 
gave  popular  lectures  in  court  circles  and,  with  Rfchard  Wagner,  shared 
the  popular  adulation  of  the  town.  When  Liebig's  new  gluten  bread  was 
put  upon  the  market  the  townspeople  stood  in  long  lines  before  the 
bakeries  to  receive  the  precious  product. 

It  may  be  of  interest  to  pass  here  to  the  viewpoint  of  Liebig  ex- 
pressed in  1870  just  before  he  died.  In  the  interim  the  work  of  Bidder 
and  Schmidt,  of  Bisehoff  and  Voit,  of  Voit,  and  of  Pettenkofer  and  Voit, 
had  appeared,  material  which  is  still  to  be  recorded. 

Liebig  writes  as  follows :  "On  the  basis  of  general  experience  I  for- 
merly expressed  the  opinion  that  the  source  of  mechanical  work  of  the 
animal  body  nmst  be  sought  in  the  metabolism,  especially  in  the  metab- 
olism of  the  nitrogen-containing  constituents  of  muscle.  The  capacity 
for  work  in  two  individuals  would  therefore  depend  upon  their  respective 
mass  of  muscle  tissue,  and  the  endurance  of  each  would  depend  on  his 
capacity  to  rebuild  the  broken-down  muscle  substance  from  the  inflowing 
food  material. 

"It  is  well  knoA\Ti  that  hard-working  men  eat  much  meat.  An  em-* 
ployee  (Briiuknecht)  in  Seldmeyer's  large  beer  brewery  consumes  daily 
810  gm.  of  meat,  600  gm.  of  bread  and  8  liters  of  beer.  One  should  be 
cautious  in  adopting  the  jwpular  Bavarian  idea  that  it  is  the  beer  which 
gives  muscular  power,  for  the  beer  drinkers  are  also  the  gi'eatest  con- 
sumers of  meat. 

The  question  regarding  the  source  of  muscle  power  has  been  confused 
through  a  conclusion  which  has  been  shown  to  be  false  and  for  which  I  am  to 


54  GRAHAM  LUSK 

blame.  It  was  an  error  to  assume  that,  if  urea  were  an  end-product  of  the 
oxidative  metabolism  of  muscle,  then  one  could  measure  the  intensity  of  the 
work  done  by  the  quantity  of  urea  in  the  urine. 

The  first  facts  contradicting:  the  idea  that  urea  is  a  measure  of  muscular 
activity  were  communicated  by  BischotI  and  by  Jiischoff  and  Voit  of  Munich, 
which  researches  are  to  be  considered  as  the  extension  of  work  accomplished  in 
Giessen.  It  is  hardly  ueeessaiy  to  state  that  these  experiments  always  excited 
my  keenest  interest  because  tliey  were  effected  with  my  method  of  urea  determi- 
nation. .  .  . 

These  experiments  firmly  establish  the  fact  that,  although  urea  elimination 
is  a  measure  of  protein  ing^estion  and  metabolism,  it  is  not  a  measure  of  the 
work  done  by  the  body. 

When  one  thinks  these  matters  over  it  is  apparent  that  the  facts  could 
not  be  otherwise.  For  if  the  metabolism  of  the  muscle  increased  with  work  a 
man  could  exhaust  his  entire  supply  of  muscle  tissue^  because  work  is  directed 
by  the  will. 

He  criticizes  Frankland's  comparison  of  the  muscle  with  a  steam 
engine,  as  follows: 

It  is  certain  that  the  wonderful  structure  of  the  animal  body  and  of  its 
parts  will  long  and  perhaps  forever  remain  an  insoluble  riddle.  But  the  proces- 
ses within  the  organs  are  of  chemical  anc^  physical  nature,  and  it  is  incompre- 
hensible that  oxygen  and  combustible  materials  are  under  the  control  of  nerves 
to  induce  their  union.  The  factor  of  voluntary  nerves  upon  muscle  activity 
must  be  of  a  different  order.  .  .  . 

X  consider  that  those  investigators  who  have  busied  themselves  with  the 
question  of  the  source  of  muscular  power  have  thought  its  solution  too  simple 
and  that  it  will  be  many  years  before  a  proper  viewT)oint  leads  to  clarity  in  the 
solution  of  this  subject.    I  have  no  desire  to  enter  into  the  dispute. 

Liebig  discusses  the  activity  of  the  yeast  cell  as  follows: 

A  close  consideration  of  the  behavior  of  the  yeast  cell  may  be  desirable  in 
order  to  give  a  more  definite  idea  of  what  transpires  in  living  muscle. 

It  is  certain  that  motions  occur  within  the  yeast  cell  through  which  it  is 
enabled  to  accomplish  external  work.  This  work  consists  in  the  cleavage  of 
carbohydrates  and  similar  substances.  This  is  chemical  work;  it  would  be 
mechanical  work  if  the  yeast  were  able  to  split  wood,  which  is  likewise  carbo- 
hydrate. 

One  part  of  yeast  can  destroy  sixty  parts  of  its  weight  in  sugar,  according 
to  Pasteur.  A  gram  of  yeast  can  produce  the  heat  equivalent  of  148,960  gram 
meters  of  work  without  the  intervention  of  oxygen. 

The  cause  of  all  these  activities  lies  in  the  motions  of  the  contents  of  the 
yeast  cells. 

In  similar  maimer  the  motions  of  life  are  present  in  muscle  cells,  without 
muscular  contraction  resulting.  When  the  movement  within  the  muscle  cells 
rises. above  a  certain  limit,  muscular  contraction  follows. 

Liebig  enters  into  a  defense  of  the  use  of  Liebig's  extract  of  meat. 
At  one  time  he  had  regarded  it,  when  mixed  with  potatoes,  as  the  equiva- 
lent of  meat.     He  quotes  Hippocrates: 


A  HISTORY  OF  METABOLISM  65 

"Soup  and  pap  were  discovered  because  experience  has  taught  mankind  that 
fio'l^  which  are  good  for  healthy  people  are  not  good  for  the  sick." 

One  need  only  compare  the  capacity  for  work  of  the  German  Avorkman,  who 
live?  on  bread  and  potatoes,  v/ith  the  English  or  American  workman,  who  eats 
meat,  in  order  to  gain  a  clear  insight  into  the  importance  of  the  kind  of  food 
taken.  The  partaking  of  meat  raises  the  capacity,  the  power  and  the  endurance 
fr.r  work.  Or  compare  an  English  statesman  who  may  speak  for  five  hours  or 
nK're  in  a  Parliamentary  debate,  and  who  in  the  full  possession  of  youth  may 
■i'^iii  engage  in  a  strenuous  hunt  at  the  agc»  of  sixty,  with  a  German  professor 
oi  the  same  age  who  sparingly  conserves  the  rest  of  his  physical  powers  and 
v.h:-  is  exhausted  by  a  walk  of  a  few  hours. 

Liebig  cannot  understand  the  modern  expressions,  "organized  protein" 
ah' I  "circulating  protein";  they  confuse  him  to  such  a  degree  that  he 
oannut  tell  his  right  hand  from  his  left. 

It  is  right  to  investigate  a  single  phase  in  order  to  comprehend  the  existence 
and  activity  of  a  whole  process,  but  in  order  to  interpret  correctly  the  results  of 
investigations  one  must  have  a  clear  picture  of  the  manifold  phenomena  and 
the  limitations  affecting  the  entire  problem. 

I  have  a  general  knowledge  (Icb  w^eiss  so  xiomlich)  of  how  to  estimate  the 
importance  of  experiments  and  facts,  and  of  their  inequality  as  far  as  draw- 
ing' conclusions  is  concerned.  The  simple  observation  of  a  natural  phenomenon 
arranged  without  our  assistance  is  more  important  and  often  much  more  diffi- 
cult than  the  phenomena  obsen'cd  in  an  experiment  produced  by  our  will.  In 
the  first  reality  is  mirrored,  while  an  experiment  represents  the  imperfection  of 
our  understanding. 

I  remember  that  many  years  ago  during  a  walk  between  Berchtesgaden 
and  the  Konigssee,  a  very  simple  observation  led  me  to  the  conclusion  of  the 
source  of  carbon  in  plants.  At  that  time  there  was  great  confusion  in  the 
subject,  and  it  was  difficult  to  exclude  humus  from  consideration  as  a  factor. 
But  on  this  walk  Nature  gave  the  proof  that  the  carbon  of  the  plant  could  arise 
only  from  carbonic  acid.  For  one  finds  rocks  there  which  had  been  dislodged 
and  had  fallen  from  the  higher  mountain  side,  aiid  trees  thirty  or  forty  feet 
high  grow  on  the  rocks,  sending  their  roots  between  the  crevices  while  the 
rocks  are  covered  only  with  moss  and  a  layer  of  dust.  It  was  impossible  to  con- 
ceive that  humus  could  have  conveyed  carbon  to  vegetation  of  this  sort. 

Similar  observations  can  be  made  in  the  laws  of  nutrition  if  one  has  but 
the  good-will  to  see  them. 

It  appears  to  me  to  be  almost  unthinkable  that  the  high  value  placed  by 
the  French  family  upon  their  "Pot-au-feu'"  is  merely  based  on  custom;  or  that 
OTie  of  the  greatest  military  physicians  of  the  French  army.  Dr.  Baudens  (Bau- 
deiis,  1S5T)  would  dare  to  say  "La  soupe  fsiit  le  soldat"  unless  he  was  absolutely 
C'-.nvinced  of  the  high  potency  of  meat  soup  coutaining  the  necessary  vegetables 
which  the  French  soldier  often  prefers  to  meat. 

Licbig  laments  the  criticism  of  his  extract  of  beef  and  quotes  Goethe, 
"The  word  of  a  wise  man  teaches  me  that  if  a  person  once  does  a  thing 
wljioh  is  good  for  the  world,  the  world  takes  pains  to  see  that  that  person 
«l"f  s  nnt  do  it  a  second  time." 

One  may  annotate  Liebig's  opinion  of  Voit's  "circulating  protein" 
and  •'organized  protein"  by  citing  a  letter  which  Liebig  wrote  to  Wohler 


56  GRAHAM  LUSK 

in  1870,  ill  which  he  says  that  he  is  considering  giving  up  his  lectures 
during  the  summer  semester  upon  the  subject  of  animal  chemistry  and 
nutrition  and  continues,  ^'I  find  so  little  to  interest  me  in  what  others 
are  doing  in  this  subject  I  lose  all  desire  to  take  part  in  it.  They  per- 
form nothing  hut  small  expeiiments  which  lead  to  nothing.  ^AFodern 
phy-;iologists  lack  a  great   idea  upon   which  all   investigations  depend." 

Wilhelm  Ostwald  comments  that  this  i-;  tjie  usual  experience  of  parents 
with  their  children,  and  is  the  greater  the  more  capable  and  important 
the  children  become. 

It  may  be  of  interest  in  this  connection  that  I  heard  Voit  tell  my 
father  in  1801  that  there  were  no  young,  promising  physiologists  of  about 
forty  in  Germany  at  that  date,  a  generalization  which  would  have  in- 
cluded Kubner  (born  1854),  Kossel  (born  1853)  and  Ilofmeister  (born 
1850). 

The  happy  ideas  obtained  as  the  result  of  Liebig's  walk  between 
Berchtesgaden  and  the  Konigssee  recalls  the  statement  made  by  Ilelm- 
holtz  at  a  festival  given  in  honor  of  his  seventieth  birthday,  in  which 
he  told  that  he  had  never  had  a  great  thought  come  to  him  at  his  desk 
nor  when  he  was  tired  nor  after  taking  a  glass  of  wine,  but  usually  wdien 
he  was  walking  in  the  garden  thinking  of  other  things. 

All  the  quotations  of  Liebig's  later  views  are  from  writings  pub- 
lished in  the  year  of  the  Franco-Prussian  War  of  1870.  In  his  ''Thier- 
chem.ie"  of  1840  and  in  several  other  of  his  publications  at  that  period 
occur  the  following  memorable  words :  "Culture  is  the  ecoTiomy  of  power, 
the  sciences  teach  how  to  produce  the  greatest  results  by  the  simplest 
means  with  the  least  expendituie  of  energy.  Every  unnecessary  use  of 
energy,  every  waste  of  power  in  agriculture,  industry,  science,  or  in  state- 
craft is  characteristic  of  crudeness  or  lack  of  culture." 

Concerning  the  results  of  the  ccnfliet  of  1870,  Liebig  moralized  as 
follows:  "It  was  a  battle  between  knowledge  and  science  on  one  side 
and  empiricism  and  routine  on  the  other,  in  which,  as  in  agriculture, 
knowledge  won." 

Hear  this  realizing  cry  of  Pasteur  (Vallery-Iiadot,  1002)  which  fol- 
lowed the  defeat  of  France  in  1870  concerning  the  "forgetfulness,  dis- 
dain even,  that  France  had  had  for  gi'cat  intellectual  men,  especially  in 
the  realm  of  exact  science."  He  says,  "Whilst  Germany  was  multiplying 
her  universities,  establishing  between  them  the  most  salutary  emulation, 
bestowing  honors  and  consideration  on  the  masters  and  the  doctors,  cre- 
ating vast  laboratories  amply  supplied  with  the  most  perfect  instniments, 
France,  enervated  by  revolutions,  ever  vainly  seeking  the  best  form  of 
government,  was  giving  but  careless  attention  to  her  establishments  for 
higher   education. 

"The  cultivation  of  science  in  its  highest  expression  is  perhaps  even 
more  necessary  to  the  moral  condition  of  a  nation  than  to  its  material 
prosperity." 


A  HISTORY  OF  METABOLISM  57 

Xor  was  the  development  of  German  science  ignored  in  England,  for 
Matrhcw  Arnold  wrote  in  INOS:  ''Petty  towns  have  a  nniversity  \vhose 
Teaching  is  famous  throughout  Europe,  and  the  King  of  Prussia  and 
(oiijit  iiismarck  resist  the  loss  of  a  great  savant  from  Prussia  as  they 
w.  Ill  Id  resist  a  political  check. ^' 

I..t  us  not  forget  the  environmental  conditions  under  which  men  like 
Lif  l>ig  may  be  fostered  and  developed. 

Bidder,  P.  W.  (1810-1894)  and  Schmidt,  C.  (born  1822).— In  order 
to  rM.niplcte  the  story  of  Liehig's  life  this  history  has  been  diverted  from 
its  chronological  sequence,  and  it  is  now  necessary  to  tell  of  the  activity 
nf  the  period  essentially  coincident  with  the  date  of  the  publications  of 
iic^^uiudt  and  Itciset.  At  the  same  time  that  these  men  were  at  work 
ill  Paris,  Bidder  and  Schmidt  (a)  were  active  in  the  German  university 
ortahlished  at  Dorpat  in  Kussia.  In  1852  they  published  their  book, 
-Die  Verdauungssiifte  und  der  Stoffwechsel."  Voit  often  referred  to 
This  book  as  a  veritable  mine  of  information.  The  book,  However,  has 
nevev  been  as  well  known  as  it  should  be.  The  statement  still  found 
in  textbooks  on  physiology  that  the  influence  of  food  upon  the  bile  flow 
has  never  been  investigated  finds  its  refutation  in  this  volume,  published 
in  the  middle  of  the  last  century.  Here,  also,  one  finds  the  method  of 
computing  the  metabolism  used  by  those  who  employed  the  Pettenkofer- 
Voit  respiration  apparatus. 

Bidder  and  Schmidt  were  much  more  profoundly  influenced  by  the 
doctrines  of  Liebig  than  were  Regnault  and  Reiset.  Had  the  methods  of 
the  four  investigators  been  combined,  much  of  value  would  probably  have 
been  rapidly  uncovered.  But  Reiset's  publication  of  1868  on  the  metabol- 
ism of  farm  animals  shows  no  knowledge  of  the  publication  of  Bidder  and 
Schmidt.  To  promote  science  one  must  know  of  contemporaneous  activi- 
ties in  many  lands,  as  well  as  of  the  older  historical  happenings. 

C.  Schmidt,  who  had  been  a  pupil  of  Liebig  and  Wohler,  began  w^ork 
-ix  years  before  (1845)  the  completion  of  the  combined  work  of  Bidder 
;iT)d  Schmidt.  Schmidt  had  planned  an  experimental  critique  of  the 
iiif  rabolism  of  the  higher  vertebrates.  His  idea  was  to  study  in  a  few 
typical  forms  the  following  main  factors:  oxygen  absorption,  carbonic  acid 
mtd  urea  elimination  and  the  energy  statistics  of  fasting  animals,  ac- 
'  'inplished  upon  the  same  individual  under  identical  conditions.  Having 
;''Miimuh\ted  this  mass  of  observations  concerning  the  typical  intensity  of 
rlif  respiration  and  the  protein  consumption  on  the  more  prominent  types 
"f  vertebrates,  it  was  planned  to  investigate  in  similar  fashion  the  size 
of  the  intermediary  metabolism,  the  effect  of  external  temperature  and 
in*'  effect  of  partaking  of  protein,  fat  and  carbohydrate,  and  then  to 
iiMluce  the  sum  total  of  all  the  observations  to  a  systematic  whole. 

It  was  beyond  the  power  of  a  single  individual  to  accomplish  this 
I'lan.      A    preliminary   investigation   established    the   specificity   of   the 


58  GRAHA:\I  LUSIv 

cnzyineSy  that  yoi\st  can  act  only  on  sugar  and  produces  only  alcohol  and 
carhonic  acid,  eniulsin  acts  only  on  aniyg<hilin,  converting  it  into  hydro- 
cyanic acid,  henzyaldchyd  and  sugar;  th(^  same  principle  follows  as  re- 
gards the  digestive  enzymes.  The  determination  of  the  cluiracteristic 
metaholisni,  including  the  re^piratiuy  exchange,  the  analysis  of  nrine  and 
feces  and  record  of  the  body  temperature  upon  a  single  animal,  each  ob- 
servation continuing  over  several  weeks,  required  such  nnreuiilting  at- 
tention by  a  single  observer  that  even  one  provided  with  a  powerful 
constitution  fonnd  it  almost  beyond  his  power  of  accom})lis]nnent. 

Bidder,  who  had  become  inku-ested  in  the  lymph  flow  as  a  possible 
measure  of  the  intermediary  metabolism,  united  his  work  to  that  of 
Schmidt  and  they  decided  to  work  together.  Bidder  edited  the  pari 
about  the  digestive  juices  and  Schmidt  that  about  the  metabolism  and, 
"as  the  result  of  mutual  exchange  of  ideas  and  intellectual  metabolism,  wq 
are  in  entire  agi'ecment." 

The  intermediary  metabolism  is  practically  terra  incognita.  To  in- 
vestigate this  the  authors  seek  especially  to  determine  the  bile  excretion 
in  relation  to  the  total  ingesta  and  excreta  of  the  body. 

They  ask,  "Is  bile  an  excrement  or  not?^'  Schwann  first  described 
bile  fistulcW  In  at  least  six  of  his  dogs  the  cause  of  their  death  could 
have  been  attributed  only  to  the  removal  of  the  bile  (1S44). 

Blondlot  disputed  as  to  this  being  the  cause  of  death  (184G). 
They  note  that  the  bile  solids  eliminated  daily  constitute  a  three-hun- 
dredth part  of  the  solids  of  the  body  and  they  inquire  into  the  question, 
of  the  quantity  of  bile  reabsorbed  by  the  intestine,  as  follows:  "We  in- 
vestigated the  content  of  bile  in  the  feces  of  a  dog  weighing  8  kg.  during 
a  five-day  period.  In  order  to  obtain  exactly  the  quantity  of  feces  be- 
longing to  this  period  the  animal  was  given  only  meat  during  the  experi- 
mental jjeriod,  and  before  and  after  the  experiment  he  received  a  diet 
of  "Schwartzbrod,"  which  yields  an  extraordinarily  voluminous  feces, 
greatly  resembling  the  bread  itself  and  therefore  easily  recognizable.  The 
fecal  matei-ial  between  these  two  portions  nuist  have  been  derived  from 
the  meat  diet  or  from  the  residues  of  the  bile  excreted  into  the  intestine." 

The  feces  following  meat  ingestion  weighed  1)7.3  gm.  and  contained 
40.9  gm.  of  dry  solids.  "Since  this  fecal  matter  contained  only  traces  of 
bile  constituents,  and  since  the  quantity  of  bile  solids  flowing  into  the 
intestine  nrust  have  aggregated  30.52  g-m.  or  nearly  the  quantity  of  the 
entire  feces,  it  necessarily  follows  that  the  larger  part  of  the  bile  must 
have  been  reabsorbed.  Still  more  convincing  is  the  fact  that  39.5  gm.  of 
bile  solids  nmst  have  contained  2.37  gm.  of  sidphur,  whereas  the  entire 
sulphur  content  of  the  feces  was  only  0.3S4  gm.,  more  than  half  of  which 
must  have  been  derived  from  hair,  for,  excluding  the  hair  in  the  feces, 
only  0.154  gm.  of  sulphur  were  found.  Almost  all  the  biliary  sulphur 
must  have  been  absorl)ed  into  tlie  blood  and  we  are  therefore  convinced 


A  HISTOEY  OF  jAIETABOLISM  59 

that  the  larger  part,  perhaps  seven-eighths  of  the  biliary  solids  return  to 
tlie  blood  and  undergo  further  metabolic  transformations  before  they  are 
renioved  from  the  body  by  other  channels.'^ 

When  Bid<ler  and  Schmidt  operated  on  about  a  dozen  cats  by  the 
method  of  Schwann  they  all  died  of  peritonitis  in  two  or  three  days,  but 
in  d<\gs  only  two  of  eleven  died  of  peritonitis. 

Liebig  had  stated  that  the  bile  was  reabsorbed  and  was  used  as  a 
^'respiration  stuff.''  It  was  formed  in  the  body  and  then  later,  when  re- 
ahsorl)ed,  was  oxidized  to  carbon  dioxid,  being  an  example  of  the  steps 
in  the  metamorphosis  of  organic  substance  during  life.  To  what  an  extent 
dov!'  this  process  take  place? 

A  cat  excreted  i)M  gm.  bile  containing  0.033  gin.  solids  per  kilogram 
of  animal  in  the  third  hour  after  a  meal. 

There  was  no  increase  in  the  flow  of  the  bile  after  giving  fat.  The 
quantity  was  the  same  as  that  after  48  hours  fasting.  But  the  ingestion 
of  meat  increased  the  volume  of  the  flow  and  the  weight  of  the  solid 
constituents. 

In  dogs  with  bile  fistula,  the  secretion  of  the  bile  cannot  be  very  far 
from  normal  because  of  the  complete  digestion  of  the  foodstuffs,  of  the 
effect  of  these  upon  the  bile  flow  and  of  the  perfectly  normal  condition 
of  the  liver  and  its  vascular  supply. 

This  fate  of  the  bile  does  not  exclude  its  having  certain  functions, 
while  it  is  present  in  the  gastro-intestinal  tract.  They  can  confirm  the 
recent  work  of  Hoffmann  regarding  the  antiseptic  action  of  the  bile  on 
the  intestinal  contents.  For  they  observed  that  dogs  whose  bile  is  con- 
ducted away  through  a  fistula  pass  feces  which  have  an  extremely  foul, 
ahnost  carrion-like,  odor,  and  that  there  is  flatulence  induced  by  a  gas  of 
evil  odor.  However,  when  bread  alone  was  given  the  feces  and  fecal 
gas  had   no  odor.' 

.Much  more  important  is  the  question  whether  the  bile  has  a  digestive 
action  in  making  materials  more  fluid.  When  meat  is  given  to  dogs 
with  biliary  fistul^e,  it  is  perfectly  digested  and  absorbed  and  no  particles 
of  undigested  meat  can  be  microscopically  detected  in  the  dog's 
feces.  This  was  true  even  when  large  quantities  of  meat  were  given. 
However,  when  113.0  pin.  of  fat  were  ingested,  72.2  gm.  of  fat  substances 
;i[)peared  in  the  feces.  When  black  or  white  bread  was  given  no  starch 
iiianules  were  present  in  the  feces  and  the  dog  even  gained  weight.  But 
when  fat  was  given  there  was  very  poor  absorption ;  in  one  case  only  one- 
tenth  was  absorbed.  Hence  a  normal  dog  absorbs  much  more  fat  than 
une  with  a  bile  fistula. 

They  find,  also,  that  there  is  much  less  fat  in  the  chyle  of  the  thoracic 
duct  of  a  dog  which  had  been  provided  with  a  biliary  fistula  than  in  that 
<d'  a  normal  animal.  The  action  of  the  bile  is  evidently  upon  fat  or 
upon  the  absorbing  intestinal  surface. 


60  GRAIIAAI  J.USK 

Xeutral  fat  in  a  melted  state  penetrates  the  epitlielia  of  the  intestinal 
wall  provided  tlic  same  is  covered  with  bile  in  a  living-  aniiJial,  whereas 
it  is  impermeable  to  fat  when  it  is  not  covered  with  bile.  There  is  a 
g:i'eater  attraction  for  fat  in  the  former  case.  If  two  capillary  tubes  be 
taken  and  one  be  soaked  in  fresh  bile,  the  other  in  water  or  normal 
valine,  and  then  both  be-  dipjxnl  in  oil,  the  fat  will  rise  much  higher  in 
the  tube  dipped  in  bile  than  in  the  other  tube  (we  nioderns  would  call 
this  a  diminution  of  the  surface  tension). 

They  state  that  when  the  bile  is  drawn  off  through  a  biliary  fistula 
there  is  an  increased  intake  of  other  food  to  compensate  for  the  losses 
through  the  bile. 

Is  the  absorbed  bile  eliminated  through  the  kidneys  or  through  the 
lungs?  The  nitrogen  content  is  too  small  to  contril)ute  much  to  the 
nitrogen  content  of  the  urine,  and  hence  Liebig  concluded  that  bile  was 
a  respiratory  material  (material  fit  for  respiration),  yielding  carbon 
dioxid  and  water  as  end  products.  Certainly,  all  the  carbon  of  the  respi- 
ration does  not  have  to  pass  through  the  bile  prior  to  oxidation,  for  the 
total  bile  contains  only  0.5  gm.  of  carbon,  the  expired  air  8.6  gm.  of 
carbon  per  kilogram  of  body  weight  in  the  dog  in  twenty-four  hours. 
However,  the  0.035  gm.  of  nitrogen  eliminated  in  the  bile  per  kilogram  of 
body  w^eight  might  readily  be  that  quantity  which  was  liberated  as  free 
nitrogen  and  was  expired  in  the  respiration. 

Bidder  and  Schmidt  describe  what  is  now  known  as  "basal  metabol- 
ism," as  follows :  "For  every  species  of  animal  there  is  a  typical  minimum 
of  necessary  metabolism  which  is  apparent  in  experiments  when  no  food 
is  given  (im  niichternen  Zustande).  The  excess  over  and  above  this 
necessary  measure  of  typical  metabolism  can  be  termed  luxwij  con- 
sumption^ although  the  well-being  and  the  energy  of  all  the  functions  of 
life  are  considerably  increased  through  this  increased  activity  of 
metabolism." 

Bidder  and  Schmidt  now  attempt  the  first  computation  of  the  total 
metabolism,  as  calculated  from  the  respiratory  as  well  as  from  the  urinary 
and  fecal  pathways  of  elimination.  They  say,  "To  give  the  total  figures 
would  involve  too  much  printing."  The  following  was  an  experiment  of 
June,  1847,  accomplished  on  a  pregnant  dog. 

In  the  first  place  they  give  the  following  elementary  analysis  of  dry 
meat  free  from  ash: 

C     .   53.01  per  cent 
H         7.02 
N       16.11 
O       22.86 
S         1.00 


100.00 


I 


A  IITSTORY  OF  ILETABOLISM  61 

During  an  ciiilit-day  period  they  give  to  a  dog  1866.7  gm.  of  meat 
of  the  aliove-nieutioned  constitution,  tooether  with  27.4  gm.  of  fat.  In 
the  urine  and  feces  of  this  period  they  find  62.36  gm.  of  nitrogen,  which 
wouhl  cu-resp-nd  to  a  destruction  of  387.00  gm.  of  dry  flesh  or  169.5.5 
gui.  of  11  villi:'  Tissue  of  the  dog. 

'I'he  balance  would  therefore  read: 

Grams 

Fle.-h  .lestroyed     160.5.5 

Flesh   inuested    1866.7 

Flesh   retained    171.2 

Add  tat  retained 27.4 

Total  maximum  assimilation 108.6 

The  gain  in  body  weight  was  337  gm.,  the  excess  was  attributable  to 
water  retention. 

Xot  only  was  the  elementary  composition  of  the  iirine  and  feces  de- 
termined (as  in  the  method  of  Boussingault),  but  on  seven  different  occa- 
ifions  the  carl)on  dioxid  in  the  respiration  was  determined  in  periods 
lasting  one  hour  each.  After  this  fashion  Bidder  and  Schmidt  were  able 
to  estimate  the  quantity  of  the  carbon  metabolism,  which  they  express 
as  follows: 

C  in 
grams 

387.00  gm.  of  muscle  metabolized  contain 205.20 

In  tlie  excreta  were  eliminated ' 104.02 

Retained  in  the  body 11.08 

Since  the  t<;tal  carbon  elimination  in  the  urine,  feces  and  respiration 
was  less  than  that  derivable  from  the  flesh  metabolizei!,  it  was  evident 
that  the  iniresred  fat  could  not  have  participated  in  the  metabolic  process, 
but  must  have  been  absorbed  and  stored  in  the  body.  Analysis  of  the 
feces  showed  the  almost  complete  absorption  of  fat. 

This  metlir.d  of  determining  the  total  metabolism  is  in  principle  that 
used  by  Petrenkofer  and  Voit  a  decade  later. 

The  authors  strike  the  following  balance,  showing  the  fate  of  100  gm. 

of  meat  protein : 

C         H        3f  O         S 

100  g-ra.  meat  protein 53.01     7.02     16.11     22.86     1.00 

In  34.52   .gni.  urea , 6.91     2.30     16.11       0.20 

In   65.4S   irm.   rest  for  respiration 

and  bile  production 46.10     4.72        —       13.66     1.00 


62  GRxVIiA]\t  LUSK 

A  very  small  quantity  of  carbon,  hydrogei)  and  oxyi.';cn  (3  to  5  per 
cent)  and  a  lesser  portion  of  the  siilpliur  as  sulphid  of  ii'on  were  elimi- 
nated in  the  feces,  but  the  greater  jwrtioii  of  the  sulphui-  was  eliminated 
in  the  urine  in  the  fojin  of  sulphuric  acid. 

From  the  data  available  they  calculate  the  oxygen  necessary  for  the 
oxidation  of  the  materials  metabolized  by  the  dog.  They  note  that 
Regnaulr  and  Kc).;ct  obtained  a  relatively  greater  volume  of  oxygen  ab- 
sorbed than  volume  of  carbon  dioxid  given  otT  and  attribute  this  to  the 
fasting  condition  of  the  animals,  since  fat  contains  relatively  more  hydro- 
gen than  protein  and  therefore  more  water  was  produced  at  the  expense 
of  oxygen  ahsorbed  than  in  the  case  of  a  protein  diet.  Bidder  and  Schmidt 
estinuite  the  respiratory  quotient  of  a  meat-fed  dog  to  be  0.84. 

They  further  estimate  that  five  per  cent  of  the  total  carbonic  acid  ex- 
pired passes  through  a  stage  of  intermediarv  metabolism  by  way  of  the 
bile. 

In  a  fasting  cat  Bidder  and  Schmidt  determined  daily  for  eighteen 
days  the  water  eliminated  in  the  urine  and  feces,  the  urea,  sulphuric  and 
phosphoric  acids  in  the  urine,  the  expired  carbonic  acid  and  (for  ten 
days)  the  dried  solids  of  the  bile.  From  the  nitrogen  excreted  they  cal- 
culated the  quantity  of  carbon  attributable  to  the  protein  metabolism  of 
the  time.  Subtracting  this  protein  carbon  elimination  from  the  total 
carbon  elimination  in  the  urine,  feces  and  respiration,  they  were  able  to 
calculate  the  quota  of  respii-atory  carbon  attributable  to  fat  metabolism 
and  from  this  the  quantity  of  fat  metabolized  during  the  fasting  period. 
This  is  again  the  method  followed  by  Pettenkofer  and  Voit. 

They  make  the  following  table  to  represent  the  starvation  period 
(eighteen  days)  : 

From  the- metabolism  of  C  11  X  OS        PgO., 

204.43  grn.  protein  ...    102.24     13.43     30.81     43.81 
132.75  gm.  fat   103.72     15.50  13.45 

Total    205.06     20,02     30.81     57.26     2.167     3.761 

Excreted  by  lungs,  urine 

and  feces   ..*! 205.06       4.67     30.81     18.42     1.127     3.565 

Rest  (to  be  expired  as 

water)     24.35     "  38.84 

O2  Gm. 

190.78     gm.  expired  C  require  to  produce  COo ..  .    508.74 

24.347  gm.        ''      H       "       "        "        HoO    .  .   104.78 

703.52 
Less  O2  contained  in  the  products  of  metabolism.  .  .  .      38.84 

Oxygen  which  must  have  been  used 664.68 


A  IIISTOEY  OF  METABOLISM  63 

What  one  now  calls  the  '^respiratory  quotient''  was  0.765,  whereas 
Kegnault  and  Keiset  had  found  0.744. 

Aficr  this  fa.shiun  the  metabolism  was  also  estimated  for  each  day. 
The  oxviieu  consumption  fell  from  44  gin.  on  the  second  day  to  31  gm.  on 
rlie  sixteenth  day.  just  before  the  premortal  fall  in  body  temperature. 

At  the  death  of  the  animal  the  body  was  sectioned  and  the  various 
paits  were  weiiihed  when  fresh  and  their  dry  weights  and  fat  contents 
wer(^  later  obtaineil.  A  normal  cat  was  then  killed  and  similarly  analyzeil. 
The  tirst  cat  before  fasting  had  weighed  2r)72  gm.,  and  at  death  1241.2  g-m. 
The  original  composition  of  the  organs  of  the  cat,  when  it  began  to  fast, 
was  c()m})utcd  on  the  basis  of  the  analysis  of  the  normal  cat.  The  loss 
of  weight  of  dili'erent  crgans  in  starvation  could  then  be  computed. 

This  is  the  historical  forerunner  of  several  similar  extremely  laborious 
experiments. 

In  1852  we  might  have  read  this  modern  statement: 

The  extent  of  the  respiration,  like  everj-  other  component  of  the  metabolism 
process,  is  to  be  regarded  as  a  function  of  one  variable,  the  food  taken,  and  one 
constant,  a  distinctly  typical  metabolism  (Respirationsgrosse)  which  varies  with 
the  age  and  sex  of  the  individual.  This  factor  characterizes  every  animal  of  a 
given  race,  size,  age  and  sex.  It  is  just  as  constant  and  characteristic  as  the 
{iiiatomical  structure  and  the  corresponding  mechanical  arrangements  of  the 
body.  It  is  in  the  main  determined  by  the  heat  consumption  in  the  organism; 
that  is  to  say,  the  reidacement  quota  for  heat  lost  to  the  body  through  radiation 
and  conduction  to  the  environment  in  a  given  unit  of  time.  It  may  therefore 
be  used  to  determine  this,  or  in  case  the  factor  of  heat  loss  is  known,  one  can 
deduce  the  extent  of  the  metabolism. 

This  typical  metabolism  ...  is  that  of  the  fasting  animal.  It  must  be 
nearly  the  same  in  animals  having  the  sam.e  body  volume,  surface  and  tempera- 
ture; the  larger  the  body  surface,  the  body  volume  and  temperature  remaining 
:'onstant,  or  the  higher  the  body  tempe.rature  with  surface  and  volume  constant, 
the  liigher  will  be  the  metabolism  as  determined  by  the  laws  of  static  heat. 

Of  course  a  sharp  mathematical  treatment  of  this  phenemenon  can  be 
thought  of  only  after  very  numerous  and  exact  experimental  determination  upon 
animals  of  most  vari(^d  form,  size  and  temperature. 

A  footnote  states:  ^^This  is  an  extensive  progi-am  and  may  require 
uiaiiy  decades  for  its  solution.''  It  is  suggested  that  experimenters  divide 
the  investigations  into  the  animal  kingdom  after  the  fashion  that  astron- 
oniers  have  divided  portions  of  the  heavens  among  themselves  for  ob- 
servations. Bidder  and  Schmidt  state  that,  acting  with  this  intent,  they 
have  dealt  almost  exclusively  with  the  cat. 

^'Animals  cannot  maintain  the  typical  metabolism  over  a  prolonged 
fasting  i3eriod." 

They  define  a  'Ujipical  food  minimum''  as  that  quantity  of  assimilable 
food  u{K)n  which  the  body  maintains  its  weight  over  a  long  })erioa  of 
time.     A  slightly  lesser  quantity  than  this  causes  the  body  to  lose  weight. 

After  giving  much  meat  ^'there  is  a  double  Luxus  consumption:  ex- 


U  GRAHAM  LUSK 

pressed  (1)  hy  excessive  oxidation,  heat  production,  by  increased  evapora- 
tion of  water,  and  (2)  by  the  cleavage  of  onf^eighth  of  the  carbon  and  one- 
third  of  the  iivdrogen  of  protein  in  the  form  of  urea.  Only  the  smallest 
(piantity  of  this  urea  production  is  necf;ssarv  for  the  maintenance  of  the 
animal;  it  arises  from  the  cleavage  of  the  metabolized  l>odv  protein  itself. 
The  larger  part  is  eliminated  in  o)'<Ier  to  yield  the  carl)on,  hydrogen  and 
oxygen  containing  rest  in  a  form  suitable  for  respiration  and  not  injuri- 
ous to  the  body.  Protein  nitrogen  cannot  be  eliminated  through  the 
lungs,  for  nitrogen  scarcely  combines  with  blood  and  if  liberated  would 
till  the  capillaries  with  gas,  nor  can  ammonia  be  produced  for  this  destroys 
the  blood  corpuscles." 

The  greater  the  quantity  of  fat  given,  the  smaller  is  the  Luxus  consump- 
tion in  carnivora.  x\mong  herbivora  it  is  usually  very  slight  because  here 
protein  is  taken  in  conjunction  with  an  excessive  quantitj'  of  carbohydrates  and 
is  almost  entirely  used  in  replacement  (Wiederersatz)  of  the  body  protein  neces- 
sarily destroyed — which  latter  is  the  typical  (minimum)  protein  metabolism. 

They  find  that  following  fat  ingestion  the  feces  contain  magnesium 
and  calcium  soaps,   as  shown  by   Boussingault. 

The  authors  suggest  that  protein  may  be  composed  of  taurin,  glyco- 
coll  and  a  carbohydrate,  a  '^respirations  rest,''  they  call  it.  One  hundred 
gi*ams  of  protein  would  contain: 

Taurin 6.2  gm. 

Glycocoll T0.3  gra. 

"Respirations  rest" 28.3  gm. 

Taurin  and  glycocoll  would  yield  33.2  gm.  of  urea  and  49.8  gm.  of 
carbohydrate. 

They  add,  "It  is  not  possible  to  formulate  a  well-gi*ounded  hypothesis 
concerning  the  formation  of  urea  because  of  the  present  uncertainty  of 
our  knowledge  of  the  composition  of  protein." 

At  the  end  of  the  book  there  is  a  beautiful  chart  showing  the  metabol-. 
*sm  of  the  fasting  cat  and  giving  the  bile  secretion  as  intermediary 
n.etal'o]ism. 

Max  von  Pettenkofer  (1818-1001). — Pettenkofer,  who  is  well  known 
as  the  man  who  first  raised  hygiene  into  a  science  of  sufficient  dignity  to 
be  provided  with  an  independent  laborat«;ry  of  its  own,  was  not  only 
resjonsible  for  the  modern  drainage  system  of  the  town  of  ^Munich, 
which  converted  it  from  the  "pestilential  city  of  Europe"  into  one  which 
was  extraordinarily  healthful,  but  he  also  made  notable  contributions  to 
the  physiology  of  nutrition. 

He  noted  that  a  child  with  St.  Titus'  dance,  who  partook  of  an  in- 
ordinate amount  of  apple  parings,  voided  a  urine  containing  a  large 
amount  of  hippuric  acid.  This  was  one  of  the  earliest  discoveries  of  the 
influence  of  food  on  the  comjx)sitioii  of  the  urine. 


A  HISTORY  OF  ]iIETABOLlSM  65 

The  celebrated  Pettenkofer  reaction  for  bile  salts  was  not  detei'mined 
by  accident.  Liebig  tliouirht  tbat  fat  aro^je  from  carboliydrate.  To  test 
this,  Pottcnkofer  treated  a  solution  of  cane-sugar  with  strong  sulphuric 
acid  in  order  to  dehydrate  the  sugar  and  obtain  a  rest  rich  in  carbon 
which  might  be  convertible  into  fat.  Since  the  liver  or  bile  was  believed 
to  further  such  a  reaction.  Pettenkofer  added  bile  salts  to  the  mixture  and 
obtained,  not  fat,  but  the  well-kiiown  color  reaction.  Using  this  reaction, 
ho  was  able  to  show  that  normal  feces  contained  no  bile  salts,  though  these 
might   be  found   in   diarrhea. 

In  1844  Pettenkofer  found  a  compound  in  the  urine  which  united 
with  zinc  chlorid  and  he  e-tablished  its  chemical  comjx)sitiou.  Its  identity 
remained  hidden  until  it  was  one  day  shown  to  Liebig,  who  warmed  it 
over  a  flame  on  a  porcelain  cover,  and  from  the  odor  evolved  immediately 
concluded  that  it  must  be  related  to  the  creatin  of  muscle.    Such  is  genius ! 

Voit,  who  was  acquainted  with  the  work  of  Bidder  and  Schmidt,  sug- 
gested to  Pettenkofer  tliat  he  devise  a  respiration  apparatus  whicli  would 
measure  the  output  of  carbonic  acid  and  water  in  a  dog  weighing  20  to 
30  kilograms.  Pettenkofer,  who  was  interested  to  work  with  men  as 
well  as  with  dogs,  constructed  the  chamber  of  the  apparatus  so  that  it  had 
the  size  of  a  moderately  large  stateroom  on  a  steamer,  in  wdiicli  a  man 
could  sleep,  work  and  eat  without  discomfort.  .The  ventilation  of  the 
chamber  was  about  r>0(>.000  liters  daily.  Portions  of  the  ingoing  air  and 
portions  of  the  outgoing  air  were  diverted  in  their  course  and  analyzed 
for  carbon  dioxid  and  water.  The  increase  in  these  materials  in  the 
total  air  leaving  the  chamber  represented  the  amounts  given  off  by  the 
subject  of  the  experiment.  This  was  the  first  respiration  apparatus 
checked  by  burning  a  candle  in  it.  Pettenkofer  criticized  Eegnault  and 
Ileiset  for  not  doing  this,  and  thus  establishing  the  limitations  of  the 
accuracy  of  their  work,  a  test  which  would  have  shown  why  nitrogen  gas 
was  apparently  at  time?  absorbed  and  at  other  times  excreted  by  their 
animals. 

Voit  writes:  'Tettenkofer's  talents  produced  the  respiration  ap- 
paratus and  after  that  we  together  began  experiments  with  it.  Petten- 
kofer and  I  had  an  eoual  share  in  the  experiments." 

Carl  von  Voit  (lS:n-ll»08)  was  born  in  Amberg  and  was  the  son  of 
August  Voit,  architect  of  the  ^lunich  Ghispalast.  In  1848  he  went  to 
^Munich  to  enter  the  university.  Ife  joined  a  students'  corps  but  soon 
left  it  in  disgiist,  feeling  it  was  no  place  for  him  and  perhaps  reflecting 
upon  the  German  witticism,  "Er  w^ar  so  dumm  dass  selhst  seine  eigene 
Corpsbrildern  es  bemerckt  haben."  He  entered  enthusiastically  into  the 
rejuiblican  ideas  prevalent  in  that  year  in  Germany.  His  revolutionary 
activities  earned  him  a  black  mark  on  the  qualiflcations  list  of  the  uni- 
versity, a  fact  w^hich  he  discovered  long  afterward  when  he  had  risen  in 
position  and  fame. 


e^ 


GKAlIA]\t  LUSK 


After  passing  liis  ^'pliyslcutu'^  cxaniination,  ho  wont  to  "Wiirzburi;- 
in  18.")],  which  was  at  that  -tiinc  a  much  more  ('clehrated  Tnediccil  center 
than  Mniiicli.  After  a  year  he  returned  to  Munich,  whicii  liad  received 
an  academic  stimu his  hy  tlie  arrival  of  Liel)ig.  lie  gra(hiated  in  medicine 
in  \>^'A  and,  in  order  to  jjrepare  himself  for  a  scientific  career,  he  de- 
vote<l  the  following  year  to  attending  lectures  in  }>hysics,  zoology,  an- 
atomy and  chemistry.     The  last-named  course  was  given  hy  Liehig.     He 

entered  the  laboratory  of  prac- 
tical chemistry  then  conducted 
by  Petteidvofer.     With  Petten- 
kofer  he  studied  an  outbreak  of 
cholera,  especially  the  accumu- 
lation of  urea  within  the  organ- 
ism during  the  infection  and  its 
olimination  subse<iuently.      He 
devoted  a  large  part  of  his  time 
to  the  study  of  the  works  of  the 
great  Liebig,  whose  reputation 
filled  the  world.      On   Liebig's 
advice   he   spent    a   year   with 
Wohler  in  Gottingen.     He  then 
planned   to    pass   a   year   with 
Bidder  and  Schmidt  in  Dorpat, 
but  he  was  turned  from  this  by 
an  offer  of  an  assistantship  to 
Bischoff,  professor  of  anatomy 
and  physiology  in  ]\rnnich.     In 
1850  he  became  professor  extra- 
ordinarius,  and  in  1803,  at  the 
age     of     thirty-two,     professor 
ordinarius     of     physiology     in 
Munich,    a   position   which    he 
held  for  forty-five  years  until 
his  death. 
During  his  early  student  days  he  had  a  desk  adjoining  that  of  Brush, 
for  many  years  the  dean   of  the   Sheflield   Scientific   School.      Of  liim 
Voit  said,  ''I  can  see  him  now,  how  accurately  he  worked !"    And  through- 
out Voit's  life  it  was  *^die  Genauigkeit''  upon  which  he  placed  the  maxi- 
mum of  stress. 

Perhaps  it  may  be  of  interest  to  present  some  of  the  earliest  of  Voit's 
work  in  this  historical  review.  The  ideas  are  largely  expressed  in  the 
light  of  the  doctrines  of  Liebig.  A  young  man  is  usually  at  first  imbued 
with  the  doctrines  of  his  master.  The  master  who  has  a  knowledge  of 
accumulated  facts  can  often  most  helpfully  attempt  to  give  the  reasons 


Fipr.  7.  Carl  Voit.  From  a  plate  in  the 
"Jubel|irtn<r  of  the  "Zeitschrift  fiir  Hiolo«rie" 
(Vol.  XF.ITi.  puhlishcd  in  honor  of  his  seven- 
tieth birthdav. 


A  IILSTORY  OF  METABOLISM  67 

why  tinners  are;   in  other  words,  the  doctrines  and  the  theories.     It  is 
only  hiter,  when  the  young  man  has  accunnilated  new  facts  out  of  har- 
ninny  with  the  oUJ  theories,  that  those  theories  are  overthrown  and  left 
its  wi-ecks  hy  the  wayside.     That  is  the  history  of  science. 
N'oit  ib)  lias  put  the  matter  thus: 

I  cannot  n.uivc  with  those  who  think  that  hecause  thoy  <lo  not  agree  with 
our  conclusion-  they  can  overthrow  tlie  wliole  piece  of  work  (that  of  Bischoff 
and  Voit).  For  even  thoujili  our  theories  sljoidd  l)e  as  ba<l  as  represented,  the 
important  i)art  of  the  work,  the  experimental  results,  would  still  remain.  Those 
who  know  the  history  of  science  should  have  no  idle  illusions  over  the  value  of 
their  own  opinions.  I'pon  every  paj^^e  of  history  one  can  read  that  the  results 
of  a  properly  devised  experiment  are  immortal,  whereas  the  theories  drawn  from 
the  observation  are  frecpiently  shown  to  be  wronjr,  because  it  was  not  possible 
at  the  time  to  take  into  consideration  all  the  factors  at  work  during  the  experi- 
ment. 

.  .  .  From  theories  further  scientific  progress  is  evolved,  they  stimulate  re- 
newal activity.  It  often  happens  to  the  investigator  that  others  with  little 
trouble  to  themselves  present  new  conceptions  of  the  work  accomplished  by  him- 
self, but  the  intelligent  man,  whose  opinion  and  not  that  of  the  world  in  general 
is  worth  while,  will  not  forget  to  whom  credit  for  the  service  belongs. 

An  early  work  by  Voit,  ^'Beitriige  zum  Kreislauf  des  Stickstoffs^'  may 
])e  thus  abstracted:  In  recent  times  one  has  sought  to  obtain  a  more 
intimate  knowledge  of  the  metabolism  in  the  animal  body  by  comparing 
the  intake  of  various  constituents  of  food  with  the  constituents  of  the 
outgoing  substances.  In  this  category  belong  the  experiments  of  Bidder 
and  Schmidt  and  of  Bischoff  (1853). 

Bidder  and  Schmidt  found  in  cats  and  dogs  that  almost  all  the  nitro- 
gen was  eliminated  in  the  form  of  urea.  In  one  cat  fed  with  meat  00.1 
per  cent. of  the  ingested  nitrogen  was  found  in  the  urine,  0.2  per  cent 
in  the  feces,  leaving  only  0.7  per  cent  for  the  respiration. 

Barral  tauglit  from  experiments  on  himself  that  S.33  per  cent  of 
the  ingested  nitrogen  was  eliminated  in  the  feces,  42.07  }>er  cent  in  the 
urine,  leaving  over  50  per  cent  for  elimination  by  the  lungs,  an  amount 
ceitainly  too  hirge  in  the  light  of  recent  exact  determinations  of  the 
nitrogen  elimination  in  the  respiration,  especially  in  those  of  Regnault 
and  Keiset,  who  never  found  more  than  1/50  and  usually  less  than  1/200 
part  of  the  iniicsted  nitrogen  thus  eliminated.  Voit  calculates  that  Reg- 
nault  and  Keiset's  dogs,  which  absorbed  between  121  and  212  gm.  of 
oxygen  daily,  could  have  eliminated  only  between  0.04  to  3. GO  gin.  of 
nitrogen  gas  in  twenty-four  hours. 

Hoth  Lehmann  and  Boussingault,  working  with  indirect  methods, 
found  that  much  of  the  ingested  protein  nitrogen  must  have  been  elimi- 
nated in  the  urine. 

Bischoff  was  the  first  to  use  the  titration  method  of  Liebig  for  the 
determination  of  nitrouen  in  the  urine.     This  method  is  exceedin2,lv  accu- 


68  GRAHAM  LU8K 

rate  and  rapid.  FJisehoff  could  not  find  all  the  ingested  iiitrogen  in  tLe 
urine  and  feces.  (Tiie  urines,  however,  were  frequently  alkaline.)  AVheu 
500  grn.  of  meat  were  given  to  dogs  a  third  of  the  nitrogen  content,  or 
6  gm.  njust  have  heen  eliminated  in  the  respiration.  As  this  contra- 
dicted Iiegmiuh  and  lieiset,  BischofF  concluded  tliat  the  nitrogen  was 
probably  expired  in  the  form  of  ammonia. 

Perljap>  I.iebig's  titration  method  might  be  wrong,  so  Voit  devised  a 
method  of  distilling  the  ammonia  derived  from  urine  dropped  upon  soda- 
lime.  He  made  fifteen  comparative  tests,  the  first  of  which  is  thus 
recorded : 

X  content  of 

5  c.c.  urine 

in  grams 

Liebig  s  mediod 0.23S0170 

Soda  lime  method 0.2277660 

(The  accuracy  of  this  method  of  checking  the  results  was  subsequently 
tested  by  Liebig  himself  and  found  to  be  correct.) 

Xeither  Bi«lder  and  Schmidt,  nor  Bischoif,  nor  Voit,  ever  observed 
undigested  meat  in  the  feces  of  a  dog.  But  tlie  dry  feces  contained  6.41 
and  6.52  per  cent  of  nitrogen. 

Voit  finds  meat  contains  varying  amounts  of  water  and  of  nitrogen, 
the  latter  between  3.41  and  3.60,  witli  an  average  of  3.50  per  cent. 
Therefore,  one  cannot  tell  the  exact  composition  of  meat  without  some 
degree  of  error. 

Forty  kilograms  of  meat,  if  estimated  at  3.4  per  cent  of  nitrogen 
and  then  at  3.5  per  cent  of  nitrogen  content,  would  mean  a  variation 
of  40  gm.  of  nitrogen. 

Voit  adopts  the  value  3.4  per  cent  of  nitrogen  and  he  chooses  well- 
selected  whole  pieces  of  lean  meat  for  his  experiments  in  feeding  animals. 

He  always  collects  the  urine  freshly  voided  from  a  trained  dog  and 
the  urine  is  always  acid. 

In  this  early  work  Voit  gave  to  a  dog  weighing  27  kg.  1500  gin.  of 
meat  for  four  days  and  collected  the  nitrogen  eliminated  in  the  urine, 
feces  and  the  bile.  The  dog  lost  255  gm.  in  Aveight  (this  multiplied  by 
3.4  was  believed  to  give  the  contribution  of  body  protoplasm  to  the  nitro- 
gen excreted).     The  nitrogen  balance  read  as  follows: 

Grams  Grams 

ISr  in  meat 204.00  N  in  urine 197.48 

X  in  lost  bodv  weight.  .  .        8.67  X  in  feces 8.65 

N  in  bile 2.00 

212.67  

208.22 


A  IIISTOKY  OF  METABOLISM  69 

In  another  experiment,  using  a  normal  dog,  the  intake  of  nitrogen 
contained  in  protein  was  180.52  g-m.  and  the  outgo  1S0.96.  In  three  of 
the  five  experiments  tlie  whole  of  the  ingested  nitrogen  in  meat  was  re- 
covered in  the  urine  and  feces.  This  did  not  supi>ort  the  idea  that  protein 
nitrogen  is  eliminated  in  gaseous  form  througli  the  lungs  and  the  skin. 

BischoiT  .-rated  that  a  part  of  the  protein  nietaholism  must  be  used 
for  the  giTOwth  cf  the  hair  and  the  epidermis,  and  this  would  still  further 
lessen  die  possibility  of  its  elimination  as  a  gas  in  the  experiments  as 
computed  hy  Voit. 

This  work  of  Voit  was  carried  further  and  puhlishetl  by  Bischoff 
(born  1807)  and  Voit  (/)  in  18G0  under  the  title,  ''Die  Gesetze  der  Er- 
nlihnmg  des  Fleischfressers,"  of  which  the  following  is  an  abstract: 

*'\Vo  pro}Xjse  to  consider  nutrition  and  the  energy  relations  therein 
involved  as  they  concern  the  animal  organism,  much  cf  which  may  seem 
to  be  theoretical  and  therefore  of  little  importance  but  which  really 
embodies  the  sum  of  the  recently  acquired  knowledge  concerning  energy 
and  matter  and  which  in  part  is  concerned  with  our  own  observations." 

All  the  exjx^riments  were  dene  by  Dr.  Voit  with  the  assistance  of  a 
laboratory  servant  and  it  is  Dr.  Bischoff's  opinion  **that  the  numberless 
analyses,  the  cond)ustions  and  nitrogen  determinations  of  various  foods, 
of  feces,  etc..  could  not  have  been  done  with  greater  care  or  more  tireless 
zeal  than  they  were  done  by  Dr.  Voit." 

They  do  not  believe  that  all  the  protein  of  the  ingesta  must  first  be 
organized  into  the  material  of  living  cells  before  it  can  be  metabolized, 
but  rather  that  the  fluid  protein  of  the  blood  penetrates  living  cells  there 
to  be  destroyed. 

A  dog  was  given  250,  500,  800,  1000  gm.  of  meat  and  still  lost  body 
nitrogen.  With  1800  gm.  of  meat  the  urea  nitrogen  was  equal  to  that  of 
the  food  and  when  2000  and  2500  gm.  of  meat  were  given  the  dog  added 
flesh  to  his  body,  but  this  had  hardly  begun  before  the  quantity  of  urea 
increased  in  the  urine  because  the  mass  of  metabolizing  body  tissue  had 
been  increased.    The  dog  would  not  eat  more  than  2500  gm.  of  meat. 

The  metliods  of  calculation  of  the  metabolism  used  by  Bischoff  and 
Voit  w^ere  much  more  crude  than  those  of  Bidder  and  Schmidt  who  pre- 
ceded them.  But  the  records  of  the  protein  metabolism,  as  measured  in 
the  nitrogen  in  the  meat  ingested  and  in  that  of  the  urine  and  the  feces, 
are  the  classical  observations  on  the  subject. 

In  one  experiment  a  dog  weighing  35  kg.  was  given  31.6  kg.  of  ryo 
bread  during  a  period  of  41  days.  The  animal  received  405.20  gm.  of 
nitrogen  in  the  bread  and  eliminated  531.67  gm.  in  the  urine  and  feces, 
indicating  a  loss  of  body  nitrogen  of  126.38  gm.,  which  corresponded  to 
a  loss  of  -flesh"  amounting  to  3717  gm.  Though  the  food  was  evidently 
insufficient,  the  dog  appeared  well  nourished  and  active  at  the  end  of  the 
experiment.     His  actual  loss  in  boily  weight  was  only  690  gm.  during 


70  GRAHAM  LUSK 

the  period.  This  was  because  of  the  satiiratioD  of  the  body  tissues  with 
water  when  taking  the  bread  diet,  for  when  )ie  was  given  1800  gm.  of 
meat  he  passed  a  great  stream  of  water,  losing  300  gra.  in  body  weiglil  in 
spite  of  a  retention  of  the  protein  of  meat  which  would  liave  been  the 
e.|nivalent  of  an  addition  to  the  body  of  GOO  gm.  of  new  ''flesh"  (vide 
experiment  of  Stark,  p.  14). 

The  autliors  found  that,  though  gelatin  could  spare  some  body  ]>rotein, 
it  could  not  entirely  ])revent  its  loss.  They  state  that  it  is  an  incomi)lete 
(ungeniigendes)  foodstuff. 

Results — briefly  abstracted. 

We  hold  it  for  proved  that  the  continued  power  to  maintain  movement  on 
the  part  of  a  fasting  orpranism  is  rlerived  from  the  luctabolisni  of  ])roteui. 

The  three  factors  which  induf-e  metabolism  are  ''blood,  organ  and  oxygen." 
and  we  believe  that  the  metabolism  of  an  organ  is  brought  about  by  the  unite<:l 
action  of  all  three  influences. 

The  mass  of  non-nitrogenous  and  nitrogen-containing  tissue,  the  quantity 
of  blood  and  blood  plasma  and  the  amount  of  available  oxygen,  these  three  fac- 
tors determine  the  height  of  the  metabolism. 

If  one  gives  to  a  fasting  dog  meat  in  such  quantity  that  a  loss  from  the 
dog-'s  body  is  not  prevented,  the  metabolism  rises.  The  increased  quantity  of 
blood  plasma  increases  the  metabolism,  although  the  mass  of  the  organs  remains 
the  same;  the  influence  of  oxygen,  on  account  of  the  increased  food  and  metab- 
olism, is  greatly  reduced.  ...  As  oxygen  is  present  only  in  limited  amount, 
its  action  is  reduced  upon  both  body  protein  and  body  fat;  the  metabolism  of 
these  is  in  consequence  reduced. 

If  we  increase  the  food  protein  and  the  blood  plasma,  the  metabolism  is 
constantly  increased  until  w^e  reach  a  point  when  loss  from  the  body  is  equal  to 
its  repair.  This  is  the  moment  when  the  metabolism  of  the  protein  parts  of  the 
organism  has  so  increased  as  to  acquire  all  the  oxygen  available,  and  the  metab- 
olism of  fat  ceases. 

If  the  amount  of  food  be  still  further  increased  the  metabolism  scarcely  in- 
creases, for  the  available  oxygen,  through  union  with  metabolic  products, 
has  been  reduced  to  a  minimum.  This  is  the  moment  when  deposit,  increase  in 
mass,  excess  for  reparation,  must  and  can  ensue.  ... 

But  this  process  hiis  a  limit.  As  the  intake  of  meat  and  the  mass  of  the 
nitrogen-containing  tissue  increases,  the  metabolic  products  also  increase. 
These  require  more  oxygen.  But  the  action  of  this  is  so  reduced  that,  in  spite 
of  the  increased  bulk  of  the  plasma  and  of  the  organs,  a  limit  to  the  metabolism 
is  set.  As  soon  as  the  limit  of  metabolism  is  reached  the  limit  of  energy  pro- 
duction is  also  reached.  If  energy  is  no  longer  i)resent  and  available,  it  is  also 
no  longer  possible  to  increase  the  metabolism.  The  animal  can  no  longer  eat  and 
refuses  food.  Witli  a  limitation  of  food  intake  the  volume  of  blood  and  plasma 
falls  and  the  former  condition  returns. 

This  process  constitutes  an  absolute  proof  that  there  is  no  such  thing  as 
Luxus  consumption  of  meat  in  the  sense  of  the  hypothesis  of  Frerichs'  and  of 
Schmidt's;  i.  e.,  that  an  oxidation  of  food  protein  in  the  blood  takes  place  without 
previous  incorporation  with  the  nitrogen-containing  parts  of  the  body  tissue. 

Sugar  reduces  the  protein  metabolism  in  the  organs  of  the  body  and  reduces 
the  quantity  of  p.rotein  in  the  food  needed  for  replacement  purposes,  and  pos- 
sesses these  influences  even  more  than  fat,  probably  because  it  has  a  greater 


A  HISTORY  OF  METABOLISM  71 

affinity  for  oxygen  than  either  ingested  fat  or  body  fat.  .  .  .  Starch  behaves  like 
sugar. 

It  is  established  for  all  time  and  is  and  must  be  correct  that  the  nitrogen- 
containing  materials  are  the  sources  of  physical  power,  of  the  phenomena  of 
motion;  also  it  is  equally  incontrovertible  that  fat  and  the  so-called  carbohy- 
drates can  yield  only  heat  and  never  motion.  From  the  foregoing  results  it 
follows  that  the  doctrine  of  Liebig  regarding  the  division  of  the  foodstulTs 
into  plastic  and  respiratory  is  correct. 

The  authors  later  suggest  the  names  "djTiamogenetic"  or  'Icinetoge- 
nectic"  for  ^•plastic"  food  substances,  and  ^*thermogenetic''  for  ^^respira- 
tory"   foodstuffs. 

The  extension  of  the  work  to  man  is  desirable.  It  should  be  known 
to  what  extent  ingested  protein  nitrogen  appears  in  his  urine  as  urea  or 
whether  it  is  eliminated  in  other  forms. 

Tliey  expect  people  to  say,  "It  is  all  self-evident  and  we  have  always 
known  these  things,"  and  still  others  to  say,  "This  is  not  true,  here  are 
facts  which   contradict  you." 

It  is  of  gi*eat  interest  to  note  the  affirmation  of  the  doctrine  of 
Liebig  in  this  early  work,  that  though  muscle  effort  was  the  cause  of  the 
metabolism  of  protein,  oxygen  caused  the  destruction  of  fat  and  carbo- 
hydrate up  to  the  limit  of  the  quantity  of  oxygen  available.  Both  of 
these  doctrines  were  subsequently  overturned  by  Voit  In  the  first  place, 
he  found,  the  very  same  year  as  that  in  which  he  published  his  w^ork  with 
Bischoff,  that  muscular  work  did  not  increase  the  protein  metabolism  of 
a  fasting  dog  or  of  one  fed  with  meat.  Later  he  showed  the  Same  to  be 
true  in  the  case  of  a  fasting  man  and  of  a  man  fed  with  a  mixed  diet 
containing  a  liberal  amount  of  protein.  He  writes:  "I  maintain  this 
as  an  incontestable  fact.  It  is  of  itself  so  important  that  I  question 
whether  it  is  desirable  to  add  a  word  of  explanation.  The  results  of  a 
propei-ly  conducted  and  properly  appreciated  experiment  can  never  be 
annuled,  whereas  a  theory  can  change  with  the  progress  of  science."  How 
quickly  came  the  upsetting  of  the  former  assertion,  "It  is  established 
for  all  time  and  is  and  must  be  correct  that  the  nitrogen-containing  sub- 
stances are  the  sources  of  physical  power,  of  the  phenomena  of  motion!" 

When  I  was  in  the  Munich  laboratory  of  Voit  and  happened  to  make 
a  positive  assertion,  the  then  second  assistant,  Max  Cremer,  said  to  me, 
"Sagen  Sie  nicht,  Herr  Lusk,  es  ist  so;  sagen  Sie  lieber  mdglicherweise 
es  Ji'ann  so  sein/*  Such  are  the  cautious  admonitions  of  those  acquainted 
with  history. 

The  passing  of  the  conception  of  oxygen  being  the  cause  of  the 
metabolism  appears  from  the  following  words  of  Voit(&),  written  in  1S65 : 
''The  conditions  of  protein  metabolism  lie  in  the  elementary  particles  of 
the  organs  of  the  body,  which  are  the  hearthstones  for  all  variations  and 
activities.  ^.The  life  of  the  body  is  the  sum  of  the  action  of  all  the 
thousands  of  minute  workshops.     A  combination  with  oxygen  is  not  first 


12  OJIMIAM  LFSK 

necessary,  but  there  is  a  breaking  up  into  various  constituents  which, 
under  certain  cireunj^tanceS;  may  remain  unoxidizcj. 

"Through  the  peculiarities  of  cellular  structure  the  conditions  of  oxi- 
dation are  entirely  different  from  those  obtaining  outside  the  cells.  Under 
ordinary  circumstances  nitrogen  content  means  ditficulty  of  decomposi- 
tion, but  in  the  body,  protein  is  most  readily  destroyed  JTydiogen  is 
the  most  inflammable  of  the  gases,  but  it  can  be  respiied  up  to  quantities 
of  hundreds  of  liters  daily  without  being  oxidized, 

'^What  the  eye  of  the  layman  regards  as  rest  is  in  reality  an  inter- 
minal)le  movement  to  an<l  fro  of  the  finest  cellular  particles,  the  most 
complicated  of  all  processes/' 

Voit's  theory  of  "oi-ganized  protein"  and  "circulating  protein'^  served 
its  purpose  in  emphasizing  the  difference  between  the  behavior  of  the 
living  protein  of  the  tissue  and  the  more  readily  metabolized  pi'Otein  of 
the  ingested  food,  even  though  the  idea  so  troubled  Liebig  that,  for  the 
thought  of  it,  he  could  not  tell  his  right  hand  from  his  left,  and  even 
though  it  is  now  known  that  protein  ingestion  does  not  materially  add 
to  the  mass  of  blood  protein. 

Voit,  in  his  necrology  of  Pettenkofer  (cZ),  thus  describes  a  few  of  the 
results  obtained  by  their  combined  efforts  with  the  celebrated  respiration 
apparatus:  "Imagine  our  sensations  as  the  picture  of  the  remarkable 
processes  of  the  metabolism  unrolled  before  our  eyes,  and  a  mass  of  new 
facts  became  known  to  us!  We  found  that  in  starvation  protein  and  fat 
alone  were  burned,  that  during  work  more  fat  w^as  burned,  and  that  less 
fat  was  consumed  during  rest,  especially  during  sleep;  that  the  car- 
nivorous dog  could  maintain  himself  on  an  exclusive  protein  diet,  and  if 
to  such  a  protein  diet  fat  were  added,  the  fat  was  almost  entirely  de- 
posited in  the  body;  that  carbohydrates,  on  the  contrary,  were  burned, 
no  matter  how  much  was  given,  and  that  they,  like  the  fat  of  the  food, 
protected  the  body  from  fat  loss,  although  more  carl)ohydrates  than 
fat  had  to  be  given  to  effect  this  purpose;  that  the  metabolism  in  the 
body  was  not  proportional  to  the  combustibility  of  the  substances  outside 
the  body,  but  that  protein,  which  burns  with  difficulty  outside,  metabolizes 
with  the  irreatest  ease,  then  carbohydrates,  while  fat,  which  readily  burns 
outside,  is  the  most  dii^cultly  combustible  in  the  organism." 

In  Voit's  gTcat  textbook,  "Der  If^ndbuch  der  Erniihrung  und  des 
Stoffwechsels"  (IS^^*!),  one  may  read  the  words:  "The  methods  deter- 
mining the  ingo  and  outgo  of  metabolic  materials  for  animals  and  man 
have  very  largely  been  devised  by  me.''  It  was  only  Bidder  and  Schmidt, 
with  a  crude  respiration  device,  who  had  in  any  way  approached  the 
methods  of  Voit. 

It  has  already  been  shown  how^  the  scientific  susceptibilities  of  nations 
may  be  aroused  and  how^  two  men  of  different  nations  may  have  their 
disagi-eements.     The  polemics  which  PflUger,  in  Bonn,  wrote  against  Voit, 


A  HISTORY  OF  :\rETABOLTSM  73 

ill  ^riiiiich,  liave,  however,  liistorical  iiifercst.  Voit  (g),  incensed  by  tlic 
]>itincf  criticism  of  Pfliiger,  adds  a  sig-ned  postscript  to  an  article  by  ]Max 
Ci ruber  (18H1)  wliich  coneliifles  as  follows:  ^*It  is  to  be  regarded  as 
self-iiii'lerstood  that  I  cannot  enter  into  a  method  of  dispute  which  is 
so  unworthy,  a  method  which  I  can  only  despise.  In  science  one  should 
seek  to  establish  the  truth  by  demonstrating  the  validity  of  one's  opinions 
after  quiet  and  searching  consideration  and  it  is  indeed  an  evil  sign 
when  one  goes  as  far  as  Pfliiger  has  gone  in  his  polemic  and  uses  lan- 
guage which  would  not  be  tolerated  in  good  society  and  would  not  be 
regarded  as  permissible  even  in  excited  political  debate.  Such  treatment 
of  scientific  problems  cannot  possibly  promote  science  but  only  hurt  it, 
and  I  am  sure  that  many  others  think  as  I  do,  others  who  through  honest 
endeavor  have  shown  that  science  was  their  primary  interest,  men  who 
have  been  able  to  open  up  new  paths  therein.  It  is  fortunate  that 
Pfliiger,  who  has  no  sense  of  justice,  is  net  the  arbiter  of  the  accom- 
plishments of  science  but  rather  the  future  and  those  contemporaries  who 
can  dispassionately  estimate  the  work  of  others.  I  declare  that  I  turn 
away  from  this  hateful  discussion  with  loathing  and  cannot  copy  Pfliiger 
in  behavior." 

To  this  Pfliiger  (i)  answers:  "The  unvarnished  truth  of  my  exactly 
critical  reply  has  seized  Voit  so  that  he  was  thrown  into  a  paroxysm  of 
raving  passion,  and  setting  aside  a  real  answer,  he  has  ix)ured  ui)on  me  the 
most  insulting  invective"   (1881). 

Answering  this  in  the  only  purely  polemical  article  he  ever  wrote, 
Voit(c)  replies:  "Gruber  completely  refuted  the  criticisms  of  Pfliiger 
concerning  our  ^vork  and  clearly  explained  Pfliiger's  continual  misrepre- 
sentation of  the  same.  It  only  remained  for  me  to  rebutt  his  gTountlless 
accusations  against  the  work  put  out  from  my  laboratory.  This  could 
only  havo  been  accomplished,  not  as  Pfliiger  says,  in  passion  and  raving, 
which  are  foreign  to  me  and  hated  by  me,  but  rather  by  quietly  explaining 
in  the  postscri})t  that  I  would  not  reply  to  remarks  of  mistrust  and  cal- 
iminy,  which  T  can  only  despise"  (1882). 

Criticism  is  invaluable*.  Pfliiger  later  in  life  wrote,  "Criticism  is  the 
mainspi'ing  of  every  advance,  therefore  I  practice  it."  But  the  quality  of 
it  must  not  descend  to  billingsgate.  Barker  has  aptly  quoted  from 
''Truthful  elames," 

"I  hold  it  is  not  decent  for  a  scientific  gent 
To  say  another  is  an  ass — at  least  to  all  intent ; 
'Nov  should  the  individual  who  happens  to  be  meant 
Reply  by  heaving  rocks  at  him,  to  any  great  extent." 

Among  the  problems  with  which  Voit  concerned  himself  was  the  eon- 
version  of  starch  into  fat  and  of  protein  into  fat  and  into  sugar.  ITis 
earlier  conception  was  that  pr<itein  was  largely  convertible  into  fat,  and 


U  GKAHAM  LUSK 

this  conception  was  in  his  mind  to  the  end.  In  1885  it  was  sljown  by 
liubner  in  Voit's  laboratory  that  the  relation  between  carbon  and  nitrogen 
in  meat  proteinj  instead  of  bei}ig  3.G8  C  l  1  X,  was  really  3.28  C  :  1  X. 
Seven  years  after  this  Piliiger's  polemical  arrai^inneiit  of  Voit's  older 
work  appeared,  which  was  based  upon  a  rc^calculation  of  the  former  experi- 
ments of  Pettenkofer  and  Voit(/j.  To  this  Voit  made  no  reply,  since 
such  a  recalcnlatioij  was  merely  in  accord  with  Voit's  lalei'  nn<lcrsta]iding. 
At  one  time  I  had  the  good  fortune  to  talk  with  Pliiiger  foi-  about  half 
an  hour.  He  saw  very  few  people  and  the  introduction  occurred  under 
especially  favo4"able  auspices.  We  discussed  the  production  of  sugiir  from 
protein,  which  he  freely  admitted  was  possible,  though  at  the  time  in  his 
writings  he  was  inveighing  against  the  idea.  He  was  cordial,  friendly 
and  appeared  to  me  to  resemble  Voit  more  closely  than  any  one  I  had  ever 
seen.     His  writings  secMued  to  belie  the  character  of  the  man. 

Voit  was  the  first  to  insist  upon  the  value  of  flavor  in  the  diet.  A 
food  was  a  icell-tasting  mixture  of  foodstuffs,  he  insisted.  A  food  without 
flavor  was  rejected  by  both  man  and  beast. 

To  give  in  detail  the  later  historical  development  appears  unnecessary. 
A  Munich  review  of  the  German  translation  of  Lusk's  ^'Science  of  Xu- 
trition"  (Stoffwechsel  und  Ernahrung)  states  that  the  development  of  the 
school  of  Voit  was  nowhere  else  so  thoroughly  ex})ounded. 

Voit  was  ahvays  keenly  intereste<l  in  his  lectures  and  his  teaching. 
He  was  precise  in  his  statements,  clear  and  interesting.  He  read  his 
lectures  or  presented  the  materials  from  notes,  but  no  one  in  the  audience 
could  tell  whether  he  was  reading  from  a  text,  as  he  often  did,  or  extemix)- 
rizing.  The  lectuic  was  in  truth  a  '^^Vorlesung."  He  was  conscientious 
in  every  relation  in  life.  A.  story  is  told  that  when  the  orders  went  forth 
that  the  university  would  end  on  the  fifteenth  of  the  month,  the  professor 
was  greatly  disturbed  as  to  whether  the  order  meant  '^including*''  or  "ex- 
cluding'" the  fifteenth.  This  was  at  a  time  when  the  average  professor 
stopped  lecturing  when  it  suited  his  convenience,  and  many  days  before 
the  time  set.  His  own  standai'ds  which  he  set  for  himself  were  rigid. 
He  was  an  upright,  honest,  fearless,  kindly  man.  At  one  time  an  assistant, 
meaning  to  flatter  him,  said,  ** Your  views  are  certainly  the  right  ones," 
to  which  he  replied  in  tones  of  sluirp  reproof,  *'It  makes  no  difference 
who  is  rifiht  so  lonii:  as  the  truth  is  ultimately  achieved.'^ 

Eubner,  Erwin  Voit  (a  brother),  Friedrich  Midler,  F.  Moritz,  Fritz 
Voit  (a  son),  Straub,  Ellinger,  Otto  Frank,  Prausnitz,  Gruber,  Cremer, 
Weinland,  Heilner,  xVtwater  and  I  ail  owe  allcgience  to  the  ^lunich  school 
of  Voit. 

Voit  taught  that  one  case  carefully  investigated  was  worth  more  than 
many  hundreds  casually  examined. 

On  the  practical  side,  his  investigations  showed  that  an  aveiage  lal)or- 
ing  man  consumed  food  containing  118  ^m.  of  jn'otein  and  about  3,000 


A  HISTORY  OF  METABOLISM  75 

calories,  or  approximately  the  same  diet  as  bad  been  estimated  by  Playfair 
ill  1SG5  (see  ]).  7<S).  The  unit  of  o,0on  calories  was  adopted  as  the 
requirement  of  energy  for  the  average  adult  male  citizen  when  the  Inter- 
allied Scientific  Fo(kI  Commission  met  in  Paris  at  the  end  of  March,  1018, 
to  determine  standards  for  the  provisioning  of  a  population  of  225,000,000 
people.  The  battleground  around  the  11"^  gm.  of  protein  lias  been  active 
for  forty  years,  with  no  greater  result  than  the  well-defined  impression  that 
those  who  take  that  (piantity  of  protein  have  a  greater  virility  than  those 
to  whom  it  is  denied. 

In  the  laboratory  Voit  was  always  enthusiastic.  A  new  discovery  was 
the  cause  of  joy.  The  figures  to  be  obtained  excited  his  curiosity,  he 
would  say,  or  the  results  were  most  interesting,  most  important.  The 
new  method  was  extraordinarily  accurate  and  the  expectations  therefrom 
fascinating. 

One  day  I  burned  my  hand  with  ether  in  the  laboratory.  Some  one 
went  for  some  cocain  to  relieve  the  pain,  for  which  I  oflFercd  to  pay. 
^loney  was  refused.  I  had  done  so  much  for  the  State  that  the  State 
could  well  afford  to  pay.  It  was  a. new  conception  to  me  of  a  fundamental 
relation  of  experimental  laboratory  work  to  the  welfare  of  the  State. 

I  look  back  upon  my  days  in  ^lunich  with  gratitude  and  to  the 
memory  of  Voit  with  respect  and  veneration. 

Of  those  who  were  educated  in  the  atmosphere  of  the  Munich  school 
of  Voit,  Friedrich  von  Miiller  is  prec'minent  among  physicians  as  the 
leading  internist  of  his  time.  And  Rubner  was  the  first  to  solve  the 
problem  initiated  by  Lavoisier,  of  demonstrating  that  the  law  of  the 
Cfjnservation  of  enerin^  held  true  for  the  animal  organism. 

Max  Rubner  (1854-.  . . .). — While  still  in  Volt's  laboratory  as  fii^t 
assistant  Rubner  {d)  determined  the  calorific  value  of  urine  and  feces  un- 
der different  dietary  conditions  and  laid  the  foundations  for  the  computa- 
tions involved  in  modern  animal  calorimetry  (1885).  Rubner  applied  the 
knowledge  he  had  won  to  the  calculation  of  the  heat  production  in  man 
and  in  many  animals  of  different  species.  He  (e)  evolved  the  law  of  sur- 
face area,  that  the  heat  value  of  the  metaMism  of  the  resting  individual  is 
proj>ortional  to  the  area  of  the  body  surface.  This  law  had  been  previously 
indicated  in  the  writings  of  Regnault  and  Reiset,  as  has  been  shown 
(p.  4:3).  Ilis  first  publication  regarding  this  was  in  1883.  A  good 
review  of  the  literature  on  this  subject  is  given  by  Benedict  {z  1019). 

Voit  had  constructed  a  calorimeter  for  measuring  the  heat  production 
of  man  and  extensive  and  laborious  experiments  were  carried  out  with  it 
during  the  years  18C0,  '70,  '71,  '74  and  1884.  The  mass  of  material 
was  never  published  on  account  of  the  imperfection  of  the  apparatus. 

Iiubner(e),  in  1801,  working  in  his  own  laboratory  at  Marburg,  vir- 
tually with  his  own  hands  and  with  a  very  small  allowance  of  money,  made 
a  calorimeter  which  accurately  measured  the  heat  production  of  an  animal. 


7C 


OTfAIIAM  LUSK 


Tlic  interior  of  the  ap[)aratus  was  connected  with  a  Pet  toils  of  er-Voit 
respiration  a|J|Kiratns.  The  heat  measured  by  direct  calonmeiry  agi-eed 
within  a  fraetivn  of  one  per  cent  with  the  heat  calculated  from  tJie  mctal> 
olisni  jH-oducfvS  by  indirect  calorirnftrn.  Voit,  when  he  heard  of  this 
trinmpli  of  taplmic,  remarked  that  it  was  the  greatest  discovery  in  its 

way  since  the  invention 
of  the  tliermoraeter. 

Kubner^s  insistence 
upon  the  importance  of 
the  energy  relations  was 
especially  upheld  in  his 
vchime,  '^J)io  Gesetze 
\  ^^  lu^.  ^  ^     des    Euergieverbi'auchs 

I  '^    J\.,.        ^  ^  bei     der     Ern  lib  rung," 

published  in  1902.  On 
account  of  the  difficulty 
of  the  style  of  presenta- 
tion adopted  in  this 
book  it  was  some  time 
before  its  suggest iveness 
was  appreciated.  En- 
tirely diffeient  in  style 
andtinely  written  in  his 
more  popular  "Kraft 
und  StoflF  in  Haushalt 
der  Xatur,"  published 
in  1900. 

Eubner    is    a    man 

who  finds  his  relaxation 

among  artists  and  can 

himself  paint  a  picture; 

a  man  of  great  talents 

and  fine  personality.    It 

is    interesting   to    note 

that  his   advice  on  the  food   prol^loms  was  largely  disregarded  by  the 

German  authorities  during  the  war  (1014-18),  and  that  bis  prophecies 

regarding  what  would  happen  were  fulfilled. 

Nathan  Zuntz  (1847-1020). — Xo  history  of  metabolism  would  be 
complete  without  mention  of  Zuntz,  in  his  early  days  a  pupil  and  assistant 
of  Pfliiger,  a  practitioner  of  medicine  for  ten  years,  and  long  chief  of  the 
agi'icultural  college  in  Berlin.  Zuntz  studied  the  metabolism  by  means 
of  the  gas  analysis  of  the  expired  air  obtained  in  short  periods,  and  devised 
a  portable  apparatus  for  the  measurement  of  the  metabolism  of  a  man 
walkin<^  at  the  sea  level  or  on  the  snow  fields  of  Monte  Rosa.     He  made 


New  York  in  1912. 


From  a  photograph  taken  in 


A  IIISTOKY  OF  ]\1ETAB0LISM  77 

several  balloon  a?cen?=ions  for  scientific  purposes.  He  also  measured  the 
coM  of  energy  at  which  horses  and  cattle  performed  work,  and  the  loss  of 
eiierizy  through  the  bacterial  putrefaction  of  the  foods  in  such  herbivora. 
Magnus- Levy,  a  pupil,  carried  the  Zuntz  respiration  apparatus  to  the 
Icdside  of  hospital  patients  and  made  pioneer  investigations  the  validity 
of  which  has  been  generally  confirmed.  Zuntz  had  a  quiet,  attractive 
personality,  without,  however,  possessing  tlie  breadth  of  view  of  Rubuer, 
who  was  the  mo-t  fre(pient  antagonist  of  his  views. 

Late  French  Work 

If  we  turn  back  to  France  for  a  moment,  which  we  left  in  the  j^ear 
1819,  we  find  an  important  paper  by  Berthelot  (1827-1907)  entitled  "Sur 
la  chaleur  animale,''  published  in  1865,  in  which  he  argues  concerning  the 
differences  in  the  quantities  of  heat  produced  when  equal  weights  of 
carbohydrate  and  fat  are  oxidized  in  the  body.  He  points  out  that  it  is 
impossible  to  determine  the  heat  production  in  the  body  by  means  of  the 
method  of  Lavoisier  because  44  gm.  of  carbon  dioxid  produced  from  the 
oxidation  of  carbon  yield  94  calories,  whereas  the  same  amount  produced 
from  methane  yields  210,000  calories.  He  thus  early  concludes  that  *the 
(piantity  of  heat  liberated  in  the  incomplete  oxidation  of  a  substance  is 
equal  to  the  difference  between  the  total  caloric  value  of  tlie  substance  and 
that  of  the  pro<lucts  formed.'^ 

Rubner^s  ealorimetric  observations  were  the  realization  of  this  theo- 
retical conceptioii. 

The  experiments  of  Charles  Eichet  (1S50-.  . ),  published  in  1885,  con- 
firmed rtubner's  Law  of  Surface  Area,  and  Eichet  affirms  that  in  future 
one  should  express  all  ealorimetric  observations  in  terms  of  surface 
area  and  not  in  weight,  a  principle  now  being  largely  followed  in  the 
ITnitcd  States.  Hichet  compared  the  heat  production,  as  measured  by  his 
caloritneter,  of  a  eat,  rabbit  and  goose  of  equal  weights,  as  follows : 

'  Calories 

»                                                                    Weight  per  kilogi*ara 

I                                                                        in  gi-aiiis  per  hour 

Cat ..     3135  3.30 

Rabbit 3100  3.32 

.    Goose 3310  3.32 

Waiting,  aboiat  this  work,  in  1889,  he  says:  *Tet  us  consider  a  horse, 
for  ex.ample,  wliich  weighs  525  kg.  and  having  a  radius,  one  may  assume,- 
of  50  \centimelers,  the  surface  area  would  then  be  31.5  square  meters. 
This  at-ea  is  the  same  as  that  of  2250  sparrows,  each  weighing  20  gi-ams. 
C'onseqii^ently,  sparrows  weighing  45  kilograms  have  the  same  surface  as  a 
horse  wel^ghing  ^2T^  kilograms." 


^8  GKAIIA^I  LrSK 

In  the  Slimmer  of  1020,  in  Paris,  Richet,  in  his  opening  address  as 
president  of  iho  Physiological  CongTcss,  ?ai(U  "Seek  to  inidei'stand  tilings; 
their  utility  will  appear  later.  Fir.st  of  all  i\  is  knowledge  wliicli  matters." 
And  ho  illustrated  this  by  citing  the  inve-rtigations  of  Claude  Bej-nard  on 
the  glycr)genic  function  of  the  liver  and  the  investigations  of  Portier  aud 
himself,  wliile  they  weio  sailing  through  tropical  waters  on  the-  yacht 
of  Prince  Albert  of  ^lonaco,  upon  the  subject  of  anaphylaxis  which  they 
carried  on  with  poisons  of  sea  anemones  injected  into  birds. 


Conclusion 

The  writer  is  conscious  of  the  fact  that  this  story  is  incomplete.  For 
example,  he  is  not  forgetful  of  the  work  of  Lyon  Playfair  (1S18-1S98),  a 
pupil  of  Liidwig  wlio  in  18G5  gave  various  dietary  standards  among  which 
that  for  a  man  working  moderately  was  about  the  same  standard  fixed 
later  by  Voit.  Xor  does  he  forget  the  recent  work  of  Eobert  Tigerstedt  of 
Hclsing-fors,  or  of  Tangl  (186G-1916)  of  Budapest,  of  Johannson  of 
Stockholm.  The  conipletf^  story  woidd  be  long,  too  crowded  with  details, 
perhaps  already  a  justifiable  criticism  of  the  material  here  presented. 

In  a  recent  address  given  in  Berlin,  Friedrich  ]Miiller  stated  that  the 
science  of  nutrition,  which  had  been  a  German  science,  had  partly  passed  to 
America.  But  before  it  became  German  it  was  French,  p.erhaps  befoi-o 
that  English,  and  at  its  dawn  Italian.  In  this  country  the  early  calori- 
metric  work  of  Wood  and  Eeichert,  both  of  Philadelphia,  ought  not  to  be 
forgotten.  Wood's  w^ork  on  fever  is  of  importance.  The  work  of  Chitten- 
den (a  pupil  of  Kiihne  of  Heidelberg),  continued  by  Aleudcl ;  of  Atwater, 
continued  b}'  Armsby,  F.  G„  Benedict  and  II.  C.  Shennan;  that  of  Mc- 
Collum,  a  pupil  of  Mendel ;  of  Steenbock.  a  pupil  of  McCollum ;  that  of 
i^furlin,  Du  Bois,  Ringer  and  me,  has  been  work  accomplished  in  the 
earnest  endeavor  to  unfold  the  truth  as  we  liave  understood  our  missicm. 
We  aie  not  umnindful  of  the  aid  given  by  those  of  more  purely  chemical 
tastes,  like  Osl>orne,  Folin,  Levene,  Stanley  Benedict,  Jones,  Van  SHyke, 
and  Dakin;  or  of  the  mighty  travail  of  Alonzo  Taylor,  chief  .scientific 
adviser  to  Herbert  Hoover  in  his  work  of  providing  nourishment  foi"  the 
nations  of  the  world. 

Across  the  water  in  that  wonderful  island  called  Great  Britain  are 
Hopkins,  T.  B.  Wood,  Halliburton,  Cathcart,  Leonard  Hill,  Hardy,  'E.  H. 
Starling  and  others  through  whose  unrecognized  efforts  the  food  progi-am 
of  their  country  was  saved  from  disaster  during  the  war.  Strong  sci.entific 
personalities  have  developed  in  Britain,  despite  lack  of  national  recog- 
Dition.  These  men  and  men  in  France,  in  Italy,  as  well  as  in  Germany, 
are  carrying  on  to-day  what  will  to-morrow  be  a  part  of  the  Hi;.story  of 
Metabolism. 


SECTION  I 


Dietary  Constituents  and  Their 
Derivatives 


The  Proteins  and  Their  Metabolism A.  I.  Ringer 

Introduction — Elementan*  Composition  of  Proteins — Classification  of  the  Pro- 
teins—The Structure  of  the  Protein  Molecule — Amino  Acids  or  "Build- 
ing Stones  of  Protein'' — The  Role  of  Amino  Acids  in  the  Structure  of 
the  Protein  ^lolecule — The  Amino  Acid  Content  of  Different  Proteins — 
Peactions  of  Protein — Color  Reaction — The  Biuret  Reaction — ^The 
Xantho  Proteic  Reaction — The  ]Million's  Reaction — The  Sulphur-lead 
Reaction — The  ]\[olisch  Reaction — The  AdamkiewiczJIopkins-Cole  Reac- 
tion— ^The  Triketolu'drinden  Hydrat  Reaction — Precipitating  Reactions 
of  Proteins — The  *\Salting  Out''  of  Proteins  by  Cleans  of  Electrolytes — 
Coagulation  and  Denaturalization  of  Proteins — The  Salt  Formation  of 
Proteins — The  Digestion  of  the  Protein — The  Absorption  of  Products 
of  Protein  Digestion  from  the  Gastro-intestinal  Canal — The  Fate  of 
Absorbed  Amino  Acids  in  the  Blood — The  Fate  of  Amino  Acids  in  the 
Tissues: — Urea  Formation — The  Fate  of  the  Xon-nitrogenous  Fraction 
of  the  Amino  Acids — Protein  Metabolism — The  Question  of  Optimum 
Versus  ^Fiidmum  Protein  Diet — The  Function  of  Protein  in  the  Diet 
— Incomplete  Proteins — The  Influence  of  Proteia  on  Metabolism — ^The 
Specific  Dynamic  Action  of  Protein. 


The  Proteins  and  Their  Metabolism 

A.  I.  KIXGEU 

NEW   YORK 

Introduction 

The  proteins  are  the  most  impoitaut  constituentfi  of  the  animal  and 
plant  kingdoms.  They  are  an  ill-defined  group,  colloidal  in  character, 
non-volatile  and  obtainable  in  a  pure  state  with  the  greatest  of  difficulty. 

Just  as  the  molecules  of  the  simple  chemical  compounds  are  built  up  of 
atoms  and  radicals,  the  protein  molecule  is  comjx>sed  of  the  union  of  a 
great  many  amino  acids.  In  all,  about  twenty-one  ditferent  amino  acids 
luive  been  found,  and  there  is  every  reason  to  believe  that  more  will  be 
found  in  the  course  of  time.  When  one.realizc»s  that  the  amino  acids  them- 
selves are  of  rather  large  size  and  that  all  of  them  may  be  present  in  most 
of  the  proteins,  one  can  readily  appreciate  the  enonnous  size  and  complex- 
ity of  the  protein  molecule.  The  exact  determination  of  the  molecular 
weight  of  the  protein  seems  at  present  to  be  a  hopeless  task,  in  spite  of 
many  ingenious  attempts.  By  means  of  the  freezing  point  method,  egg  al- 
bumin is  found  approximately  to  possess  a  molecular  weight  of  about  14- 
000,  and  calculating  the  molecular  weiiiht  of  hemoglobin  on  the  basis  of 
one  atom  of  iron,  one  gets  the  figure  of  16000.  The  protamins,  which 
are  the  simplest  proteins,  have  a  molecular  weight  of  approximately  4000. 

Elementary  Composition  of  Proteins 

The  proteins  are  composed  of  the  following  elementary  constituents: 
Carbon,  Hydrogen,  Nitrogen,  Oxygen  and  Sulphur.  The  quantitative 
relationship  of  these  elementary  constituents  is  found  to  fluctuate  in 
tlie  different  proteins  within  narrow  limits.  Carbon,  50  to  55  per  cent; 
hydrogen,  ({.5  to  7.5  pc^r  cent;  nitrogen,  15  to  17.5  per  cent;  sulphur,  0.3 
to  2  per  cent ;  phosphoi-us,  0.4  to  0.8  per  cent:  oxygen,  21  to  23  per  cent. 

Classification  of  the  Proteins 

Fp  to  the  present  we  have  not  yet  arrived  at  any  definite  knowledge 
concerning  the  structural  fomiula  of  the  protein  molecule,  and  until  that 

81 


82  A.  L  EIXGEK 

is  achieved  a  satisfactory'  chemical  classification  will  not  be  possible.  All 
the  known  proteins  possess  certain  chemical  and  phj'sical  properties  in 
common,  and  differ  in  others.  The  classification  at  present  is  based  on 
these  difl'crences.  It  is  based  ujx)n  differences  in  their  solnbiiitioSj  coa^t^u- 
hitions,  precipitations,  etc.  It  is  a  crude,  and  more  strictly  physical  tban 
chemical  classification,  but.  it  answers  the  purpose  to  a  certain  extent  by 
bringing  some  order  out  of  chaos. 

Tlie  proteins  are  divided  into  three  main  groups: 

I.  The  simple  proteins  which  yield  on  hydrolysis  ct-amino  acids. 

II.  Canjur/ated  proteins  which  are  composed  of  simple  proteins  chem- 
ically united  with  another  organic  com}x>und. 

III.  Derived  proteins  which  are  proteins  that  are  found  in  the  in- 
complete digestion  or  hydrolysis  of  either  of  the  above  naturally  occurring 
jjrotein. 

These  three  main  groups  may  be  further  subdivided  into  the  follow- 
ing groups : 

I.    Simple  Proteins. 

a.  Albumins 

b.  Globulins 
e.  Glutelins 

d.  Prolan! ins  (alcohol  soluble  proteins) 

e.  Albuminoids  or  Scleroproteins 

f.  Ilistones 

g.  Protamins 

11.    Conjugated  Proteins. 

a.  !N"ucleoproteins 

b.  Glucoproteins 

c.  Phosphoproteins 

d.  Chroiuoproteins 

e.  Lentoproteins 

III.    Derived  Proteins. 

A.     Primary  B.     Secondary 

a.  Proteins  a.  Proteoses 

b.  ^letaproteins  b.  Peptones 

c.  Coagulated  proteins  c.  Peptides 

The  alhunnvs  are  present  extensively  in  the  animal  and  plant  king- 
doms. The  most  important  ones  of  this  group  are  senimalbumin  (from 
blood),  ovalbumin   (from  the  white  of  egy;),  lactalbumin    (from  milk). 

As  a  class  they  are  characterized  by  tlieir  solubility  in  distilled  water, 
dilute  acid  and  alkali.    In  the  presence  of  neutral  salts  they  are  coagidated 


THE  PKOTEIXS  AND  THEIR  ]\rETABOLISM  83 

],v  heat,  and  are  prrcipitatcd  by  alcoliol,  concentrated  mineral  acids  and 
ilie  .<alts  of  heavy  nietai.-f.  They  are  quantitatively  precipitated  by  satura- 
tion with  anmiouium  .-;ul2>)iate  iu  neutral  solution.  Most  of  them  may  lie 
olitaiiud  in  pure  crystal  line  form. 

Tl«e  glohuJins  are  also  present  extensively  in  the  animal  and  plant 
kiiii:<lonis.  They  are  found  in  the  blood  as  serum  glol)ulin,  fibrinoiien 
jintl  its  derivative  fibrin  :  in  the  muscles  as  myosinoi^en  and  myosin ;  iu  the 
cLiii'  as  ovo«ilr»bulin ;  in  milk  as  lactoglobulin ;  in  the  crystalline  lens  of  tlic 
evo  as  lentoiilobulin ;  in  the  thyroid  gland  in  combination  with  iodin  as 
rhyreoglobulin  or  iodothyreoglobulin ;  in  the  nrine  as  Hence  Jones'  pro- 
tein. 

As  a  class  they  are  characterized  by  their  insolubility  in  pure  distilled 
water  and  dilute  acid  solutions.  They  are,  however,  soluble  in  dilute  neu- 
tral salt  solutions  and  in  dilute  alkaline  solutions.  They  are  coagidated 
by  heat  and  precipitated  by  alcohol.  They  are  completely  precipitatc^d 
by  saturation  with  magnesium  sulphate  and  hy  half  saturation  with  am- 
monium sulphate.  They  are  strongly  acid  in  reaction  and  jwsscss  the 
power  of  turning  blue  litmus  red. 

The  gluielins  are  a  group  of  proteins  which  are  present  in  the  plant 
kingdom  only.  AVe  know  the  glutelin  of  wheat  and  the  oxyzenin  of  rice. 
They  are  soluble  in  dilute  alkali,  forming  salts. 

The  proJamins  or  alcohol  soluble  proteins  are  a  group  of  proteins  found 
in  cereals.  They  are  gliadin  of  wheat,  hordenin  of  barley  and  zein  of  maize. 
They  are  characterized  by  their  solubility  in  70  to  80  per  cent  alcohol, 
and  by  their  insolubility  in  water,  neutral  solvents  and  absolute  alcohol. 

The  albuminoids  or  scleroproteins  are  a  group  of  proteins  found  in  tlie 
Iraniework  of  all  connective  tissues.  In  this  gi*oup  belong  elastin,  gelatin 
and  collagen,  keratin  from  hair,  bones,  hoofs,  nails,  turtle  shell,  also  silk 
uclatin,  reticulin,  etc.  They  are  characterized  by  their  marked  insolubility 
ill  any  of  the  neutral  solvents  and  their  resistance  to  chemical  decom- 
jMi^irion. 

The  hist  ones  are  a  sharply  defined  group  of  proteins  strongly  alkaline 
ill  iraction,  and  not  found  free  in  nature  but  in  combination  with  acids  or 
•iIk  r  proteins.  They  contain  a  large  amount  of  the  dibasic  amino  acids 
'-•■<•  pjiue  nT),  lysin.  arginin  and  histidin.  They  are  found  in  ct>m- 
li  nation  with  nucleic  acid  in  the  nuckoproteins  and  with  hematin  in  henio- 
i:!"l>in.  They  are  soluble  in  water  and  precipitated  by  alkali.  They  are 
'■"a-ulated  by  heat  in  the  presence  of  small  amounts  of  salts,  and  are  pre- 
'•i|»ir;ited  by  other  proteins. 

The  protamins  are  the  simplest  of  all  the  proteins.     Similar  to  the 

;ii>r.iii('s,  they  are  strongly  alkaline  in  reaction.     They  contain  25  to  30 

!'<'i'  cent  of  nitrogen  and  are  made  up  almost  entirely  of  the  dibasic  amino 

•'<"id>  (ninety  per  centj.     They  are  found  in  combination  with  nucleic 

'i't  in  the  nuclei  of  the  spermatozoa  of  numerous  fish.     They  arc  soluble 


84  A.  I.  EINGER 

in  water,  and  are  nut  coagulated  by  beat,  Tbey  turn  red  litmus  blue.  Be- 
cause of  tbeir  basicity  tbey  bavo  tbe  power  of  absorbing  carbon  dioxid 
from  the  air,  forming  carbonates.  Tbey  form  stable  salts  witb  mineral 
acids  and  have  tbe  power  of  precipitating  otber  proteins. 

Tbe  conJLifjaU'd  /trotcins  will  be  taken  up  in  a  separate  cbapter.     The 
derived  proteins  will  be  discussed  in  tlic  chapter  on  digestion. 


The  Structure  of  the  Protein  Molecule 

It  has  been  known  for  a  long  time  that  if  acids,  alkalis  or  digestive 
fennents  like  pepsin  or  trypsin  be  allowed  to  act  on  protein  under  suitable 
conditions,  there  sets  in  a  decomposition  of  tbe  protein  molecule,  which, 
if  carried  on  for  a  long  enough  time,  will  cause  an  almost  complete  disap- 
pearance of  the  protein.  In  the  process  of  this  decomposition  a  number 
of  cleavage  products  are  produced  which  have  been  isolated,  purified  and 
identified.  Tbey  are  all  amino  acids — i.  e.,  organic  acids  which  have  an 
omino  ( — J^Hg)  radical  attached  to  their  a-carbons.  These  amino  acids 
ore  obtained  from  tbe  splitting  of  all  proteins,  and  because  of  that  tbey  are 
known  as  the  "building  stones"  of  protein.  To  date,  twenty-one  different 
amino  acids  have  been  obtained  as  cleavage  products  cf  the  protein  mole- 
cule, and  there  is  every  reason  to  believe  that  the  list  is  not  yet  complete, 
though  it  may  be  said  with  certainty  that  the  most  important  ones  have 
been  accounted  for. 


Amino  Acids  or  "Building  Stones  of  Protein" 

The  known  amino  acids  may  bo  considered  under  ihe  follow^! ng  head- 
ings: 

A.     Monobasic  ^Eono  Amino  Acids, 

1.  Glycocoll  or  glycin  or  a-amino  acetic  acid. 

CH2NII. 

COOH  i 

2.  Alanin  or  a-amino  propionic  acid. 

CH3 

I 

I 

coon 


Ivfono amino  acids 
reaction  neut r al 

u 

Glycocoll 


D\peptid 


Glycyl-glyciri 


^> 


^^> 


Alar.in  Alanyl-  alanin 

Tv/o  possible  dloeotids  between  glycocoll  and  alanin 


r:]]e> 


^o> 


Giycyl-alanir* 


Alanyl- glyc  in 


m 

Leucin 


Six  possible  iripeptida 
between  glycocoll,  alanin. 
and  leucin 


Giycyl-leucyl-  alanin 


^ 


Alanyl-  glycyl-leucin 


Aianyl-leucyl-  glycin 


Leucyl-alanyl-glycin 

m 


L  e  ucyl-  glycy  1-  alanin 


m 


Tyro^in 


Tryptophda 


Histidin 


Cystein 


straight  chain  polypeptid  (heptapeptid.) 
Glycyl-alanyl-leucyl^tyrosyl-tryptophyl-histidyl- cystein 

PLATE  L     SCHEMATIC  REPRESEXTATIOX  OF  THE  AMINO  ACIDS. 

The  neutral  amino  acids  eacli  contain  a  basic  amino  group  (blue)  and  an  acid 
carboxyl  group  (red),  which  neutralize  eacli  other.  These  amino  acids  can  link 
themstdves  to  one  anotlu-r  in  .straight  chains,  in  any  combination  and  permutation, 
tlje  amino  group  uniting  with  the  carboxyl  group. 


Aspartic  Acid 

Dibasic  acid, 
reaction  acid 


Ar^inin 

Di amino  acid,- 
reaction  basic 


Branched  Polypeptid. 

Glycyl-alanyl-dia^partic-Acid 


This  tetrapeptidcan  develop  :;r.V:3ges  a^or.g 
two  brancnes,  beside  the  main  chain,  iis 
reaction  is  acid  due  to  the  prerorderance 
ofcarboxy]  groups.  Such  polyp  =ptids 
linl<ed  v/ould  give  an  acid  protein.' 


Serin  Prolin 


Valin 


Schematic  representation  of  a  protein  molecule 

PLATE  11.     SCIIKMATIl    KKIMIKSKXTATIOX  OF  A  PROTKIX  MOLKCULE. 

This;  is  the  supposed  composition  of  the  protamin  of  the  .'talmon  |sahnine».  .Six 
tript'piids.  v.H-h  conipo^fd  oi  tu«>  rnoleoules  of  the  diauiiiio  acid  arginin  and  one 
ii.uiii.amiiio  acid,   are   linked   to,L'^4'ther.     The   proleiii   is   stronglv    bajiie  btt-uuse  '»i   the 


pivpiiinleriUKe   of   (he   amino   «rroiips. 


THE  PROTEIiSrS  AND  THEIR  METABOLISM  85 

3.  a-ainino  butyric  acid. 


CIl 


I 
c^CIIXIIs 

I 
COOIT 


4.  Valin  or  a-amino  iso-valerianic  acid  or  a-amino  P-methyl  butyric 
acid. 

CH.CH, 

\  y 

P^CII 

I 

a-CHNH., 

I  ' 

COOH 


5.   Leiicin  or  a-amino  Y-methjd  valerianic  acid. 

C113CH3 
\/ 

Y-CH 

I 

I 

I 

coon 

11.   Iso-lt'in'in  or  a-amino  P-methyl  valerianic  acid. 

CH3 

I 
Y-OH, 

I  .        ■ 

OIL-p-CH 

i 
a-CIIXH, 

I 
COOH 


86  A.  T.  ETXGER 

7.  formal  Lcucin  or  a-amino  caproic  acid. 

I 

I 

I 
P-CF., 

I    ■ 
a-CIIXIIa 

COOTI 

These  amino  acids  arc  neutral  in  reaction,  l)ut  have  the  property  of 
uniting  with  hoth  acids  and  alkali.  Glycocoll,  for  example,  can  comhine 
with  XaOIi  forming  sodium  glycocollate: 

I  +   XaOH       .        I  +   II2O 

coon  COOXa 

GlvcocoU         Sodium  Sodium  Glvcocollale 
hydroxid 

which  is  still  capable  of  combining  with  an  acid  radical,  because  of  the 
free  basic  amino  radical  ( — Xllg). 

On  the  other  hand,  glycocoll  can  combine  w^ith  an  acid  like  hydrochloric, 
forming  a  well  defined  salt,  glycocoll  hydrochlorid,  which  is  acid  in  re- 
action. 

CH2XII2  CII2XII3CI 

I  +      HOI     -»  I 

cooH  coon 

Glycocoll    Hydrochloric  Glycocoll  hydrochlorid 

acid 

and  is  capable  of  uniting  with  alkali  because  of  its  free  acid  radical 
( —  COOH)  known  as  carboxyl. 

B.     Dibasic  Mono  Amino  Acids. 

1.  Aspartic  acid  or  a-aniino  succinic  acid. 

COOH 

I 
P-CH2 

I 
a-CHXHo 

I  ^ 

COOH 


THE  PKOTEJXS  AND  THEIR  METABOLISM  87 

2.  Glutamic  acid  or  a-amino  glutaric  acid. 

cooir 

I 

Y-C'IIo 

I 
I 

a-ciixiro 

t 

C'OOII 

T}k'><'  amino  acids  are  strongly  acid  in  reaction  because  of  tlie  fact 
ilijit  rh»  y  j)o>se.ss  two  acid  radicals  and  only  v.ne  base.  In  spite  of  the  fact 
;!iat  tbey  are  strongly  acid,  they  jx)ssess  the  p«jwer  of  combining  with  other 
:u'id>.  fanning  salts. 

cooH  coon 

It 

CIL>  CIL. 

I         +     IICl        ->      I 

aixii,  ciixii.ci 

!  I 

COOII  COOH 

Aspartic  acid  Aspartic  acid 

hydrochlorid 

Tl;^  y  also  have  the  power  of  combining  with  two  alkali  radicals  be- 
>  ;mse  r>i  the  two  carboxyl  ( —  COOII)  radicals. 

COOII  COOXa 

I  I 

CH,  CIL. 

I  +  2XaOn     -^     I  -f-     2IL.0 

CIIXII.  CHXIIo 

I  "  I.  ' 

COOH  COOXa 

('.     Ilvilroxy-  and  Thio-a-amino  acids. 

1.  Serin  or  a-amino  P-hydroxypi'opionic  acid. 
P-CH.OH 

■         I 

«-CIIXIl2 

i 

COOII 


88  A.  I.  EIXGER 

f 

2.  Cvsteiu  or  a-amino  P-thio-propionic  acid.  * 
P^CHgSII 

I  § 

I 

cooir 

3.  Cystin  or  dicvstein. 

I    '  I 

ClIXIL,  ciiKir^ 

I      '         I 

cooii  coon 

These  three  substances  are  neutral  in  reaction,  and  have  properties  sim- 
ilar to  those  in  group  ^'A''.  The  two  latter  are  the  only  amino  acids  which 
contain  sulphur,  and  there  is  every  indication  to  prove  that  only  the  latter 
exists  in  protein  and  that  the  fomier  is  only  a  product  of  its  hydrolysis. 

4.  15-IIydroxyglutamic  acid,  Bakin  (1918,  1919). 

COOII 

CHg  I 

P-CHOH      .  I 

a-CH:^rH2  I 

I  I 

COOH 

This  acid  is  similar  to  the  dibasic  acid  glutamic  acid,  except  that  it 
has  an  hydroxyl  radical  attached  to  the  P-carbon.  This  is  the  youngest 
member  of  the  amino  acid  family,  having  been  discovered  by  H.  D.  Dakin 
in  1918.  '  ,      ; 

D.     Diamino  acids. 

1.  Lysin  or  a-Erdiamino  caproic  acid. 
E-CII.NH2 

.  r 

I  } 

Y-CH,  I 

I      ■  f 

P-CH2  I 

I  I 

a-cimii2  .    •  I 


cooir 


THE  PROTETXS  AND  THEIIl  :METABOLIS]y: 


80 


2,  Ornitliin  or  a-amiuo  5-amino  valerianic  acid. 
6-CII..X1I2 

I 
Y-CIIo 

I 

I 

I 
COOII 

3.  x\rginiR  or  a-amiiio  5-giianidin  valerianic  acid. 

II  .  •'        •     : 

8.CHoXir  ^  G  —  XH2 

I 
Y-CHo 

I 

■I     ■  .  "■■■'■'-;;-•■■•■ 

a-CIINHg 

I 
COOH 

These  substances  are  strongly  alkaline  in  reaction.  The  last  substance, 
on  hydrolysis  with  alkali  or  an  enzyme  known  as  arginase,  splits  into  urea 
iHid  ornithin.  This  latter  substance  is  not  found  as  such  among  the  pro- 
tein cleavage  products. 


K.     Arom.atic  amino  acids. 

1.  Plicnyl-alanin  or  a-amino  /3-pli 

CII          1 

/    \ 
HC          CII 

1 
HC          CII 

\  / 
C 

1 

enyl  propionic  acid. 
-Phenyl  radical 

1 

CHo 

1 

- 

CHXHo- 

Alanin  radical 

COOH 

00 


A.  I.  KIXGEK 


2.  Tvrosin  or  a-amiuo  pam  Iivflroxy  plienyl  propionic  acid. 

COIL 
/    \ 

lie       cir 


lie         CII 

\  / 
c 

I 
CII2 

I 
eiixH. 


COOH 

These  amino  acids  are  similar  to  those  of  the  monobasic  mono-aniino 
acid  group,  except  that  they  are  derivatives  of  the  phenyl  group. 


Heterocyclic  amino  acids. 

1.  Prolin  or  a-pyrolidin  carboxylic  acid. 


H.C  —  eHj 

"I     I 

HoC     eir 
\  / 

NH 


eooH 


Pyrolidin 
radical 


or 


NR 


t 


2.  Oxyj)rolin  or  hydro xypyrolidin  carlK)xylic  acid. 


HOHC 

I 
HoC 


CHo 


eil  ~  eOOH       or 


\  / 

xn 


NH 


TllK  PROTEINS  AXD  THEIR  METABOLISM 


91 


3.  Ilistidin  or  a-amino  ^iminoazol  propionic  acid. 
OH  — Xll 

II  V 


:CII 


-  Iminoazol  radical 


I 

I 

CIIXIL  Alanin  radical 

I  '  ■ 

COOII 


4.   Tryptophan  or  Indol  or-ainino  propionic  acid. 
CII 

/    \ 
HO  C  —  C  —  CII..  —  CIIXII.  —  COOH 

I  II       II       P    "       « 

HO  C      CH 

\    /\/ 

CII  xir 


Indol 
radical 


Alanin 
radical 


The  Role  of  Amino  Acids  in  the  Structure  of  the  Protein 

Molecule 

From  the  above  it  is  seen  that  all  the  amino  acids,  no  matter  how  simple 

'•r  complex  their  strnctnre,  possess  at  least  one  amino  ( —  ^Ho)  radical  and 

r  Icii.st  one  acid  ( — COOII)  radical.    These  two  radicals  impart  to  each 

iiiiiio  acid  the  power  of  nnitinir  with  at  least  two  other  amino  acids  of 

iinilitr  or  ditferent  structure,  fonning  what  are  known  as  peptids. 


/ 

<  II.— N 

\ 

(■(M»l| 

(ilvcocull 


n 


II 


+ 


+ 


II 


H 


\ 


H 


/ 


X  —  CII.> 


COOII 

Glvcocoll 


in 

II 

/ 

CIL  — X 

"       \ 

H 

CO         X       CII, 

/          1     ' 

II            COOH 

Gl\'cyl-glycin 

+  IL0 


92  A.  I.  EIXGER 

In  this  reaction  two  glycocoll  molocules  are  allowed  to  interact.  The 
basic  amino  radical  of  II  unites  with  the  acid  carboxyl  radical  of  I,  pving 
rise  to  the  ji'lvevl-g-lycin  peptid  III.  This  compound,  while  larger  and  more 
complex  than  tlie  original  glycocoll,  still  possesses  one  free  — JSTIIa  and  one 
free — COOII  at  either  end,  wdiich  again  makes  it  capable  of  uniting  with 
other  amino  acids  at  either  end  or  with  other  peptids. 


B 

III 

I 

IV 

H 

H 

H 

/ 

/ 

CH^  — N< 

CIL  —  N 

CIL  — N 

H                     H 

1     "        \ 

1    '         \ 

/ 

1               H 

1                 H 

CIL  — N  — OC 

! 

+ 

HOOC 

1 

CO N  — CH,. 

-:». 

CO        N      CH^ 

/ 

/        1 

H           COOH 

H          COOH 

Glycyl-glycin 

+ 

Glycocoll         -^ 

Glycyl-gl}xyl-glycin 

III  III 

H  HOOC  — CH2 

CH,- X<  I 

I    '  H  I     H 

I  +  N<  H 

CO  —  X  —  CH2  OC  —  CH;,  —  X< 

/        \  H 

H  COOH 

Glycyl-glycin  +  Glycyl-glycin 


V 

H 

/ 
CH2  — N  — OC  — CH2 

CO  —  N  — CIL        N<  H 

/         I  OC  — CH2  — N< 

H  COOH  H 

Tetra-glycyl-glycin 


illh:  PROTEINS  iVXD  THEIR  METABOLISM  93 

D 

III 


H 

(  H,  — X< 


H       +      HOOC  —  CH 


I 

V 

H 

H 

N< 

H               X< 

1       H 

CH,~X< 

/        H 

1 

j 

00  — cii^ 

-  CH, 

! 

CO        X 

-  CH, 

/ 

! 

CH, 

1 

H 

CO  — X  —  CHg    ■ 

/     ! 

coon 

H          COOH 

(  O  — X  — CH,         H 

/         I       + 
H  COOH      H 


riiyfvl-oflycin      -f-     2  molecule?  of  glyfocoll       — ^      Tetra-glycyl-glycin 
In  tlieso  reactions  we  have  illustrations  of  the  various  reactions  that 


olycocoll  and  its  peptids  may  undergo.  In  B.  we  have  a  molecule  of  glycyl- 
iilycin  unite  with  one  molecule  of  glycocoll,  giving  rise  to  a  tri-peptid 
XL  iycy  1-g  lycy  1-glycin. 

In  C.  one  molecule  of  glycyl-glycin  unites  with  another  molecule  of 
iilycyl-glycin^  giving  rise  to  a  tetra-peptid,  while  in  D.  one  molecule  of 
t:lycyl-olycin  unites  with  two  molecules  of  glycocoll^  giving  rise  to  the 
j^ame  tetra-peptid. 

From  these  illustrations  we  also  learn  that  no  matter  how  many  amino 
iici(.ls  are  ho(>ked  on  to  one  another,  they  will  always  have  one  — XITo  free 
at  one  end,  and  one  — COOH  at  the  other,  making  the  possibility  of  the 
!•  hi:th  of  tiiis  chain  indefinite. 

We  may  therefore  conceive  of  an  amino  acid  as  an  individual  with 
nil  arm  at  either  side,  capahle  of  clasping  two  other  individuals.  The 
chain  that  may  thus  1)0  formed  is  theoretically  endless. 

If  a  prcitein  were  made  up  hy  the  union  of  a  large  numher  of  molecules 
•  f  a  -intile  amino  acid  the  problem  would  be  comparatively  simple.  AVe 
V'  n!.]  1)0  dealing  with  a  straight  chain  of  amino  acids.  The  difference 
t'-^\v<en  one  protein  and  another  would  depend  only  upon  the  number  of 
amino  acid  molecules  that  go  to  make  the  protein  molecule.  But  in  the 
J.,  uiial  proteins  we  have  to  deal  with  a  union  of  about  twenty-one  amino 
a'id:?,  which  introduces  an  entirelv  new  factor,  namelv  that  of  isomerism 
ai.'I  >rf*reo- isomerism. 

Only  one  kind  of  union  is  possible  between  glycocoll  and  glycocoll. 
r>er\veen  glycocoll  and  alanin,  however,  two  unions  are  possible,  glycyl 
alauin  and  alanyl-glycin. 


94 


A. 

I. 

mXGER 

CJI, 

1 

CILXH. 

ClIXH. 

ir        0H3 

1     \      1 

CO~X  — C'll 

1 

H 
\ 

CO  — X  — CKo 

COOH 
Glvcvl-alanin 

coon 

Alaiivl-iilycin 

That  there  is  a  difference  between  these  two  compounds  we  know  from 
the  fact  that  they  behave  differently  in  their  physical  property  of  rotating 
the  plane  of  polarized  light.  Glycyl-alanin  rotates  the  plane  of  polarized 
light  50*^  to  the  left,  whereas  alanyl-glycin  rotates  it  50°  to  the  right 
(Abderhalden  and  Fodor,  1012). 

In  the  union  of  glycocoll,  alanin  and  leucin,  we  have  six  different  pos- 
sible combinations,  depending  upon  the  position  each  amino  acid  occupies 
in  tho  molecule  with  reference  to  the  other  amino  acids.  That  there  is 
a  difference  between  these  compounds  we  know  from  the  fact  that  they  all 
have  a  different  power  of  rotating  the  plane  of  polarized  light :    Thus ; 

I.  Glycyl-alanyl-leucin 

II.  Glycyl-leucyl-alanin 

III.  Alanyl-glyc^'l-leucin 

IV.  Alanyl-leucyl-glycin 

V.  Leucy  1-a  I  a  ny  1-glyciu 

VI.  Leucyl-glycyl-alanin 

With  the  inci*ease  in  the  number  of  amino  acids  the  number  of  isomers 
increases  tremendously,  as  the  following  table  taken  from  Abderhalden 
shows : 

Xuniber  of  amino  acids  Xumber  of  possible  compoiuids 

2  2 

3  6 

4  2-1: 

6  120 

6  720 

7  5,040 

8  40,320 

9  362,850 


r  .20  = 

—  90^ 

—  GO^ 

i(                    _ 

—  IP 

H                   __ 

.30^ 

i(                   

—  17^ 

((                   

-f  20^ 

THK  PIJOTEINS  AND  THEIK  :METAB0LISM 


95 


Xinulicr  of  amino  acids 

10 
11 

12 
13 
14 
15 
16 
17 
18 
11) 
20 


Numl>er  of  possible  compounds 

3,028,800 

39,016,800 

470,001,600 

6,227,020.800 

87,178,2u  1,200 

l,307,674',:]r;S,000 

2O,l)22,789,$SS',000 

3:>r),687,428,006,000 

6,402,373,705,72>i,000 

121,645,100,408,832,000     . 

2,432,002,008,176,040,000 


Tf  it  were  possible  to  iirrange  twenty  amino  acids  in  one  straigbt  line 
forming  a  [)roteiii  molecule,  2,432,002,008,176,640,000  different  kinds 
of  protein  molecules  could  be  formed.  This  figure,  however,  does  not 
v(  t  bv  anv  means  complete  the  list.  While  most  of  the  amino  acids  are 
lilile  to  form  unions  with  other  amino  acids  in  a  straight  line,  the  dibasic 
moiio-amino  acids  and  the  diamino  acids  are  able  to  fonu  branched  chain 
compounds. 


COOH 


<1L 


H\ 
+     H/ 


CITX 

\n 


<  DOH 


I 

COOH 

cir, 
I 

CIIXHo 

I 
IIOOC^     — ^ 

( OOH 


Clio 

•+       H\| 

KCII 
H/l 

COOH 


Aspartic  Glycocoll 

Jteid  Alanin 

Aspartic  acid 


CH,  —  COOH 


COOH 


06  A.  I.  KINGEE 

In  this  reaction  we  see  the  possibility  of  a  molecule  of  aspavtic  acid 
uniting  with  one  niolpcule  of  glycocoll,  one  of  alanin,  and  one  of  aspartic 
acid;  the  resultant  tetra-peptid  has  one  free  —  XIL  and  three  -COOII 
radieals,  which  means  it  can  further  form  compounds  along  two  branch 
lines  outside  of  the  original  line.  The  dili'erent  possibilities  can  be  best 
illustrated  graphically, 

Fvom  the  a])ove  consideration  one  can  readily  see  the  difficulties  that 
confront  the  investigator  of  the  chemistry  of  the  proteins,  and  when  one 
also  realizes  that  one  cannot  claim  to  understand  the  nature  of  a  chemical 
compound  until  he  has  a  knowledge  of  its  structural  formula,  one  can 
readily  ap])reciate  how  far  from  our  goal  wo  are.  One  can  then  also 
reiilize  how  crude  is  our  cla<siiication  of  proteins  that  has  been  given 
above.  Under  the  heading  of  what  we  call  albumins  we  may  have  billions 
of  different  proteins,  resembling  ojie  another  in  some  respects,  and  differ- 
ing in  others. 


The  Amino  Acid  Content  of  Different  Proteins 

Until  the  technique  of  the  quantitative  determination  of  the  amino 
acids  reaches  the  point  where  it  will  be  possible  to  recover  100  per  cent  of 
amino  aeids  from  a  known  mixture,  an  exact  answer  to  the  problem  of 
the  amino  acid  content  cannot  be  given.  The  figures  we  can  gather  to-day 
are  therefore  more  of  relative  value  than  of  absolute. 

l^ot  all  proteins  contain  all  the  amino  acids.  We  shall  learn  later 
that  from  the  nutritional  point  of  view  proteins  are  divided  into  "com- 
plete" and  "incomplete"  and  that  under  the  latter  we  include  those  pro- 
teins which  lack  some  of  the  amino  acids  which  are  essential  for  the 
maintenance  of  proper  nutritional  conditions  of  animals,  like  tryptophan, 
tyrosin,  lysin  or  cystin. 


Reactions  of  Proteins 

Color  Reaction. — The  prot<?ins  give  a  numl)er  of  color  and  precipitating 
reactions,  which  are  characteristic  of  a  group,  though  not  specific. 

The  Millon's  Reaction. — When  a  protein  is  boiled  in  Millon's  reagent, 
which  consists  of  a  mercury  solution  in  nitric  acid  and  to  which  a  small 
amount  of  nitrous  acid  is  added,  the  solution  will  turn  rose  colored  to 


f 

dark  red.     This  reaction  is  given  by  all  substances  having  an  oxyphenyl  i 


radical.  In  the  proteins  it  is  the  tyrosin  radical  which  gives  this  reaction. 
Proteins,  like  gelatin,  which  do  not  contain  tyrosin,  do  not  give  this  re- 
action. I 


THE  PKOTEINS  AND  THEIR  METABOLISM      .      97 


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S 

OQ 

0 

'c 
u 

■1 

0 

Oh 

.5 

as 
a 

1 

0 

98  A.  I.  RIXGER 

The  Biuret  Reaction. — When  protein  is  treated  with  a  strong  sodium 
hydroxid  solution  and  tlien  a  few  drops  of  a  very  dilute  copper  sulphate 
solution  is  added,  a  l)eautirul  violet  Mue  color  develops.  This  reaction 
is  due  to  the  presence  of  the  Biuret  group. 

CILNHo  CHo  — X'TI.. 


Biuret  group. 


COOK 

CO 

4- 

"^          \ 

cir.,NiT,> 

xn 

/ 

COOII 

CH2 

1 

COOII 

Glycocoll 

Glvcvl-^lycin 

All  proteins  and  polypeptids  give  this  reaction. 

The  Xanthoproteic  Reaction. — When  a  protein  is  boiled  with  strong 
nitric  acid,  a  yellow  solution  is  formed,  which  after  making  alkaline  with 
sodium  hydroxid,  turns  red  brown,  and  with  ammonia,  turns  orange  red. 
This  reaction  is  due  to  the  presence  of  the  benzene  group. 

The  Sulphur-lead  Reaction. — When  protein  is  heated  in  a  solution 
of  sodium  hydroxid  in  the  presence  of  lead  acetate,  a  black  color  is  pro- 
duced, due  to  the  presence  of  sulphur  in  the  protein  molecule.  This  re- 
action in  protein  is  produced  by  cyst  in. 

The  Molisch  Reaction. — When  a  few  drops  of  an  alcoholic  solution  of 
a-napthol  is  added  to  a  protein  solution  and  this  mixture  stratified  upon 
concentrated  sulphuric  acid,  a  beautiful  violet  mixture  is  formed  at  the 
point  of  contact.  This  reaction  is  not  given  by  the  proteins  themselves 
but  by  the  carbohydrate  radical  which  is  frequently  bound  to  certain  pro- 
teins (glucoproteins). 

The  Adamkiewicz-Hopkins-Cole  Reaction  is  obtained  when  to  a  solu- 
tion of  protein  a  small  amount  of  glyoxylic  acid  is  added,  and  the  mix- 
ture stratified  upon  concentrated  sulphuric  acid.  A  beautiful  violet  blue 
color  develops  at  the  point  of  contact.  This  reaction  is  given  by  the  amino 
acid  tryptophan,  and  proteins  which  do  not  contain  this  amino  acid,  like 
gelatin,  zein,  protamins,  etc.,  do  not  give  it.  The  presence  of  sodium  or 
potassium  nitrate  will  interfere  with  this  reaction. 

The  Triketohydrinden  Hydrat  Reaction  (.Yt7i/?7/(fn/t).— When  a  sinall 
amount  of  0.1  per  cent  of  triketohydrinden  hydrate  is  added  to  a  dilute 
protein  solution,  and  the  mixture  boiled  for  a  minute  or  two  and  then 
allowed  to  cool,  a  beautiful  blue  color  will  develop.    This  is  characteristic 


THE  PROTEIXS  AND  THEIR  :METAB0LISM  99 

of  all  proteins  and  is  given  due  to  the  presence  of  an  a-amino  radical  next 
to  a.  free  carboxjl  (— COOH). 

Precipitating  Reactions  of  Proteins. — All  proteins  are  precipitated  by 
ahsohitc  alcoliol.  With  dilute  alcohol  the  pre<-ipitating  point  of  the  differ- 
ent proteins  is  different,  and  C.  Tehh,  IDO-l-,  has  worked  out  a  means  of  dif- 
forentiatinti'  between  ditlerent  proteins. 

Various  mineral  aeids,  lik<»  nitric,  nietrjthosphoric,  and  ferrocyanic 
acid,  as  well  as  the  alkaloidal  reagents  like  phosphotungstic,  phosphomo- 
Ivbdic,  tannic  and  picric  acids,  potassium  mercuric  iodids  and  potassium 
l.isniuth  iodids,  have  the  power  of  precipitatinir  the  proteins. 

l*ractically  all  the  salts  of  the  heavy  metals  have  the  power  of  precipi-* 
rating  the  proteins.  Tlutse  that  are  employed  for  that  purpose  most  frc- 
<|uently  are  ferric  chlorid,  ferric  acetate,  copper  sulphate,  mercuric  chlorid, 
itasic  or  neutral  lead  acetate,  zinc  acetate  and  uranyl  acetate.  The  strongly 
basic  proteins,  like  histones  and  protamins,  also  possess  the  power  of  pre- 
cipitating the  proteins.  ^lost  of  the  above  prei-ipitations  are  irreversible, 
i.  e.,  by  removing  the  precipitating  agent  the  proteins  cannot  be  diss^dved 
in  water.  On  adding  an  excess  of  seme  of  the  salts  of  the  heavy  metals 
to  precipitated  proteins,  the  proteins  may  i;o  into  solution  again.  This 
is  accounted  for  by  the  fact  that  the  proteins  undergo  a  certain  degree  of 
hvdrolysis  and  break  up  into  molecules  which  are  smaller  and  soluble. 

The  "Salting  Out"  of  Proteins  by  Means  of  Electrolytes. — It  was  al- 
ready recognized  by  Denis  (1856  («))  and  worked  out  in  gi-eat  detail  by 
Ivuhne  (188G),  Hofmeister  (1887  (&)),  and  T.  B.  Osborne  and  his  collab- 
orators, that  a  great  many  salts  have  the  power  of  throwing  the  proteins 
"ut  of  their  solutions  by  precipitating  them.  These  precipitated  pro- 
reins,  after  removal* of  the  salts,  can  be  rediss»>lved  in  distilled  water,  which 
makes  the  reaction  a  reversible  one.  It  was  further  found  that  diiferent 
proteins  will  be  precipitated  out  by  the  different  salts  at  definite  points  of 
salt  concentration.  This,  therefore,  enabled  the  above  workers  to  frac- 
tiiaiate  the  proteins  and  to  obtain  them  in  fairly  pure  state. 

Kauder,  working  in  Ifofmeister's  laljorat^'ry  (1886),  found  that  when 
>niall  quantities  of  ammonium  sulphate  was  added  to  blood  senmi,  tlie 
precipitation  of  globulins  commenced  when  rLf  salt  concentration  reached 
!•)  per  cent  of  complete  saturation,  and  endr.l  when  it  reached  24.11  per 
'cnr.  After  the  globulins  were  filtered  off  and  fresh  ammonium  sulphate 
was  added,  no  precipitation  took. place  iinti!  the  concentration  of  the 
iinmiouium  sulphate  reached  33.55  per  cent,  when  the  albumin  fraction 
ix'gau  to  be  precipitated.  The  latter  precij'iration  was  completed  when 
Hie  coneentraticm  reached  47.18  per  cent. 

Hofmeister  further  studied  the  relative  influence  of  anions  and  the 
♦•ari(nis  on  the  power  of  precipitating  proteins.  His  results  are  summarized 
in  the  following  table. 


100 


A.  I.  KIXGEK 


TABLE  II 
Relativk  Ino.uenck  of  Axioxs  and  C  ations  o.\  thk  Precipitatiox  of  Proteins 


1     Lithium 

Sodium 

Potassium 

Ammonium 

Magnesium 

r^ulphate 

8.01 

11.30 

No  pp. 

13.30 

15.93 

Phosplmte   

Not  iiiM'si- 
tin^ated 

11. GO 

13.99 

10.57 

Slightly  soluWe 

.Acetate   

it 

13.83 

10.38 

No  pp. 

No  pp. 

Citrate    

li 

14.42 

17.07 

21.99 

.Vot  investigated 

Tartrate   

" 

15.11 

17.08 

25.05 

»< 

bicarbonate    .... 

C( 

No  pp. 

25.37 

Not  inves- 
tigated 

ti 

Cliromate 

(( 

21.22 

25.59 

No  pp. 

€( 

Chlorid   

i( 

21.21 

26.28 

« 

No  pp. 

Nitrate   

Chanp^es 
proteins 

40.10 

No  pp. 

(( 

it 

Chlorate  

Not  inves- 
tigated 

58.82 

t( 

Not  inves- 
tigated 

Not  investigated 

From  this  it  is  evident  that  botli  the  cation  and  the  anions  exert  their 
influence  on  the  precipitation  of  the  proteins,  and  that  the  relative  order 
of  their  efficiency  is : 

For  Cations    Mg<NII.5<K<XA<L; 

For  Anions     CL0:.<^^03<  Bicarhonate<Tartrate<Citrate< 
Acetate  <P04<S0i 


Coagulation  and  Denaturalization  of  Proteins 

Because  of  the  colloidal  nature  of  the  proteins,  they  are  very  susceptible 
to  even  slight  changes.  Solutions  of  albumin  will  fall  out  of  solution 
merely  on  standing.  A  good  many  proteins  will  become  coagulated  even 
on  small  rise  in  temperature,  while  most  proteins  coagulate  on  boiling. 
This  reaction  in  most  instances  is  irreversible,  i.  e.,  the  proteins  become 
denaturalized  and  cannot  be  brought  back  into  solution  again. 

Colloids  that  carry  an  opposite  electrical  charge  may  also  coagulate 
the  proteins. 

The  Salt  Formation  of  Proteins 

Until  recently  the  question  of  salt  formation  of  proteins  was  one  of 
the  most  puzzling  questions  in  biological  chemistry.     The  proteins  did 


THE  PKOTEINS  AND  TIIEIK  METABOLISM  101 

not  seem  to  unite  with  the  different  ions  in  the  same  stoichiometrical  ra- 
tios a-  they  unite  with  crystalloids,  and  because  of  that,  the  proteins  were 
credited  with  special  "absorption"  properties.  These  were  attributed  to 
all  the  colloids. 

The  recent  researches  of  Jacques  Loeb  (1919-1921)  seem  to  clarify  the 
\vli"le  problem.  He  ])rove(l  that  the  proteins,  and  perhaps  all  other  am- 
ph'teric  colloids,  can  exist  in  three  states  and  that  these  states  depend 
entirely  upon  the  hydrogen  ion  concentration  of  the  medium  in  which 
rhev  are  dissolved ;  that  each  protein  has  a  critical  point  in  the  hydrogen 
lull  concentration  at  which  it  does  not  dissociate  and  at  which  it  is  incapable 
nt  -raving  united  with  either  anion  or  cation.  At  this  point  a  protein  like 
in'hitin  is  almost  completely  insoluble,  hence  all  the  properties  which  are 
dependent  upon  the  solubility  of  gelatin,  like  its  osmotic  pressure,  viscosity, 
.-welling  and  conductivity,  are  at  a  minimum.  This  point  is  known  a* 
th.'  "isoelectric''  point.  For  gelatin  this  isoelectric  point  lies  at  a  hydro- 
iren  ion  concentration  of  0^  =2.10'^  or  pH  =  4.7,  for  casein  4.7,  for 
e-ir  allnimin  4.8,  and  for  oxyhemoglobin  at  6.8,  and  at  these  points  we 
find  the  proteins  to  be  almost  inert  bodies. 

On  either  side  of  this  isoelectric  point  the  protein  molecule  dissociates 
ill  two  different  states.  On  the  acid  side,  i.  e.,  if  the  hydrogen  ion  con- 
centration of  a  gelatin  solution  is  raised  and  the  pH  falls  below  4.7,  the 
|;r«  .rein  dissociates  into  a  cationic  state,  carrying  a  positive  electrical  charge 
and  capable  of  forming  salts  with  anions  forming  protein  chlorids,  protein 
sulphates,  etc.  In  this  state  the  amino  radical  becomes  chemically  active, 
while  the  carboxyl,  the  other  binding  post  of  the  protein  molecule,  is  en- 
tirely inert. 

On  the  other  hand,  if  the  hydrogen  ion  concentration  of  the  solution 
i-  krvvered  and  we  have  a  rise  in  the  pH  above  4.7,  the  protein  dissociates 
into  an  anionic  state  carrying  a  negative  electrical  charge  and  capable 
"t  foiiTiing  salts  wdth  metals  or  cations,  forming  metal-proteinates,  like 
so.Iium  gelatinate,  calcium  albuminate,  potassium  caseinate,  etc. 

He  further  foimd  that  all  proteins  at  their  isoelectric  points  w^ill  aban- 
'l'>u  the  chemical  union  they  may  have  had  with  either  anion  or  cation  or 
"liier  protein,  and  may  be  obtained  in  a  state  of  high  purity.  He  also 
I  r.nl  that  for  each  given  hydrogen  ion  concentration  the  proteins  com- 
I'iii"  with  the  various  anions  or  cations  in  definite  stoichiometrical  ratios 
similar  to  those  of  the  crvstalloids. 


The  Dij^estion  of  the  Protein 

During  the  process  of  mastication  the  proteins  suffer  only  physical 
elation  by  being  broken  up  into  smaller  particles.     The  saliva  contains 


102  A.  I.  EIXGER 

no  enzyme  which  has  any  effect  on  the  protein  molecnlc;  by  causing  it  to 
split  into  smaller  componnds. 

In  the  stomach  we  find  an  enz\Tne.  pepsin,  which  is  secreted  in  an 
inactive  or  zymouen  slate,  and  whicl]  is  activated  by  the  hyd)'ochh>ric  acid 
of  the  gastric  juice.  The  activation  of  this  enzyme  can  be  accomplished 
also  by  orpmic  acids,  like  oxalic,  lactic  and  tartaric  acids,  or  })y  inor«^anic 
acids  like  nitric,  phosphoric  atid  sulphuric. 

The  pepsin  in  acid  solution  has  th<.'  power  of  splitting  the  protein  mole- 
cule into  simpler  or  ^Merived  proteins."  The  longer  digestion  proceeds  the 
smaller  will  he  the  size  of  the  molecules  of  the  ''derived  proteins"  and  the 
further  these  molecules  will  get  away  from  the  colloidal  state  and  ap- 
proach the  ciystalloidal.  l>y  means  of  fractional  precipitation  with  am- 
monium sulphate  or  zinc  sulphate,  various  tractions  can  be  recognized, 
representing  different  stages  in  the  digestion.  These  fractions  are  not 
definite  chemical  entities,  but  mixtures  of  what  are  known  as  meta-pro- 
teins,  coagulated  proteins,  proteoses  and  peptones.  Under  no  circumstances 
and  no  matter  for  hov/  long  pepsin  is  allowed  to  act  on  protein  does  its 
digestion  lead  to  amino  acid  formation. 

The  hydrochloric  acid  plays  an  important  part  in  the  protein  digestion. 
It  causes  a  swelling  of  the  proteir,  and  a  breaking  up  of  the  larger 
particles,  converting  it  into  a  sort  of  gelatinous  mass.  The  pepsin  is  thus 
enabled  to  make  its  way  into  the  interior  of  the  particles  with  much  greater 
ease. 

The  products  of  protein  digestion  are  passed  on  into  the  intestines, 
where  they  meet  the  secretions  from  the  pancreas,  liver  and  intestines. 
These  render  the  mixture  alkaline  and  thus  prepare  it  for  the  action  of 
trypsin,  which  acts  only  in  alkaline  mediums,  and  which  is  secreted  by 
the  pancreas  in  an  inactive  state,  trypsiuogen,  and  which  is  activated  by 
the  enterokinase  of  the  succus  entericus. 

The  trypsin  acts  on  the  peptic  digestive  products  and  also  on  the  native 
proteins  which  have  entered  the  intestines.  The  trypsin  carries  the  di- 
gestion of  the  proteins  mostly  to  the  peptid  stage,  i.  e.,  small  chain  com- 
pounds of  amino  acids,  and  to  a  considerable  extent  to  the  amino  acid 
stage.  Tyrosin,  leucin,  tryptophan  and  cystin  are  the  amino  acids  that 
usiially  appear  first  in  trypsin  digestion. 

When  a  protein  is  completely  digested  the  products  fail  to  give  the 
biuret  reaction,  and  when  trypsin  acts  on  protein  long  enough  it  carries 
the  digestion  to  the  stage  where  no  biui*et  reaction  is  obtainable.  E.  Fischer 
and  Abderhalden  have  shown  that  cenain  peptids  exist  vvdiich  are  composed 
of  phenylalanin  and  prolin,  which  resist  the  action  of  trypsin  and  can 
only  be  broken  up  by  another  enzyme  which  is  secret(?d  by  the  intestinal 
glands  and  is  known  as  erepsin.  This  enzyme  has  the  power  of  breaking 
up  all  peptones  into  amino  acids, 


THE  PROTEIXS  AND  THEIR  :N[ETAB0LISM 


103 


Schematic  illustration  of  the  Digestion  of  Proteins  in  the  Gastro- 
intestinal Canal 


y 

^PROTEIX.. 
1             ^ 

^lotaprotcin. 

1 

1 

1 
Proteose. 

Peptone. 

Pepsin-HCl  diges- 
tion in  the 
stomach. 

I'loteose. 

Proteose. 

Polvpeptids. 
1 

Proteose. 

Peptones. 

1                     ^ 
Dipeptids. 

1 

Peptones. 

1 

Polvpeptids. 

/I 

^  1 
Amino-acids. 
Tyrosin. 

Tn-psin   diges- 
'     tion  in  the  in- 

Pulypeptids. 

Dipeptids. 

Tryptophan. 

Cystin. 

Leucin. 

testines. 

Dipeptids. 

Amino-acids. 

Aniiuo-acids. 
Prolin. 

Erepsin  diges- 
tion. 

Phenylalanin 

,  etc. 

The  above  shows  in  a  general  way  the  scheme  of  protein  digestion,  and 
is  reproduced  to  show  that  the  protein  molecule  does  not  hi*eak  up  in  an 
explosive  manner,  by  which  the  whole  molecule  disintegrates,  but  that  it 
t.ikos  place  in  stages,  and  that  a  larae  number  of  intermediary  bodies  arc 
possible  in  the  course  of  protein  digestion. 


The  Absorption  of  Products  of  Protein  Digestion 
from  the  Gastro-Intestinal  Canal 


From  what  was  said  above  it  is  evident  that  digestion  in  the  stomach 
<!«'('s  not  proceed  to  the  point  where  products  are  foiTned  that  are  ab- 
•  >r])able.  Hence  very  little  or  no  absorption  of  protein-digestiori-products 
takes  place  normally  (London-Abderhalden).  If  amino  acids  or  peptones 
jiic  introduced  into  the  stomach  they  are  absorl^ed  with  considerable  rapid- 
ity (Folin  and  Lyman,  1012  (a)). 

The  greatest  bulk  of  the  absorption  takes  place  from  the  intestines, 
Irom  which  the  lower  pcptids  and  amino  acids  are  absorbed  with  gi-eat 
i'lpi'^itv,  and  carried  bv  the  blood  stream  to  the  various  organs  of  the 


104  A.  I.  RINGER 

Until  about  ten  years  ago  it  was  bolieved  that  the  amino  acids  were 
resynthesized  into  senim  albumin  and  scrum  globulin  while  passing  through 
the  cells  of  the  intestinal  wall,  and  that  tlicse  two  products  constituted 
the  sole  source  from  which  all  the  bod>'  proteins  were  built  up.  The  rea- 
son for  that  view  was  that  while  amino  acids  could  be  found  in  the  in- 
testines, none  could  1)0  discovered  in  the  blood  stream.  Jhit  since  Van 
Slvke's  introduction  ^if  his  micro  method  for  amino  acid  detenninatioii, 
this  view  had  to  be  abandoned.  Amino  acids  were  then  found  to  be  pres- 
ent in  the  blood  of  fasting  animals  to  the  extent  of  3  to  5  mg.  per  100  c.c. 
of  blood,  and  after  a  meal  of  meat  the  figures  rose  to  10  and  11  mgs. 
(calculated  as  amino  acid  nitrogen;  Van  Slyke,  G.  M.  Meyer,  1913). 
Similar  results  were  also  obtained  by  Abderhalden  and  Lampe,  1912,  and 
Folin  and  Denis,  1912  (a). 


The  Fate  of  Absorbed  Amino  Acids  in  the  Blood 

The  amino  acids,  after  they  enter  the  blood  stream,  disappear 
from  it  fairly  rapidly.  This  we  know  from  various  sources.  First  from 
the  fact  that  there  is  but  a  very  moderate  rise  in  the  amino  acid  nitrogen 
content  of  the  blood  during  the  height  of  digestion  of  a  protein  meah 
Second  from  the  results  of  the  Xan  Slyke  and  Meyer  s  experiments  (1913) 
which  will  \ye  briefly  summarized. 

They  found  after  injecting  intravenously  into  a  dog  1.90  grams  of 
amino  acid  nitrogen  obtained  from  digested  casein,  that  the  blood  amino 
nitrogen  rose  from  4.05  mg.  per  100  c.c.  before  the  injection  to  19.7  mg. 
one-half  hour  after  the  injection  and  came  down  to  7.85  mg.  three  and 
a  half  hours  after  the  injection.  At  the  same  time  they  also  found  a 
rise  in  the  urea  nitrogen  of  the  blood,  and  on  examining  the  tissues  of 
the  body  they  found  that  their  amino  acid  nitrogen  content  was  increased 
considerably.  Thus  in  one  experiment,  after  injecting  intra-v-enously 
4.06  grams  of  amino  acid  nitrogen  they  found  that  the  blood  amino  nitro- 
gen, thirty  minutes  after  the  injection,  rose  from  3.0  mg.  per  100  c.c. 
to  45.2  mg.  In  the  liver  it  rose  from  31.5  to  93.5,  in  the  muscles  from  43 
to  70  mg.,  while  in  the  kidneys  it  rose  from  45  to  10f>  mg. 

From  these  e:^perinieiits  they  concluded  that  there  w^as  a  much  larger 
amount  of  amino  nitrogen  retained  in  the  tissues  than  in  the  blood,  and 
that  the  tissues  abstracted  the  amino  nitrogen  from  the  blood  at  a  rapid 
rate  so  as  to  keep  its  concentration  in  the  blood  at  a  comparatively  low  and 
constant  figure.  They  also  concluded  that  the  diilerent  tissues  have  differ- 
ent powers  of  absorbing  amino  nitrogen  and  that  the  amino  acids  are  kept 
in  the  tissues,  either  by  a  process  of  mechanical  absorption  or  in  a  loose 
chemical  union  witli  its  proteins. 


THE  PKOTEINS  AND  THEIR  METAB0LIS:5J:         105 


The  Fate  of  Amino  Acids  in  the  Tissues 

In  the  tissues  the  amino  acids  may  undergo  a  number  of  changes,  de- 
pcndiiiir  upon  the  requirements  of  the  cells.  They  may  undergo  de- 
jnainati"!!  by  a  process  of  hydrolysis  in  which  the  NIIo  is  replaced  by  an 
hydroxy]  radical,  giving  rise  to  the  corresponding  alcohol,  forming  hy- 

droxylacids. 

CII,  CH3 

i  I 

CHNH2  +  HOH    ->   CHOH     +     NH3 

I  I 

COOH  COOH 

Alanin  Water       Lactic  acid      Ammonia 

They  may  undergo  deamination  by  a  process  of  oxidation  giving  rise 
to  the  corresponding  keto  or  oxy-acids. 

CH3  CH3 

I  I 

cimHj  +  o     -^    CO      +   NH3 

I  'I  ■-'■' 

COOH  COOH 

Alanin      Oxygen       Pyruvic  acid    Ammonia 

They  may  Ixj  utilized  by  some  cell  in  the  synthesis  of  some  organic 
ImkIv  like  a  feniient,  product  of  internal  secretion,  scrum  albumin,  serum 
globulin,  nucleoprotein,  cell  protein,  etc. 


Urea  Formation 

Durinir  the  process  of  deamination  ammonia  is  set  free.  This  am- 
uMmm  is  converted  to  its  greatest  extent  into  urea.  We  know  that  from 
the  fact  that  if  an  ammonia  salt  is  fed  to  an  animal  most  of  it  is  excreted  in 
rlie  Innii  of  urea  (v.  Schroeder,  Salomon.  Zaleski,  Xencki  and  Pawlow), 
and  also  from  the  fact  that  if  a  single  amino  acid  is  fed  to  an  animal,  all 
"l"  the  nitrogen  is  excreted  as  urea  (Levene  and  Kober,  1909).  We  also 
know  that  the  liver  is  the  organ  which  has  the  greatest  power  of  convert- 
iiiir  ammonium  salts  into  urea,  and  if  amino  acids  are  perfused  througli 
tiio  suniving  liver,  urea  is  formed  (Fiske  and  Karsner,  1913;  Fiske  and 
'"^umner.  1014). 


106  A.  I.  RIXGEIi 

The  reaction  involved  is  no  doubt  the  following:  The  ammonia  as  it 
is  set  free,  combines  with  the  carbon  dioxid  and  water  of  Iho  blood  and 
tissue,  fomiing  ammonium  carbonate. 

/OH 
IL.0     +     CO.     -^     CO 

\oir 

Water         Carbon  Carbonic 

dioxid  acid 

/OH            XH3  /OXH, 

CO              +  ">        CO 

\0H         NH3  \oxn. 

Carbonic         Ammonia  Ammonium  carbonate 

acid 

The  ammonium  carbonate,  on  losing  one  molecule  of  water,  is  con- 
verted into  ammonium  carbamate. 

/OXH^  /OXH4 

CO               —    H.>0  -^        CO 

\OXH,  \NHo 

Ammonium  carbonate  Ammonium  carbamate 

which  substance,  on  losing  another  molecule  of  water,  is  converted  into 
urea. 

/oxH^  /mi., 

CO  —    HoO.       -^        CO 

\XHo  \NHo 

Ammonium  carbamate  Urea 

In  normal  individuals,  on  normal  diet,  from  80  to  00  per  cent  of  all 
the  nitrogen  is  excreted  in  the  fonn  of  urea,  while  about  3  to  6  -por  cent 
escapes  in  the  fonri  of  anmionia. 

Thus  the  nitrogenous  element  of  the  protein  molecule  plays  a  com- 
paratively simple  role  in  the  physiological  economy.  As  long  as  it  is  at- 
tached as  an  amino  radical  it  forms  one  of  the  binding  posts  of  the  amino 
acid ;  it  may  enter  into  the  formation  of  protoplasm,  it  may  be  built  up 
into  complex  protein  bodies,  ferments,  etc. ;  in  other  words  it  may  play  an 
important  role  in  the  life  of  cells.  The  moment  it  becomes  dissociated  it 
becomes  dead  matter,  ready  to  be  cast  off  and  excreted  in  the  urine. 

There  is  no  heat  liberated  in  the  transfonnation  of  proteins  to  the 
amino  acid  stage,  nor  is  there  any  heat  liberated  in  the  process  of  deamina- 
tion  or  transfonnation  of  the  ammonia  into  urea. 


I 


THE  PJ^OTEIXS  AXD  THEIR  METABOLISM  107 

The  Fate  of  the  Non-Niiro^enous  Fraction  of  the 
Amino  Acids 

Tlu'  fate  of  the  non-nitroiionoiis  fnictioii  of  the  amino  acid  in  tlie  ani- 
Tiuil  IkkH'  hiis  been  the  subject  of  carci'ul  study  (hiring-  the  par^t  fifteen 
vear^.  and  the  infirmatiou  obtained  forms  to-day  one  of  the  most  interest- 
iiiu  chapters  in  physiological  chemistry. 

\'iiri(»us  methods  have  been  employed  in  attacking  this  complex  prob- 
lem. The  amino  acids  were  fed  to  nonnal  aTiimals,  phlorhizinizcd  and 
th'painreatized  animals,  and  the  results  studied.  They  were  perfused 
tlirouiih  surviving  organs  like  liver,  kidneys  and  muscles,  and  products 
of  their  metabolism  sought  for.  They  vv'ere  incubated  with  different  ex- 
tracts of  tissues,  with  ground  up  tissues,  and  their  changes  stadied.  Chem- 
ical -ubstances  that  are  related  to  the  amino  acids  were  fed  to  animals 
with  the  object  of  determining  along  which  path  the  catabolism  of  the 
amino  acid  could  possibly  proceed. 

In  sununing  up  all  the  work,  the  following  conclusions  may  be  dra^vn:^ 
(lJ>/rocoU  is  completely  converted  into  glucose  (Ringer  and  Lusk,  1910). 
Afttjr  deamination  either  glycollic  acid  or  glyoxylic  acid  may  be  formed. 


CH2NH0 

I 
COOII    . 

Glycocoll 


COH 

I 
COOH 

'CHoOH 

I 
COOH 


Glyoxylic  acid 


Glycollic  acid 


Xeither  one  of  these  intermedial^  substances,  however,  has  been  found 
to  -ive  rise  to  sugar  when  admini.>-terod  to  diabetic  animals  (Grcenwald, 
il'l^  i  r/) ;  Ringer  and  Dubin,  unpublished). 

^ilycocoll  also  plays  a  role  in  the  formation  of  one  of  the  bile  salts, 
i!lye'.rholic  acid,  in  which  substance  it  exists  combined  with  eholic  acid. 
i  hi-  is  the  first  instance  where  a  product  of  protein  catabolism  may  be 
used  by  the  cells  in  the  synthesis  of  a  tlefinite  compound  that  is  essential 
for  tljo  welfare  of  the  animal  body. 

AJfinin  is  also  completely  converted  into  glucose.  On  deamination  it 
may  oive  rise  to  lactic  or  pyruvic  acid. 

'  I  liis  subject  is  thoroughly  reviewed  in  the  Third  Edition  of  Lusk's  ^'Science  of 
Nutrition."  pp.   184-207, 


108 


A.  I.  RINGER 


cir3 

I 
CTIXH2 

I 

COOH 


Alanin 


CII3 

I 
CHOH 

I 

coon 

cir, 
I 

CO 

I 

COOII 


Lactic  acid 


Pyruvic  acid 


Of  the  two  substances  lactic  acid  is  always  and  completely  converted  into 
jjclucose  (Mandel  and  Lusk,  1900).  Pyruvic  acid,  however,  Avhile  it  also 
goes  over  into  glucose,  does  not  do  it  in  a  quantitative  way  (Ringer,  1913 
(&)).  Dakin  and  Dudley  assumed  the  transformation  of  lactic  acid  into 
glucose  in  the  following  way : 

CH3  Clla  CH2OH  CIIoOH 

I  I  I  I      ' 

HOCK        ■->        CO        ->     HCOH  \  HCOH 


COOH 


COH 


COH 


IICOH 


CH3 

I 
HCOH 


CH3 

I 
CO 


CH20H 


HCOH 


HOCH 

I      ' 
HCOH 


COOH  COH  COH  COH 

2  Lactic  acid      Pyruvic  2  Glyceric  Glucose 

Aldehyd  aldehyd 

a-Amino  butyric  acid.has  not  been  investigated  properly.  In  one  single 
and  uncorroborated  experiment  the  giving  of  10.3  grams  of  the  substance 
to  a  phlorhizinized  animal  was  followed  by  the  excretion  of  3.0  gi'ams  of 
extra  glucose  (Ringer,  unpublished).  On  theoretical  grounds  this  sub- 
stance may  be  assumed  to  give  rise  to  propionic  acid,  which  was  shown 
to  be  converted  into  glucose. 


CH, 


CH, 


CH3  CH. 

1  I 

CH,      --       CHo 


CH. 


CHo 


Glucose 


CHXH, 

I 
COOH 


CHOH 

I 
COOH 


CO 

I 
COOH 


COOH 


CO. 


THE  PROTEINS  AND  THEIR  METABOLISM 


109 


The  fate  of  valin  in  the  body  is  not  definite.  Dakin  (1913)  has  found 
that  it  does  not  give  rise  to  either  ghieosc  or  acetone  bodies.  From  a  priori 
rea.^"uii'J-'«  and  from  experiences  that  were  obtained  with  substances  chcm- 
icalh'  related  to  it,  one  would  have  expected  the  transfonnation  into  glu- 
co-e  •^f  tiiree  of  its  carbons. 

The  fate  of  leucin  is  definitely  known.  It  does  not  give  rise  to  any 
lihico.-e.  but  ii'ives  rise  to  hirge  amounts  of  P-hydroxybutyric  aci<f  and 
;u(  tone.  Baer  and  Bkun,  1900  (a)  ;  Halsey,  1903;  Dakin,  1913;  Riager, 
Fiankel  and  Jonas,  1913  (a) ;  Embden  Salomon  and  Schmidt,  190G).  The 
fx-('aih»n  is  probably  the  first  to  suffer  oxidation  and  the  molecule  becomes 
onii verted  into  iosovalerianic  acid,  which  on  demcthylation  is  converted 
iiir.)  butyric  acid,  and  which  on  p-oxidation  is  converted  into  P-hydroxy- 
Imfviic  acid,  aceto-acctic  acid  and  acetone. 


(11.    CH3 
\/ 
("Ho 


CII,    CH3  CII,    CH,  CH3    CIIj 

\y  \/  \/ 

CH.,  CH2  P-CH2 

r         i  "  I  1 

P-CH2    Deami-    ^CH^^    Oxida-  P-CII^    Oxida-    a-CIIj,  Demethyl- 

!           nation        |            tion  |            tion  |            at  ion 

I         ^         I            >  I          >  I            > 

a-CHXHo           ouCHOH  o-CO  COOH 


COOH 
Leucin 


COOH 


COOH 


COo 

Isovalerianic 
acid 


(11     :  CH. 


GH^ 


CH 


CH 


CIL.  Oxidation  CHOH  Oxidation  CO  Decarboxylation  CO 
I     "    >     I  >     I ^  I 


CHo 

I 
COOH 

Butvric  acid 


CIL, 

I 
COOH 

P-hydroxy 

butyric  acid 


CIL 

I     " 
COOH 

Aceto-acetic 
acid 


CH. 


CO:, 


Isohuctn  and  normal  leucin. — In  Dakin's  experiments  (1913)  we  find 
an  increase  of  3.8  and  2.9  grams  of  glucose  after  administering  15 
urams  of  isoleucin.  Dakin  is  not  inclined  to  consider  that  as  conclusive 
I'luuf  that  it  is  glucogenetic.  P^rom  the  structure  of  the  normal  leucin, 
liouever,  one  may  assume  the  possibility  of  sugar  formation.  Normal 
valerianic  acid  may  be  formed  after  deamination  and  decarboxylation  and 
this  has  been  sho\NTi  to  be  glucogenetic  to  the  extent  of  three  of  its  carbons. 


110 


A.  I.  RIXGER 


That  normal  leucin  does  give  rise  to  glucose  was  demonstrated  by  Greeu- 
wald  (1910(e)). 

AspaHlr  acid  is  definifelv  known  to  "ive  rise  to  glncosc  to  the  extent 
of  three  of  its  carbons.  (Kingcr  and  Ln.-k,  1010;  Ringer,  Frankel  and 
Jonas,  VM'\  {h)).  It  does  not  give  rise  to  acetone  bodies.  In  all  probability 
the  process  of  its  conversion  into  glucose  is  the  following: 

COOH  COOH  coon  COOH 


CHo      - 

I 

CIIXHo 

I 

COOH 


I 

CHOII 

I 
COOH 


^    CIL, 

I 
CO 

I 

COOH 


CK. 

I    ' 
COOH 


CO., 


Aspartic  acid     Malic  acid     Oxalacetic  acid     Malonic  acid 


CO, 


COOH 

I 


CH3 

1 

CHOH 

1 

Hy 

CH., 

1 
CH^OH 

COOH 
Lactic  acid 

CO. 
dracrylic  acid 

Glucose 


Glutamic  acid  is  convertible  into  glucose  to  the  extent  of  three  of  its 
carbons.  It  does  not  give  rise  to  acetone  l:>odies.  (Lusk,  1908  (a)  ;  Ringer, 
Frankel  and  Jonas,  1913  (6)). 

After  deamination  it  probably  passes  Through  succinic  and  malic  stages 
and  then  proceeds  as  indicated  under  aspartic  acid. 

COOH       COOH     COOH     COOH     COOH 

:  I  I  I  i 

CHo                     CH.                Q\U                CH.  CH. 

'    "Deamination    |    Oxidation    |    Oxidation    |    Oxidation    |     -^  Glucose 
CH, CH,  — CIL CHo CHOH 


CHXH. 


CHOH 


CO 


COOH 


COOH 


COOH  COOH  COOH  CO. 

Glutamic  a-hydroxy-  «-k(»to  Succinic  Malic 

acid  glutaric  acid     glutaric  acid         acid  acid 

^-hydroxijglufamic  acid  is  convertible  into  glucose  to  the  extent  as  is 
glutamic  acid.     (Dakin,  1919). 


THE  PROTEINS  AND  THEIR  METABOLISM  ill 


It  does  not  ^ive  rise  to  acetone  Iwdios.     Its  conversion  into  glucose  in 
all  prol lability  is  also  through  a  malic  acid  stage. 
COOII  COOII  CO. 

i  I  


CH., 

1 

1 

L  liwll 

1 

CHXH, 

1 

*       V  llvyil 
1 

COOH 

1 

COOII 

i:J-hydroxyglutaraic 

CO. 
[Malic 

CH, 


^    CHOII 

I 
COOII 


■»    Glucose 


Lactic 
acid  acid  acid 

Serhi  is  converted  into  glucose,  in  all  probability  quantitatively.  After 
deaniination  it  may  give  rise  to  glyceric  acid,  which  is  convertible  into  glu- 
c()?t\    (Dakin,  Ringer  and  Lusk.) 

CH2OH 


CH.OH 

I 
CHNHo 


Deaniination 

^ > 


CHOII 


Glucose 


COOII  COOH 

Serin  Glyceric  acid 

Cyst  in  in  the  bod}'  is  broken  up  into  two  molecules  of  cystein. 
Clio  —  S  S  —  CH.  CH2SH 


CHNH, 


CHNH. 

I 
COOH 


^2  CIINII2 

I       •     ' 
COOII 

Cystein 


COOH 
Cystin 

Cystein  may  undergo  deamination  and  desulphurization  yielding  a 

ilirco  carbon  compound  which  is  completely  converted  into  glucose  (Dakin). 

riio  intermediary  products  are,  in  all  probability,  similar  to  those  of  serin. 

Cystein  to  a  small  extent  may  also  undergo  decarboxylation,  giving 

.  ise  to  thioethylamin,  which  on  oxidation  gives  rise  to  taurin. 

Cn.SII  CH.SH  CH2  —  SO2 

I         Decarboxylation      ]  Oxidation       I 


OH 


CHNIL 

I 
COOII 

Cvstein 


CH.NHo 


CHoNIL 


CO2 

Thioethylamin  Taurin 

This  taurin  is  used  by  the  liver  cells  to  combine  it  with  cholic  acid,  form- 
iiiii'  taurocliolic  acid,  which  is  one  of  the  bile  salts.     This  is  therefore  the 


112 


A.  I.  EIXGER 


second  illustration  of  the  }x)dy's  ability  to  utilize  split  products  of  protein 
for  synthetic  purposes.  Tlio  hair  and  nails  of  animals  are  especially  rich 
in  cystin  and  no  doubt  a  certain  proportion  of  the  eystein  goes  into  the 
formation  of  these  continually  growing  cflls. 

The  gr<?atest  portion  of  the  sulphur  fraction  of  the  eystein  molecule 
is  oxidized  to  a  snlplu'te  state  and  excreted  in  the  urine  in  the  form  of  in- 
organic salts.  A  sn»all  proportion  of  the  oxidized  sulpliur  combines  with 
ethereal  substances  like  cresol,  phenol  and  iiidoxyl,  probably  for  dctoxieat- 
ing  purpo  es,  and  is  excreted  in  the  urine,  while  a  third  portion  of  the 
sulphur  reaches  the  urine  in  an  unoxidized  fonn  (neutral  sulphur),  prob- 
ably in  the  fonn  of  taurin,  small  traces  of  eystein,  sulphocyanid,  etc. 

Lysin  is  completely  burned  in  the  body  without  leaving  any  clue  as 
to  the  path  of  catabolism.  It  does  not  give  rise  to  either  glucose  or  acetone 
bodies  in  the  intennediary  stages.  After  deaniination  it  may  pass  through 
a  glutaric  acid  stage, 

CHoX^IL  COOII 

r  "  I 


CIL: 

I 

I 

I 
CHXH, 


Deaniination 
^ 

and  Oxidation 


I 
CHo     - 

I 
CH2 

I 
COOH 


As  yet  unknown 
process  of  combustion. 


COOH  CO2 

Lysin  Gkitaric  acid 

Arginin  is  first  broken  up  into  urea  and  ornithin.  This  is  accom- 
plished by  a  ferment  arginase  which  is  found  in  the  liver,  kidneys,  intes- 
tinal mucous  membranes,  thymus  and  muscles.  (Kossel  and  Dakin,  1904 ; 
and  1905 ;  Otto  Riesser,  1906  (a)  ;  Charles  Kichet,  1894  (e)). 

NH 

H    i          / 
-K ;— C XIIo 


CIL,  — 

I    " 
CH.> 

I 
CH. 

I    " 
CHXIL 


Hvdro  lysis 


H;OH 


CILXIL 

I 
CH.,         + 

I     ' 
CH^ 

I 
CHNHo 


CO 


/NH, 
\NH, 


COOH 

Arffinin 


COOH 
Ornithin 


Urea 


THE  PKOTEINS  AND  THEIR  METABOLISM 


113 


Ornitliin  gives  rise  to  glucose  to  the  extent  of  three  of  its  carhon  atoms. 
( Dakin,  Ringer,  Frankel  and  Jonas,  1913  (&)).  After  deamination  it 
probably  passes  through  succinic  acid  stage. 

CH0XII2  COOH 


CH2 

I 
CHo 

I 
CHNH2 


Deamination 
and  oxidation 


CH. 


Q\l, 


■♦    Glucose 


COOH 


COOH 
Phenylalamn  and  tyrosin  liave  the  same  fate  in  the  animal  hody 


The 


former  can  be  converted  into  the  latter  on  perfusion  through  a  surviving 
liver.     (Embden  and  Balder,  1913). 

OH 


CH2 

CHNH2 

I 
COOH 

Phenvlalanin 


CH2 
CHNHg 


COOH 

Tyrosin 

They  are  burned  in  the  body,  giving  rise  to  acetone  bodies  in  the  in- 
termediary metabolism  (Ringer  and  Lusk ;  Dakin ;  O.  Neubauer  and  Gross, 
1010;  E.  Schmitz,  1910),  but  not  to  glucose. 

Phenylalanin  and  tyrosin,  as  will  be  seen  later,  are  indispensable 
amino  acids  (see  page  000)  i.  e.,  an  animal  cannot  maintain  itself  on 
proteins  which  do  not  contain  these  acids.  When  one  views  that  fact  in 
conjunction  with  the  relationship  that  exists  between  the  structure  of  the 
adrenalin  molecule  and  tyrosin,  one  is  justified  in  the  conclusion  that  these 
two  amino  acids  form  the  building  material  for  adrenalin,  even  though 
we  have  no  direct  proof  that  such  is  the  case.  (Stolz,  1904;  E.  Fried- 
man, 1905  (a)  ;  Abel  and  Crawford,  1897). 

OH 
/\0H 

K) 

CHOH 

I 
CH,NII  — CH3 

Adrenalin  or  Epinephrin 


114 


A.  I.  EINGER 


ProVui  is  burned  in  the  body,  passing  tlirongh  a  gluco?c  stage.  Three 
of  its  carbons  are  convertible  into  glucose.  (Dakin.  lOl^J ;  Jvinger,  Frankel 
and  Jonas.)  hi  all  probability,  similar  to  ghitaric  acid,  it  passes  througli 
a  succinic  acid  rfage.     It  does  not  give  rise  to  aceton  bodies. 


CIL, 

I 
CIL 

I     ' 
CHo 

I 
CH/ 


XII 


COOII 

I 
CII., 

I  '  - 

CH2 

COOII 


CO. 


Glucose 


COOII 

Prolin  Succinic  Acid 

The  fate  of  oxijprolin  has  not  been  worked  out  definitely.    Botli  prolin 
and  oxvprolin  are  intimately  related  to  the  pyrrol  ring 
CII 


NH 


which  fomis  the  framework  of  hematin,  one  of  the  important  derivatives 
of  hemoglobin.  Prolin  is  also  found  in  a  number  of  other  coloring  sub- 
stances of  the  l)ody,  like  in  hair,  the  skin  of  dark  races,  melanins,  etc. 
There  can  hardly  be  any  question  but  that  the  body  uses  prolin  and  oxy- 
prolin  in  thf-  manufacture  of  the  crloring  materials. 

The  fate  of  histidin  in  the  body  is  not  clear.  It  does  give  rise  to 
small  amounts  of  glucose  when  fed  to  diabetic  dogs  and  it  also  causes  a 
slight  rise  in  the  acetone  bodies  fonnation  when  perfused  through  the 
surviving  liver.  Keither  reaction,  however,  is  definite  nor  conclusive. 
We  must  theri  fore  wait  for  further  research  with  this  substance.  Because 
of  its  stnictural  relationship  to  creatinin,  the  possibility  of  its  being  the 
mother  substance  of  creatinin  has  been  suggested  by  Abderhaklen. 


CH  — xn 
IS   -N/^H 
I 

CIIo 

I  ^ 

CHXHo 


CII. 


CO 


-X— CII. 

\ 

C=:XH 

/ 

XH 


COOII 

Histidin 


Creatinin 


THE  PROTEINS  AIs^D  TIIEIE  METABOLISM 


115 


Tryptophan  does  not  give  rise  to  glucose  nor  to  acetone  bodies.  It  is 
,,ji<'  of  the  indisjK'usable  amino  acids  (see  paiic  125).  It  may  be  con- 
.-idered  the  mother  suhstance  of  thyroxin,  the  principal  substance  of  the 
hormone  of  the  thyroid  gland  (Kendal,  1919  (c)). 


ll/V 


cn,-CHxiio-coon 


iji 


CH.. 


cii^-coon 


H\/\/H  in\/\/o 

H     Nil  H     XH 

Trvpto]t]iaii  Thyroxin 

The  fate  of  the  amino  acids  in  the  body  may  be  summarized  in  the 

t'()lIowine:  table : 

TABLE  III 

FaTe  of  Amino  Acids  in  tiie  Animal  Body 


Araino-acid 

Cilycocoll    

\laiiin    

X'aliii    ^ 

Lt'iuin     I 

Ixdt'ucin    

Niirnml  Leucin 

Aspiirtic  Acid 

Glutamic  Acid    

(^-Iiydroxygkitaniic   Acid    . 

Serin    

Ivstin    

I.Vsin 

Aiijiiiin    (Ornithin)    

I'lifiiylalaiiin     

I  yi  (Kin    , 

I'lolin    

>\ypn)lin   

Ili>ti(lin     

Irypioplian    


Gives  Rise  to  Acetone 
Bodies 


+ 


Ten  of  the  amino-acids  are  known  definitely  to  give  rise  to  glucose,  and  it 
:>  very  possible  that  the  four  marked  with  the  cpiery  may  also  give  rise  to 
uhieose. 

It  was  found  by  Lusk  that  dogs  rendered  diabetic  by  means  of  pldo- 
:iiiziu  c'xcr*»te  3.0  grams  of  glucose  for  every  0.25  grams  of  protein  that 
th(>y  catabolize.  Lusk  and  Mandel  showed  that  severe  human  diabetics 
:!iay  excrete  sugar  in  the  same  proportion,  which  means  that  from  every 
»no  hundred  grams  of  proteins  catabolized.  fifty-nine  grains  of  sugar 
•:in  he  formed. 

This  does  not  yet  complete  the  tale  for  three  of  the  amino-acids  give 
•">o  to  not  inconsiderable  quantities  of  acetone  bodies.  Glucose  and 
i^-hydroxybutyric  acid  seem  therefore  to  be  the  two  important  stations  along 


116 


A.  I.  RIKGER 


the  highway  of  protein  mctaholisiu  tliroiigh  which  most  of  the  amino  acids 
have  to  travel  while  on.  their  catabolic  j)ath. 

Protein  Metabolism 

The  .rtudies  of  the  metabolism  of  proteins  date  back  to  the  days  of 
•BischofT  and  Voit,  in  th<*  middle  of*  the  last  coutury,  when  it  was  recog- 
mzf^d  that  the  nitrogen  excreted  in  (lie  urine  was  derived  from  the  catab(jl- 
ized  proteins.  Twenty-fonr  hours  are  usually  considered  the  unit  of  time 
t'>r  a  protein  metal>olism  experiment.  Analysis  is  made  of  all  the  ingested 
fo'jd  and  of  all  the  excreta.  By  determining  the  amount  of  nitrogen 
and  multiplying  that  figure  by  6.25,  the  protein  factor  is  obtained.  If 
the  amount  of  nitrogen  in  the  exci*eta,  urine  and  feces,  is  equal  to  the 
amount  of  nitrogen  in  the  food,  we  speak  of  the  individual  as  being  in 
a  state  of  nitrogenous  equilibriuni.  If  there  is  less  nitrogen  excreted  in 
the  urine  and  feces  than  was  ingested,  the  individual  has  stored  some 
of  the  ingested  nitrogen  in  the  body.  We  therefore  speak  of  his  being  in 
po-ritive  nitrogen  balance.  If,  on  the  other  hand,  more  nitrogen  is  ex- 
creted in  the  urine  and  feces  than  was  ingested  in  the  food,  the  individual 
must  have  lost  nitrogen  from  his  body,  and  we  speak  of  that  as  his  being 
in  a  negative  nitrogen  balance. 

If  an  animal  or  human  individual  is  allowed  to  fast  for  a  long  period  of 
time,  we  find  that  nitrogen  is  excreted  in  the  urine  throughout  the  entire 
period  of  the  fast  up  to  the  moment  of  death.  This  shows  that  protein 
destruction  goes  on  in  the  body  irrespective  of  any  protein  ingestion  in 
the  food.  The  amount  of  nitrogen  excreted  in  the  urine  gradually  di- 
minishes in  amount,  in  all  probability  due  to  the  gradual  depletion  in  the 
mass  of  the  body  proteins.  Thus  in  the  experiments  by  E.  and  O.  Freund 
ri901)  on  Succi  they  obtained  the  following  results: 

TABLE  IV 


Da.T  of  Fast 

Nitrogen  in  Urine 

Day  of  Fast 

Nitrogen  in  Urine 

1 

17.0 

12 

6.84 

2 

11.2 

13 

5.14 

3 

10.55 

14 

4.66 

4 

10.8 

15 

5.05 

o 

11.10 

16 

4.32 

6 

11.01 

17 

5.40 

7 

8.79 

18 

3.60 

8 

9.74 

19 

5.70 

9 

10.05 

20 

3.30 

10 

7.12 

21 

2.82 

11 

6.23 

THE  PKOTEIXS  Am^  TIIKIR  METAB0LIS:N[ 


117 


Kiniicr  aiul  Dubiii  in  cxporinionting  on  a  dog  weigliin.o-  17.0  kg.  which 
tasted  tor  forty-seven  days,  ohtaincd  the  following  results: 


tap.lf:  V 


Day  t.f  Fast 

Xitrogon  in 
Urine 

1      Day  of 
1         Fast 

Xifrniron  in 
Irine 

Dav  of 
Fast 

Nitrogen  in 
Urine 

1 

3.00 

'           14 

2.:>3 

30 

1.98 

2 

3.51 

!           15 

1.9.5 

31 

209 

3 

2.97 

i           16 

1 

1.93 

32 

2.04 

4 

2.99 

;      " 

2.05 

33 

1.96 

o 

2.87 

18 

1 

2.20 

37 

1.74 

6 

2.91 

19 

2.04 

39 

1.63 

7 

2.81 

1           20 

2.0S 

42 

1.55 

S 

2.96 

1          2^ 

1.03 

44 

1.44 

9 

2.89 

1          22 

2.04 

45 

1.39 

10 

2.C0 

1          23 

2.07 

46 

1.57 

11 

2.48 

24 

2.05 

47 

1.59 

12 

2.49 

26 

2.11 

13 

2.27 

28 

2.04 

During.  staiTation  the  various  processes  of  life  require  a  certain 
II  mount  of  fuel,  which  is  derived  from  the  body's  own  protein,  carbohy- 
drat<*  (glycogen)  and  fat.  If  the  necessary  amount  of  carbohydrate  and 
fat  is  supplied  in  the  food,  but  no  protein,  the  individual  is  kept  in  a  state 
«  t'  "iiirr(;i:{'u  hunger,"  and  after  five  or  six  days  tho  nitrogen  excretion 
rcaehes  the  lowest  level  that  is  compatible  with  life.  Landergren  calls 
that  tlie  minimal  nitrogen  metabolism,  whereas  Rubner  views  that  as 
representing  the  "wear  and  tear"  quota. 

Tal'Ie  Vr  gives  the  results  of  a  numlH?r  of  experiments  by  different 
antli(»r>  ou  the  urinary  nitrogen  excretion  in  man  when  kept  on  carbohy- 
'irarc  and  fat  diet  but  h'0(^  from  protein. 

l*r<  111  this  talde  we  seo  that  0.045  grams  of  nitrogen  per  kg.  of  body 
xv.i-h(  per  twenty-four  hours  is  the  minimal  amount  on  which  the  lx)dy 
'-11  uet  along.  It  represents  the  "wear  and  tear"  quota.  This  is  an  ir- 
H'rlneihle  minimum.  It  corresponds  to  that  part  of  the  protein  which  can- 
<i'  t  Itf  I'eplaced  dynamically  by  any  other  foodstuiT.  It  is  that  which  is 
n.-td  for  the  formation  of  blood  corpuscles,  honnones,  for  the  growth  of 


I,. 


Ill 


*.  -kill,  nails,  epithelial  cells,  etc. 


If  the  carbohydrates  arc  also  removed  from  the  diet  and  an  isodynamic 
'iiiaiitity  of  fat  added,  i.  e.,  if  an  individual  is  given  a  diet  free  from 
hoth  proteins  and  carbohydrates,  with  all  the  energy  requirements  supplied 


118 


A.  I.  PtIXGKR 

TABLE  VI 


Dav  of 

Nitrogen  \i\ 

liodv  WVight 

Nitrogen  per  Kg. 

Author 

Experiment 

Trine  in  Grams 

in   Kg. 

of  Body  Weiglit 

10 

3.8 

n4..o 

0.0.->l>4 

Folin 

4 

3.70 

09,7 

0.«)530 

Landergreft 

5 

3.5 

70.5 

0.0497 

F<»lin 

4 

3.04 

«2.4 

0.0487 

Eand«rrgren 

5 

2.7 

55.7 

0.0485 

Folin 

8 

3.12 

03.5 

0.0480 

Klenjpi-rer 

7 

3.34 

71.3 

0.0408 

Landcrgren 

7 

2.42 

57.5 

0.0421 

Roelie 

12 

2.0 

04.0 

0.0400 

Folin 

8 

2.51 

<>5.(> 

0.0395 

Kleniperer 

2.98 

70.2 

0.0391 

Thomas 

6 

2.01 

88.0 

0.0319 

Afklerfccr 

7 

1.84 

58.0 

0.0317 

Siven 

Average 

2.897 

00.0 

0.0440 

in  the  form  r»f  fat,  we  also  have  a  condition  of  nitrogen  hunticr  and  should 
expect  the  nitrogen  excretion  to  be  on  as  low  a  level  as  in  the  former  case. 
But  this  is  not  so.  With  fat  alone  the  protein  metabolism  rises  to  about 
double  the  ^'minimar'  level.  A  typical  experiment  is  that  of  Landergi'en's, 
which  is  tabulated  hei*e: 

TABLE  VII 


On  the  fourth  day  the  nitrogen  readied  the  '^minimal"  level  which 
wotild  have  continued  thus  had  not  the  carljohydrates  been  replaced  by 
fat  ill  the  diet.  I'hc  carlx^hydrates  have  th(^  power  of  sparing  body  pro- 
tein to  an  extent  whicli  is  not  p(]>ssessed  by  any  other  foodstuif.  A  (iict 
niade  u|>  so  that  half  tbc^  calorics  are  derived  fr«)m  carlH)hvdrates  ami  half 
from  far  will  give  the  same  results  as  a  diet  consisting  entirely  of  carlxdiy- 
d  rates. 

Landergreu  assumes  that  the  reason  why  protein  metabolism  is  higher 
when  carbohydrate  is  absent  from  the  diet  is  because  a  certain  ara<nint 
of  protein  is  destroyed  in  order  to  maintain  the  sugiir  concentration  of  the 
blood,  -which  is  always  kept  at  a  deiinite  level  even  during  stanation. 
He  designates  that  fraction  of  the  protein  metabolism  as  "glucose  nitro- 
gen.'- This  fraction  is  equivalent  approximately  to  0.045  gram  per  kgi 
of  body  weight.  Rubner  and  Cathcart  have  corrol>orated  Landei'gren's 
findings,  but  do  not  agree  with  his  interpretation. 


1 


Day 

Diet 

N'itrogen  in  Urine  in  Grams 

-^ 

1 

Carbohydrate 

8.91 

2 

Carbohydrate 

.5.15 

3 

Carl  lolivd  rate 

4.30 

^ 

4 

Carb<»livdrute 

3.76 

f 

5 

Fat  alone 

4.28 

* 

6 

Fat  alone 

8.86 

■4; 

7 

Fat  alone 

9.64 

THE  PROTEINS  AND  TIIEIK  METABOLISM  119 

The  Question  of  Optimum  Versus  Minimum  Protein  Diet 

When  protein,  in  amounts  corresponding  to  the  "wear  and  tear"  quota 
(0.045  grams  per  kg.  of  bodv  weight),  is  added  to  a  diet  consisting  of 
ear1)ohvdrates  and  fats  sufficient  to  cover  all  the  caloi^ic  requirements  of  an 
individual,  ho  will  not  maintain  nitrogenous  equilibrium.  For  short 
periods  of  time^  Siven  (1900)  was  able  to  maintain  himself  in  nitro- 
genous equilibrium  on  a  level  of  0.08  gram  per  kg.  of  body  weight  (almost 
double  the  "wear  and  tear"  quota). 

When  Voit  studied  the  nitrogen  excretion  of  a  number  of  individuals, 
who  lived  on  general  diets  following  the  dictates  of  their  appetites,  he 
found  the  average  excretion  for  a  man  of  70  kg.  in  body  weight  was  19 
grams  of  nitrogen  per  twenty-four  hours.^  He  therefore  came  to  the  con- 
clusion that  for  a  nonnal  man  to  keep  himself  in  a  good  condition  of 
nutrition  a  supply  of  118  grams  of  protein  per  day  was  necessary.  This 
corresponds  to  0.271  gram  per  kg.  of  body  weight  or  six  times  as  much 
as  the  "wear  and  tear"  quota. 

These  figures  of  Yoit's  were  obtained  after  a  statistical  and  not  after 
a  physiological  study,  and  therefore  caused  considerable  discussion  and 
inquiry  into  their  justification.  The  literature  is  filled  with  series  of 
experiments,  of  shorter  or  longer  duration,  tending  to  prove  that  physical 
comfort  and  nitrogenous  equilibrium  can  be  maintained  at  much  lower 
levels  of  protein  metabolism  than  Voit's  fig-ures.^  The  most  convincing  of 
these  are  the  ones  repoi-ted  by  Chittenden  and  Hindhede.  In  a  series 
of  well-planned  experiments  on  different  individuals,  representing  different 
classes  of  workers,  and  carried  on  for  a  period  of  eight  months,  Chitten- 
den (1904)  obtained  results  which  led  him  to  the  conclusion  that  normal 
adults  can  maintain  themselves  in  nitrogenous  equilibrium^  and  in  good 
health,  on  levels  from  0.098  to  0.171  gram  of  nitrogen  per  kg.  of  lx)dy 
weight,^  with  the  greatest  number  maintaining  equilibrium  with  0.120  to 
0.140  gram  per  kg.,  which  is  approximately  three  times  the  "wear  and 
tear"  quota.  Taking  the  mean  of  the  gi-eatest  number — 0.130  grams 
per  kg.  of  body  weight — a  man  of  70  kg.  would  require  9.1  grams  of 
nitrogen  per  day,  which  is  equivalent  to  57  grams  of  protein  or  one-half  of 
Voit's  figures. 

Hindhede  went  a  step  further  than  Chittenden.  His  life  for  twenty- 
cne  years  has  been  practically  one  continuous  experiment.  He  and  his 
family  lived  on  an  average  of  50  grams  of  protein  per  person  per  day  as 
the  maximum.     The  nitrogen  output  in  his  urine  kept  close  to  7.0  grams. 

^  For  a  complete  review  of  the  literaturo.  see  "Theorien  ties  Kiweissstoffweehsels 
iiebst  eini;reii  ])rakti?iclien  Konsequenzen  (ItTsellu-n."  L.  IJ.  ^londel.  Ergebnisse  tier 
Physiolojiie,  1011,  Vol.  XI,  pp.  418-52o. 

*0f  the  twenty-six  men  studied  one  maintaine<l  equilibrium  on  a  level  of  0.003, 
three  between  0.100  and  0.100,  three  between  0.114  and  0.119,  sixtei'n  between  0.120 
and  0.147,  two  at  0.150  and  0.1.51  and  one  at  0.171. 


120  A.  I.  RIXGER 

His  children,  who  were  brought  up  on  this  low  protein  diet,  measured  and 
weighed  as  much  as  others  two  years  older,  and  possessed  gxeat  endurance. 

In  another  series  of  experiments  his  assistant  lived  for  a  period  of 
178  days  on  a  diet  consisting  of  30.75  grams  of  protein  (4.76  gTams  of 
nitrogen)  with  a  total  food  supply  of  3500  calories  per  day.  Throughout 
the  entire  period  he  enjoyed  excellent  health  and  maintained  his  body 
weight. 

During  .l^he  period  of  the  World  War  opportunity  was  afforded  to  study 
this  problem  on  a  large  scale  because  of  the  forcejd  reduction  in  protein  in- 
gestion by  most  of  the  poo})Ie  of  the  Central  European  empires. 

Thus  Lichtwitz  (19H)  reports  the  maintenance  of  nitrogenous  equilib- 
rium by  citizens  of  Gottingen,  living  on  2100  calories  and  64.9  grams  of 
protein  per  day  and  weighing  70  kg. 

Jansen  (1917  (a))  carried  on  a  series  of  experiments  on  thirteen  indi- 
viduals for  periods  of  several  months  (^farch  to  May,  1917).  They 
were  engaged  in  light  work  and  received  00.5  grams  of  protein,  with  car- 
bohydrates and  fats  to  make  up  a  total  energy  supply  of  1600  calories  per 
day.  On  this  diet  they  were  unable  to  maintain  either  nitrogenous  equilib- 
rium or  body  weight. 

The  average  loss  per  day  was  0.28  kg.  of  body  w^eight  and  11.77  grams 
of  protein  (1.9  grams  nitrogen).  He  then  increased  the  carbohydrate 
and  fat  in  the  diet  to  the  extent  of  500  calories,  i.  e.,  they  received  the 
same  amount  of  protein,  but  a  total  energy  supply  of  2100  calories.  Doing 
the  same  amount  of  work,  they  were  able  to  maintain  nitrogenous  equilib- 
rium and  body  weight.  The  average  weight  of  his  subjects  was  62.1  kg., 
the  nitrogen  ingested  was  9.68  grams;  hence  the  amount  of  nitrogen  per 
kg.  was  0.156  gram,  or  slightly  above  Chittenden^s  figures. 

Thiese  experiments  by  Jansen  prove  definitely  that  it  was  not  the  low 
protein  in  the  diet  that  was  lesponsible  for  the  loss  in  body  weight  and 
negative  nitrogen  balance,  but  the  low  caloric  supply. 

The  question  of  optimum  versus  minimum  protein  supply  in  the  diet 
of  man  cannot  be  answered  on  the  basis  of  physiological  experiments  alone. 
In  a  great  many  instances,  it  is  purely  an  economic  question,  and  at  the 
same  time  psychological  factors  and  the  influence  of  habit  pla}'^  a  tre- 
mendous role. 

Advocates  of  a  low  protein  diet  describe  in  glowing  terms  the  psychic 
state  of  well-being  when  on  a  low  protein  diet,  whereas  the  man  accustomed 
to  a  full  protein  diet  complains  bitterly  when  forced  to  live  on  a  restricted 
protein  diet.    • 

The  consensus  of  opinion  of  most  workers  in  this  field  seems  to  be 
that  for  a  normal  individual  the  ingestion  of  Yoit's  quota  of  118  gi'ams 
of  protein  per  day  (19  grams  of  nitrogen  or  0.271  gram  per  kg.  of  body 
weight)  is  not  objectionable,  but  offers  no  special  advantage.     Man  can 


THE  PROTEINS  AND  THEIR  METABOLISM  121 

get  along  perfectly  well,  grow  to  maturity,  maintain  his  body  weight  and 
nitrogenous  equilibrium  on  protein  levels  exactly  one-half  that  of  Voit's 
(that  is,  0.K50  gram  per  kg.  of  hody  weight)  provided,  of  course,  that  he 
has  a  plentiful  supply  of  dynamogenetic  substances  in  the  form  of  carbohy- 
drates and  fats  to  cover  all  of  the  body  requirements. 

From  the  mere  fact  that,  the  hardest  possible  physical  work  is  not 
associated  with  any  increase  in  protein  metabolism  we  may  justly  con- 
clude that  protein  was  not  intended  for  dynamogenetic  purposes.  Its  main 
function  is  to  supply  the  "wear  and  tear"  quota,  '^growth'^  quota  with  a 
reasonable  surplus  to  allow  for  resei-ve  and  "factors  of  safety." 

Sufficient  data  seem  to  have  been  gathered  to  date  to  show  that  0.130 
gram  of  nitrogen  per  kg.  of  body  weight  per  twenty-four  hours  covers  all 
of  these  requirements. 


The  Function  of  Protein  in  the  Diet 

Incomplete  Proteins 

The  object  of  all  food  is  to  supply  fuel,  which,  in  the  process  of  its 
catabolism,  will  yield  energy  to  the  cells.  The  use  of  protein  sei*ves  a 
double  function.  While  it  may  be  used  for  dN-namogenetic  purposes,  of 
far  greater  importance  is  its  use  in  supplying  the  building  stones  of  the 
protein  to  the  body,  i.  e.,  the  amino  acids. 

Originally  it  was  believed  that  the  peptones  in  the  digested  protein 
were  the  products  that  were  resorbed  and  used  for  protein  regeneration, 
and  that  the  protein  derived  from  thei  same  species  were  utilized  to 
gi'eater  advantage  than  proteins  derived  from  foreign  species  (Michaud, 
1909).  It  was  further  believed  that  in  those  peptones  were  nuclei  of 
linked  amino  acids,  which  con-esponded  to  those  of  the  animals  experi- 
mented upon,  which  made  it  possible  for  that  animal  to  maintain  equilib- 
rium with  a  smaller  amount  of  nitrogen  derived  from  protein  that  was 
similar  to  its  own  protein.  This  conception,  however,  cannot  stand,  in 
view  of  the  results  obtained  by  Loewi  (1902  (a) ) .  He  was  the  first  to  keep 
an  animal  on  a  diet  consisting  of  carbohydrates  and  fats,  with  all  the 
nitrogen  that  it  required,  supplied  in  the  form  of  digested  protein,  that 
gave  no  biuret  reaction,  i.e.,.  digested  to  the  amino  acid  stage;  proving 
that  the  animal  body  is  capable  of  synthesizing  its  own  protein  from 
the  elementary  amino  acids.  These  experiments  have  been  repeated  by 
Abderhalden  and  corroborated  in  a  very  convincing  way.  He  not  only 
cleared  up  the  problem  as  to  the  possibility  of  synthesizing  protein  from 
the  simple  amino  acids,  but  also  introduced  a  new  method  for  studying 
whether  cei-tain  amino  acids  were  dispensable  or  indispensable  in  the  ani- 
mal economy,  and  whether  the  body  has  tbe  power  of  producing  them 


122 


A.  I.  RINGER 


de  novo  or  iiot.     Abderhalcleu  prepared  a  mixture  of  amino  acids  con- 
sistinjr  of  the  followiiiir: 


^      Amino  Acid 

Orams 

Xitrofji'H  Content  in  Grams 

GlvpocoH         

.'>.0 

10.0 
.3.0 
2.0 
n.O 

10.0 
.'>.0 
0.0 

15.0 
5.0 
5.0 
5.0 
5.0 

10.0 
5.0 
5.0 

0  03.35 

Alauin . 

1.5730 

Serin    .- 

0.4002 

Cvstin    

0.2330 

Valin    

0.5980 

Leucin    

1.0690 

Isoleiicin 

0  5345 

A'^partic  Acid 

0  5265 

Clutmnic  Acid   

1.4250 

Phcnvlalaiiiii 

0  4"i>45 

Tvro'sin    

0.3370 

Lvsin  (COa)    

0  9585 

Ar«''inin  (CO3) 

1  6090 

Prolin   

1.2170 

Histidin    

1,2980 

Tryptophan    

0  6860 

100.0  grama 
amino  acids 

=          13.87  grams  nitrogen 

Of  this  mixture  he  gave  25.  grams  per  day  to  dogs  whose  nitrogen  metabo- 
lism had  been  studied  for  periods  of  over  seventy  days.  In  addition  to  the 
amino  acids,  the  dogs  received  daily  2.0  gi-ams  of  predigested  nucleic  acids 
from  thymus  and  yeast,  50.0  grams  of  a  mixture  of  glycerin,  oleic,  stearic 
and  palmitic  acids,  20,0  grams  of  cholesterin,  50.0  grams  of  glucose,  5.0 
grams  of  nitrogen-free  bone  ash  and  salts.  This  experiment  lasted  for 
eight  days,  and  throughout  the  entire  period  the  animal  was  able  to  main- 
tain nitrogenous  equilibrium  and  to  retain  its  body  weight. 

The  remarkable  thing  about  this  experiment  is,  that  the  animal  received 
all  of  its  food  in  its  elementary  fonn,  and  it  had  to  synthesize  not  only  its 
own  protein,  but  also  its  fat. 

This  method  of  study  is  of  great  importance^  because  it  enables  us  to 
make  any  kind  of  desirable  mixture  of  amino  acids,  and  also  enables 
us  to  eliminate  one  or  more  amino  acids  and  study  their  individual  influ- 
ences. 

Thus  lie  found  that  an  amino  acid  mixture,  containing  no  glycocoll  or 
prolin,  will  enable  an  animal  to  maintain  nitrogenous  equilibrium.  He  also 
found  that  he  can  replace  arginin  by  ornithin  and  obtain  nitrogenous 
equilibrium.  This  proves  that  the  body  is  capable  of  fonning  its  own 
glycocoll  and  prolin  and  that  the  arginin  union  can  be  accomplished  in 
the  body. 

He  also  proved  that  animals  can  utilize,  with  ecpial  completeness,  the 
amino  acid  mixtures  obtained  fi-om  the  following  digested  proteins:  casein, 
ox  beef,  milk  powder,  c^g  albumin,  horse  meat  and  dog  meat. 

Incomplete  Proteins. — In  the  early  studies  of  protein  metabolism  it 
was  discovered  that  certain  proteins  could  not  maintain  nitrogenous  equilib- 


THE  PKOTEIXS  AND  THEIR  METABOLISM 


123 


riiim.  Gelatin  was  foinul  to  be  one  of  these.  No  matter  bow  mucb  gela- 
tin was  administered  to  an  animal,  tbe  animal  would  still  continue  to 
burn  some  of  its  own  protein  in  addition.  Knmimacher  (ISDOa)  went  so 
far  as  to  administer  all  of  the  animal's  caloric  requirements  in  the  fonn  of 
gelatin,  but  was  not  able  to  obtaiu  nitrog<*uous  ecjuilil^rium.*  Various  the- 
ories were  advanced  which  were  suppo.sed  to  explain  the  reasons  for  this. 
Kaufl'maii,  in  11)05,  conceived  the  idea  that  the  explanation  niav  be  fuuiul 
in  the  fact  that  gelatin  lacks  certain  amino  acids  which  may  be  indispens- 
able to  the  animal  organism.  These  are  tiyptophan,  tyrosin  and  cystin. 
He  therefore  added  small  amounts  of  these  to  gelatin,  carried  out  a  series 
of  experiments  on  man  and  dog,^nd  found  that  nitrogenous  equilibrium 
could  be  maintained  under  those  circumstances.  Abderhalden  confimied 
the  experiments  and  went  a  step  further.  lie  took  casein,  digested  it  to 
the  amino  acid  stage,  and  fed  it  to  a  dog  for  a  period  of  seven  days.  Dur- 
ing those  seven  days  the  dog  gained  20.0  grams  in  weight  and  retained 
0.12  gram  of  nitrogen  per  day.  (See  Table  VIIT,  Section  II.)  During 
the  succeeding  six  days  the  animal  was  given  a  corresponding  amount 
of  casein  digest  minus  tryptophan.  The  animal  lost  250.0  grams  in  body 
weight  and  lost  nitrogen  to  the  extent  of  0.83  gram  per  day  or 
5.0  grams  for  the  period  of  six  days.  "  (See  Table  VIII,  Section  III.) 
During  the  succeeding  six  days  the  animal  was  put  back  on  its  original 
diet.  It  regained  100.0  grams  in  weight  and  on  the  fourth  day  established 
nitrogenous  equilibrium. 

TABLE  VIII 
Abderhaldex's  Experiments 


DOG  WAS  FED  22  CRAMS  OF  PKEDIGESTED  DOG  MEAT.      EXPERIMENT  SHOWS  THAT  NITROGEN- 
OUS EQUILIBRIUM  AJSD  BODY  WEIGHT  CAN  BE  MAINTAINED  ON  IT 


Day 

Diet 

Body 

Weight 

in  Grams 

Nitrogen 
in  Food 

Total 
Nitrogen 
Excretion 

Nitrogen 
Balance 

1 

2 

3 

4 

5 
6 

7 

22  grams   of   predi- 
gjestcd  dog  moat 
2  grams    predigostod 
nucleic  acid 
50  gr.  glycerin-fat 
mixture 
2  gr.  cholesterin 
50  gr.  glucose 
5  gr.  bone  ash  salts 

8250 

8245 

8240 

8245 
8240 
8250 
8250 

2.50 

2.50 

2..50 

2.50 
2.50 
2.50 
2J50 

2.27 

2.32 

2.32 

2.32 
2.32 
2.35 
2.26 

+  0.23 

-f  O.IS 

-f  0.18 

-f  0.18 
-1-0.18 
4-0.15 
-f-0.24 

Total                

i:..50 

16.16 

-4-1.34 

+  0.19 

*For  complete  review  of  literature  see  Murlin,  J.  R.,  American  Journal  of  Physi- 
olof/tf,  1907,  vol.  19,  p.  285  and  1007,  vol.  20,  p.  234. 


124 


A.  I.  EIXGEE 


II 

DOG  WAS  FEp  18  GRAMS  OF  PREDICESTED  CASF.IX.      EXPERIMENT  PROVES  THAT  NITROGENOUS 
EQUILIBRIUM    AND   BODY  WOGHT  CAN    BE    MAINTAINED   ON    IT 


Day 

Diet 

Body 

Weight 

in  Grams 

Nitrogen 
in  Food 

Total 
Nitrogen 
ExcretrSn 

Nitrogen 
Balance 

41 
42 
43 

44 
45 
46 
47 

18  grama  of   predi- 
gested  casein 

The  rest  as  above 

8300 
8315 

8320 
8310 
8320 
8320 
8320 

2.51 
2.51 

2.51 
2.51 
2.51 
2.51 
2.51 

2.32 
2.37 

2.42 
2.20 
2.40 
2.41 
2.42 

4-0.19 
4-0.14 

4-0.09 
4-0.11 
4-0.11 

4-0.10 

4-0.09 

Total    

17.57 

16.54 

4-  0.83 

4-  0.12 

i 

III 

DOG  WAS  FED  22  GRAMS  OF  PREDIGESTED  CASEIN,  MINUS  TRYTOPIIAN.  EXPERIJIEXT  PROVES 
THAT  ANIMAL  LOSES  ITS  OW.X  NnTROGETN'  BY  BEING  IN  NEGATIVE  NITROGEN  BALANCE, 
AND  ALSO  LOSES  IN  BODY  WEIGHT 


Day 

Diet 

Bodv 

Weight 

in  Grams 

Nitrogen 
in  Food 

Total 
Nitrogen 
Excretion 

Nitrogen 
Balance 

48 
40 
60 

51 
52 
53 

22  g  r  a  m  8   of  predi- 
gested    casein    mi- 
nus tryptophan 

The  rest  as  above 

8290 
8300 

8250 
8210 
8150 
8070 

2.52 
2.52 

2.52 
2.52 
2.52 
2.52 

3.03 
3.07 

3.67 
3.65 
3.40 
3.30 

—  0.51 

—  0.55 

—  1.15 

—  1.13 

—  0.8S 

—  0.78 

Total          

15.12 

20.12 

—  5.00 

—  0.83 

IV 

DOG  WAS  FED  20  GRAMS  OF  PREDIGESTED  CASEIN  PLUS  TRYPTOPHAN.  EXPERIMENT  SHOWS 
THAT  NITROGENOUS  EQtriLIBRIUM  WAS  REACHED  ON  THE  FOURTH  DAY.  ANIMAL  GAINED 
IN   WEIGHT  PROVING  THAT  TRYPTOPHAN  IS  AN  ESSENTIAL  AMINO  ACID 


Day 

Diet 

Bodv 

Weight 

in  Grams 

Nitrogen 
in  FockI 

Total 
Nitrogen 
Excretion 

Nitrogen 
Balance 

54 
55 
56 

57 
58 
59 

22  g  r  a  m  s    of   predi- 
gested  casein  plus 
tryptophan 

The  rc.<t  as  above 

8100 
8125 

8150 
8150 
8150 
8170 

2.51 
2.51 

2.51 

2.51 

2.51 

'  2.51 

2.97 
2.87 

2.62 
2.4S 
2.46 
2.51 

—  0.46 

—  0.36 

—  0.11 
4-0.03 
4-0.05 

0.00 

Total    

15.06 

15.91 

—  0.85 

—  0.14 

THE  PROTEINS  AND  THEIR  METABOLISM 


125 


POG  WA.S  FED  25  CRAMS  OF  THK  AMINO  ACID  MIXTURES  A«  THE  SOLE  SOXJRCE  OF  NITROGEN 
SUPPLY.  EXPERIMENT  PROVES  THAT  NITROCIENOU.S  EQUILIBRIUM  AND  BODY  WEIGHT 
CAN   BE  MAINTAINED  ON  IT 


Day 

Diet 

Bo<ly     , 
Weight 
in  Grams 

Nitrogen 
in  Food 

Total 
Nitrogen 
Excretion 

Nitrogen 
Balance 

60 
61 

62 
63 
64 
65 
66 
67 

2o  grains  of  amino 
acids  mixture 

The  rest  as  above 

8100 

8200 

8200 
8200 
8200 
8200 
8200 
8200 

3.47 

3.47 
3.47 
3.47 
3-47 
3.47 
3.47 
3L47 

3.15 

3.27 
3.40 
3.58 
3.48 
3.49 
3.34 
3.65 

+  0.32 

+  0.20 
+  0.07 

—  0.11 

—  0.01 

—  0.02 
+  0.13 

—  0.18 

Total    

27.76 

27.36 

+  0.40 
4-  0.05 

Average    

These  experiments  are  of  the  utmost  importance  because  they  show 
the  vahie  of  tryptophan  in  the  physiological  economy.  They  prove  defi- 
nitely that  if  an  animal  is  kept  on  a  diet  free  from  tryptophan,  the  body 
has  to  burn  its  own  protein  to  supply  tryptophan  to  the  cells  that  require 
it.  (See  the  relationship  between  tryptophan  and  thyroxin,  the  active 
principle  of  the  thyroid  secretion,  pa^i^e  115.) 

The  proteins  that  do  not  contain  all  the  indispensable  amino  acids  are 
designated  incomplete  proteins,  and  the  above  experiment  shows  that  a 
complete  protein  like  casein  can  be  made  incmnplete  and  cause  it  to  be  a^ 
non-sustainer  of  nitrogenous  equilibrium  by  aierely  removing  the  trypto- 
phan. 

The  study  of  the  physiological  values  of  the  incomplete  proteins  and 
the  influence  of  the  individual  amino  acids  have  been  carried  on  in- 
tensively for  the  past  fifteen  years. 

In  1907  Hopkins  and  Willcock  published  a  series  of  experiments  on 
mice.  They  fed  mice  on  a  diet  in  which  all  the  protein  was  supplied  in 
the  form  of  zein,  a  protein  derived  from  maize,  containing  neither  lysin 
nor  tr\'ptophan.  The  zein  was  mixed  with  carbohydrates,  fats,  lecithin 
and  salts.  In  the  first  series  of  experiments  five  young  mice  were  kept  on 
this  diet  for  seven  days.  On  the  seventh  day  they  all  showed  the  follow- 
ing losses  in  weight  in  per  cent:  11.8,  17.6,  13.1,  23.2,  27.1. 

As  a  control,  four  mice  were  kept  on  a  similar  diet,  but  the  zein  was 
replaced  by  a  similar  quantity  of  casein.  On  the  seventh  day  the  following 
increases  in  weight  in  per  cent  were  recorded:  20.2,  21.8,  9.1,  21.0. 

One  of  the  mice  of  the  first  series  was  then  given  half  of  its  protein 
in  the  form  of  zein  and  the  other  half  in  the  form  of  casfein,  and  it  promptly 
began  to  gain  in  weight.  After  fifteen  days  it  gained  in  weight  to  the 
extent  of  46  per  cent. 


12G 


A.  I.  KIXGEE 


In  another  series  of  experiments,  also  on  young  mice,  they  studied  the 
leng-th  of  time  the  animals  were  able  to  survive  the  zein  diet,  and  com- 
pared it  with  the  controls  that  received  two  per  cent  of  tryptophan  in  ad- 
dition to  zein.    They  found  that  of  fifteen  mice  kept  on  the  zein  diet  all 

died  between  the 
twelfth  and  twenty-sec- 
ond day,  whereas  of  the 
fifteen  on  the  zein  plus 
tryptophan  diet  only 
three  died  before  .  the 
twentieth  day  and  all 
the  others  lived  from 
twenty-four  to  forty-five 
days. 

There  is  therefore 
no  question  whatsoever 
but  that  the  addition  of 
tryptophan  prolonged 
the  time  that  the  ani- 
mals could  live  on  zein. 
In  studying  the  weights 
of  the  animals,  however, 
they  could  not  find  any 
differences,  i.e.,  t  h  e 
animals  lost  about  as 
much  in  weight  with 
the  tryptophan  as  with- 
out it. 

Osborae  and  Men- 
del took  up  the  study  of 
this  subject  on  a  very 
large  scale  (1011). 
Tiiey  kept  thousands 
of  rats   for  periods  of 


D/^s 


4     a    12    16    20    24  28  32   36   40  44  48 


Diagram  I.  Diagram  constructed  from  the  results 
of  Kopkms'  and  Willccck's  experiments  5,  6,  7.  The 
heavy  lines  show  the  survival  periods  (in  days)  of 
twenty  one  individual  mice  upon  the  zein  diet  with 
tyrosiii.  The  light  lines  show  the  same  for  nineteen 
mice  upon  the  zein  diet  with  tryptophane. 


years,  under  absolutely 


controllable  conditions 
of  diet.  They  were  thus 
ahle  to  study  the  influ- 
ence of  isolated  food 
substances.  They  found 
tht?  study  of  the  changes  in  the  body  weight  of  the  rat  a  most  satisfactory 
index  of  the  rate  of  growth.  They  selected  the  white  rat  because  it  is 
easily  reared  and  cared  for  and  because  its  food  requirements  are  com- 
paratively small.     It  also  offers  advantages  because  of  the  fact  that  it 


THE  PROTEIXS  iVNB  THEIR  METABOLISM 


127 


thrives  well  on  unvaried  diets  and  maintains  its  health  even  though  con- 
stantly confined  to  a  cage.  As  the  longevity  of  the  white  rat  is  ahout 
three  years,  they  were  able  to  study  the  influence  of  certain  diets  practically 
throughout  the  whole  life  time  of  the  animal. 

From  hundreds  of  experiments  published,  four  are  selectied  here  to 
illustrate  the  physiological  value  of  some  of  the  amino  acids. 


210 

^ 

3 

\ 

Vc 

190 

N 

k 

\ 

X 

170 

V 

\, 

\ 

150 

^ 

- 

V 

s, 

/■ 

'N 

"v 

130 

^ 

% 

.< 

y 

\ 

r* 

— ^ 

^ 

Y. 

-J 

110 

1 

^c 

TR"! 

pTn= 

>HAK 

■i 

^ 

7^ 

( 

^    1 

^ 

4' 

A 

¥ 

90 

1 
^ 

/^ 

T 

^; 

■ 

m 

ff 

f 

70 

A 

r 

X*' 

« 

A 

*/ 

" 

^^ 

££i 

</ 

/ 

90O< 

f 

^v^^1 

-/ 

i 

11 

DAYS        20        40         60        80        100.     120       140        160        180       200 
Diagram  II  illustrates  graphically  the  result  of  Osborne  and  MendeVs  experiments 


Rat  Ko.  710  was  kept  under  observation  from  May  9,  1913,  to  Sep- 
tember 5, 1013,  a  period  of  120  days.  During  that  period  the  animal  lived 
on  the  following  food  mixtures:  zein,  18.0  grams;  protein-free-milk,  28.0 
grams;  starch,  27.0  grams:  butter  fat  and  lard,  27.0  grams;  water,  15  c.c. 
The  influence  of  this  diet  on  the  animal's  body  weight  is  presented  in 
Table  IX.  Every  one  of  the  rats  that  was  kept  on  this  diet  lost  in  weight. 
Rat  710  lost  39  per  cent  of  its  body  weight  in  120  days. 

The  experiment  on  Rat  1519  started  on  May  9,  1913,  and  ended  Nov. 
7,  1913.  Between  ^lay  9  and  August  8  it  was  kept  on  a  mixture  of  zein, 
10.92  grams,  tryptophan,  0.54  gram,  the  rest  as  al)Ove.  During  this 
period  the  animal  lost  weight  steadily,  reaching  the  lowest  level  of  100.0 
grams  on  August  8 ;  0.54  gram  of  lysin  was  tlu^n  added  to  the  diet. 
There  followed  an  immediate  gain  in  body  weight,  reaching  the  highest 


128 


A.  T.  RINGER 


TABLE  IX 

OSBOENE  AND  MeXDEL's  EXPERIMENTS 
RAT   710 


Boily 

Bodv 

Date 

Diet 

Weight 

Date 

Weight 

in  Grams 

in  Grams 

1913 

* 

1013 

Mav   9 

18  gram?  zein 

218 

July 

11 

168 

13          ... 

28  grains  protein-free  milk 
27  grams  starch 

218 

15 

169 

16 

212 

18 

iro 

20 

27  grams    butter    fat    and 

205 

22 

159 

23. 

lard 

201 

25 

165 

27 

15  c.c.  water 

199 

29 

156 

31 

191 

Aug. 

1 

157 

June  3 

194 

5 

147 

6 

186 

8 

154 

10 

184 

12 

148 

13 

187 

15 

150 

17 

183 

19 

143 

20 

180 

22 

144 

24 

175 

26 

137 

27 

180 

29 

138 

July   1 

177 

Sept- 

2 

136 

4 

177 

5 

133 

8 

170 

ILVT    1519 


Bodv 

Body 

Date 

Diet 

Weight 
in  Grams 

Date 

Weight 
in  Grams 

1913 

•      1913 

May  9 

16.92  grams  zein 

128 

Aug.  15 

109 

13 

0.54  gram  tryptophan 

122 

19.. 

109 

16 

The  rest  as  above 

123 

22 

113 

20 

117 

26 

118 

23     

115 
114 

29 

Sept.     1 

118 

27 

119 

30 

113 

5 

118 

June  3 

111 

109 

9 

12 

116 

6 

116 

10 

100 

16 

118 

13 

107 

i            19 

121 

17 

105 

23 

122 

20 

106 

2G 

120 

24 

106 

30 

123 

27 

105 

Oct.      3 

129 

July   1 

106 

7 

135 

4........ 

107 

10 

143 

8 

102 

14 

150 

11 

102 

17 

loO 

15 

104 

21 ;. 

148 

18 

103 

24 

147 

22 

103 

28 

148 

25 

102 

31....... 

149 

29 

102 
100 

N^ov.     4 

7 

145 

Aug.  1 

141 

5 

100 

8 

100 

12 

0.54  gram,  lysin  added 

104 

, 

THE  PROTEINS  AND  THEIR  METABOLISM 


129 


TABLE  X 
BAT  1773 


Body 

Body 

Date 

Diet 

Weight 
in  Grams 

Date 

Weight 
in  Grams 

Sept.  23,  1913 

70 

Dec. 

5,  1913 

78 

26 

66 

9 

79 

30 

zem 

61 

12 

81 

Oct.      3 

58 

16 

86 

7 

57 

19 

88 

10 

56 

23 

93 

14 

•53 

26 

99 

17 

53 

30 

101 

21 

49 

Jan. 

2,  1914 

105 

24 

49 

6 

112 

28 

48 

9 

113 

31 

46 

13 

115 

Sow     4 

46 

16 

118 

7 

45 

20. ..... . 

120 

11 

43 

23 

121 

14 

41 

27 

125 

18. 

zein  +  tryptophan  -f-  lysin 

47 

30 

130 

21 

67 

Feb. 

3 

132 

25 

67 

6 

13.1 

28 

71 

10 

137 

Dee.      2 

76 

BAT   1900 


Body 

Body 

Date 

Diet 

Weight 
in  Grams 

Date 

Weight 
in  Grams 

Nov.   10,  1913 

49 

Jan.      1,  1914 

55 

13 

zein  +  lysin 

50 

5 

65 

17 

45 

8 

69 

20 

45 

12 

80 

24 

43 

15 

83 

27 

44 

19 

87 

Dee.      1 

40 

22 

90 

4 

39 

26 

91 

8 

zein  -f  tryptophan 

39 

29 

98 

11 

39 

Feb.      2 ,. 

99 

15 

41 

6 

103 

18 

42 

9 

113 

22 

43 

25 *.. 

42 

29 

zein  -f  tryptophan  -f  lysin 

49 

point  of  150  grams  on  October  14.  It  will  be  noticed  in  this  experiment 
that  on  zein  plus  tryptophan  the  loss  in  weight  was  not  as  marked  as  on 
zein  alone  (rat  710).  In  many  other  experiments,  Osborne  and  Mendel 
found  that  on  zein  and  tryptophan  the  animals  were  able  to  maintain  their 
body  weight,  but  in  no  instance  was  an  animal  able  to  grow  until  after 
lysin  was  added.  This  led  them  to  differentiate  between  maintenance 
and  growth  in  nutrition.     AYithout  tryptophan,  they  showed,  all  animals 


130  A.  I.  RIXGER 

win  lose  in  body  weight  quite  sharply;  after  adding  tryptophan,  tlic  curve 
of  body  weight  bcx'omes  more  horizontal.  For  an  adult  to  just  maintain 
his  body  weight  is  perfectly  normal.  Cut  merely  maintaining  body  weight 
for  a  child  or  growing  animal  is  a  decided  al)n<»riiiality.  They  have  to 
grow,  and  growth  dues  n';t  occur  nntil  lysin  is  added  to  the  diet. 

The  records  of  ilats  1773  and  lUOO  are  corroborative  of  the  first  two. 

From  all  the  above  data,  the  conclusion  must  be  reached  that  the  pro- 
teins in  the  dietary  of  all  animals  fulfill  a  scries  of  functions  which  are 
not  fulfilled  by  any  of  the  other  foodstuffs.  They  supply  amino  acids 
which  the  body  itself  cannot  manufacture.  Tyrosin,  tryptophan  and  lysin 
are  indispensable  amino  acids  without  which  nutritional  equilibrium  can- 
not be  established.     Only  plant  cells  have  the  power  of  synthesizing  these. 

For  a  protein,  therefore,  to  be  physiologically  adequate,  it  must  con- 
tain all  of  these  amino  acids  and  in  sufficient  quantities. 

The  study  of  the  protein  metabolism  really  resolves  itself  into  a  study 
of  the  metalxdism  of  the  amino  acids.  When  we  speak  of  a  minimum 
protein  requirement,  we  may  in  reality  translate  that  into  a  minimum  re- 
quirement of  indispensable  amino  acids  and  the  "wear  and  tear"  quota 
may  really  represent  that  amount  of  protein  w^hich  contains  all  the  indis- 
pensable amino  acids  that  are  necessary  for  our  maintenance. 


The  Influence  of  Protein  on  Metabolism 

The  Specific  Dynamic  Action  of  Protein 

The  final  stage  of  all  the  metabolic  processes  in  the  animal  body  is 
one  of  oxidation,  whereby  energy  is.  liberated  in  the  fonn  of  heat.  The 
amount  of  heat  produced  depends  entirely  upon  the  amount  of  material 
that  is  oxidized.  When  an  animal  is  at  rest  and  fasting,  the  oxidation 
processes  are  at  a  low  ebb,  the  heat  production  is  at  a  correspondingly  low 
level.  (We  speak  of  its  hosal  metabolism.)  If  the  subject  becomes  more 
active,  the  oxidative  processes  and  heat  production  increase  in  definite 
proportion,  so  that  by  doing  fairly  hard  physical  work  the  metabolism  may 
reach  a  point  double  and  triple  the  basal  level. 

A  most  reniarkable  phenomenon  was  observed  by  Voit  in  his  early 
respiratory  metabolism  experiments.  He  found  that  even  though  at  per- 
fect physical  rest,  the  heat  metabolism  of  an  individual  increases  after 
the  ingestion  of  food ;  to  a  slight  extent  after  carbohydrates,  to  a  gi*eater 
extent  after  fat,  and  to  a  most  marked  extent  after  protein.  In  other 
words,  if  we  determine  the  starvation  caloric  requirements  of  an  individual, 
and  put  him  on  a  protein  diet  sufficient  to  cover  those  requirements,  the 
individual's  metabolism  will  increase  as  a  result  of  ingesting  the  food  and 
produce  more  heat  than  before. 


THE  PROTEIXS  AXD  THE  III  METABOLIS]t[ 


131 


Tn  diagram  ITT  we  liav(;  a  graphic  illustration  of  one  of  Lnsk's  experi- 
ments on  a  doir  showing  tlio  influence  of  the  ingestion  of  1200  grams  of 
k^an  meat  on  the  metaholism  of  the  dog.  During  the  two  hours  before 
the  meat  ingestion,  the  licat  production  was  22  to  23  calories  per  hour. 
Within  two  hours  after  tlic  meat  ingestion  the  heat  production  went  up  to 
over  35  calories  per  hour,  reached  44  during  the  third  hour  and  remained 


AO  Calories 


35 

30 

25 

2j06hs. 
N. 

1.0 
5 


/ 


v. 


^N 


^ 


22  23  0    I    2    3    4    5    6    7   8    9    10  IJ    I?  13  14  15  16  17  18  19  20  21 
HOURS  AFTLR  1200  6RAMS  MEAT 


Diagram  HI.  Showinjr  the  respiratory  quotient,  the  total  inetaboHan  determined 
by  indirect  (heavy  bUick  line)  and  direct  (broken  line)  cahuimetry  as  well  as  the 
nitrogen  elimination  (dotted  line)  during  hourly  periods  after  the  ingestion  of  1200 
jframs  of  nnfat. 


at  that  high  level  for  ahout  eight  hours,  gradually  coming  down  and  reach- 
ing the  hasal  level  at  the  end  of  twenty-two  hours.  Ordinarily  we  notice 
increased  heat  production  as  a  result  of  increased  oxidation  processes  going 
on  in  the  cells,  as  during  periods  of  greater-  activity.  The  increase  in 
Lusk's  experiments  corresponds  to  an  increase  in  metaholism  caused  by  vio- 
lent exercise,  and  yet  the  animal  was  lying  perfectly  quietly  and  at  rest. 

Voit  assumed  that  this  marked  increase  in  oxidation  and  heat  forma- 
tion was  due  to  the  cells  heing  stimulated  by  the  presence  of  food  in  the 
blood  brought  to  them,  and  that  the  intensity  of  metabolism  of  a  cell  was 
a  function  of  the  quality  and  (juantity  of  food  material  surrounding  the 


132  A.  I.  RINGER 

cell.  The  greater  the  amount  of  food  brought  to  the  cell,  the  more  was  it 
stimulated  to  catabolize  it. 

Ruhner,  Zuntz  and  Lusk  have  performed  a  great  many  experiments 
which  may  throw  light  on  the  cause  of  this  increase  in  metabolism.  Be- 
cause of  the  specificity  of  each  foodstufT  to  stimulate  metabolism,  Rubner 
called  it  the  ^'specific  dynamic  action''  of  the  foodstuffs.  lie  believes  that 
because  the  carbohydrates  and  fats  are  directly  available  to  the  cells  for 
their  nutrition  there  is  therefore  comparatively  little  increase  in  heat  pro- 
duction after  their  ingestion.  In  the  case  of  protein,  however,  it  can  con- 
tribute to  the  cell  metabolism  only  in  so  far  as  it  can  give  rise  to  glucose,  and 
all  the  intennediary  products  which  cannot  go  over  into  glucose  are  burnt, 
but  their  heat  is  given  oiT  as  free  heat  and  cannot  be  used  by  the  cells. 

Lusk  2)roceeded  to  look  for  the  cause  of  the  specific  dynamic  action 
of  the  proteins  along  new  lines.  He  realized  that  in  order  to  analyze 
the  action  of  protein  on  metabolism,  one  must  take  up  the  study  of  the 
influence  of  the  individual  amino  acids,  for  it  is  they  which  come  in 
intimate  contact  with  the  cells  of  the  bod  v.  Then  he  reasoned  thus:  if 
Rubner's  hypothesis  be  correct — that  the  fraction  of  the  protein  molecule 
which  goes  over  into  glucose  is  the  one  which  contributes  to  the  life  of 
the  cell,  and  that  the  fraction  w4iich  does  not  go  over  is  burned,  giving 
rise  to  free  heat — then  amino  acids  like  glycocoli  and  alanin,  which  are 
completely  converted  into  glucose,  should  exert  no  specific  dynamic  influ- 
ence at  all,  whereas  glutamic  and  aspartic  acids,  which  contribute  only 
three  of  their  carbons  to  glucose  formation,  should  have  a  marked  djmamic 
effect.  Also,  substances  like  leucin  and  tyrosin,  which  do  not  give  rise  to 
any  sugar,  should  have  a  most  pronounced  dynaiaic  effect. 

Experiments  not  only  failed  to  lend  any  suppori  to  Rubner's  theory, 
but  revealed  just  the  contrary  of  what  was  expected.  Glycocoli  and  alanin 
were  found  to  possess  a  very  pronounced  power  of  stimulating  metabolism 
and  heat  production.  Leucin  and  tyrosin  possess  that  power  to  a  lesser 
extent,  and  aspartic  and  glutamic  acids  have  none  at  all. 

In  another  series  of  experiments  Lusk  found  that  the  administra- 
tion of  5.5  gi*ams  of  glyeccoll  raised  the  heat  production  of  a  dog  7.3 
j>er  cent  and  5.5  grams  of  alanin  raised  it  7  per  cent.  AVhen  he  gave  the 
two  amino  acids  together  there  was  a  summation  of  influences  and  the 
heat  production  was  raised  18  per  cent.  Ten  grams  of  glycocoli  caused 
a  rise  of  15.0  and  17.5  per  cent  in  two  successive  experiments,  and  the 
giving  of  20  grams  of  glycocoli  caused  a  rise  of  33.5  and  34.0  per  cent  in 
two  experiments.  Similar  results  were  obtained  after  administering  20 
and  30  grams  of  alanin. 

These  experiments  prove  beyond  any  question  that  the  stimulus  these 
amino  acids  exert  is  directly  proportional  to  the  amount  of  material  ad- 
ministered. 

Since  glycocoli  and  alanin  have  been  shown  to  be  completely  converted 


THE  PllOTEIXS  AND  THEIK  METABOLISM  133 

into  glucose  in  tho  diabetic  animal,  the  question  naturally  presented  itself, 
Will  these  amino  acids  exert  a  specific  dynamic  influence  when  given  to  a 
phlorhizinized  diabetic  animal  ? 

In  a  series  of  experiments  Lusk  proved  that  in  spite  of  the  fact  that 
all  of  glycocoll  and  alanin  are  converted  into  glucose  and  that  none  of  it 
is  oxidized,  it  still  possesses  the  power  of  raising  the  heat  production.  The 
respiratory  quotient  in  all  cases  remaining  at  the  low  diabetic  level  lends 
additional  confirmation  to  the  belief  that  none  of  these  amino  acids  are 
oxidized  in  the  diabetic  animal. 

From  all  this  it  becomes  evident  that  the  specific  dynamic  action  of 
protein  is  a  stimulus  to  metabolism  which  is  given  to  the  body  by  certain 
of  the  amino  acids.  It  is  not  the  result  of  these  substances  burning  up 
as  a  sort  of  a  bonfire,  giving  rise  to  free  heat.  They  act  as  catalytic  agents, 
spurring  up  the  oxidative  processes  in  the  cells.  The  reaction  is  in  reality 
much  more  "specific"  than  Voit  and  Eubner  realized.  It  seems  to  reside 
in  certain  amino  acids  and  not  in  others. 

What  the  significance  is  of  this  spurring  of  metabolism  by  protein  we 
do  not  know.  All  physiologists  are  agreed  that  the  extra  heat  is  waste- 
ful and  physiologically  uneconomical.  Advocates  of  the  high  protein  diet 
seem  to  attach  a  great  deal  of  importance  to  the  sense  of  well-being  a  per- 
son experiences  after  a  meal  rich  in  protein,  but  whether  a  psychic  state 
of  well-being  can  be  taken  into  consideration  in  determining  physiological 
requirements  and  laws  seems  highly  questionable.  The  drinking  of  wine 
and  other  alcoholic  beverages  certainly  puts  one  in  a  psychic  state  of 
well-being,  but  no  one  will  claim  that  this  is  sufficient  evidence  for  its  physi- 
ological requirement. 


Nucleic  Acids Walter  Jones 

Chemical  Part — Plant  Xucleic  Acid — The  Fumlaraental  Groups  of  Yeast 
Kucleic  Acitl — The  Xucleoticles  of  Yeast  Nucleic  Acid — The  Nucleotide 
Linkages  of  Yeast  Xucleic  Acid — Inosinic  Acid  and  Guanylic  Acid — The 
Nucleosides  of  Yeast  Xucleic  Acid — Animal  Xucleic  Acid — The  Partial 
Decomposition  Products  of  Thymus  Xucleic  Acid — Physiological  Part^ — 
The  Physiological  Decomposition  of  Xucleic  Acid — The  Formation  of 
Uric  Acid  from  Xucleic  Acid — The  Formation  of  Uric  Acid  from  the 
Oxy-piirines — The  Formation  of  Oxy-purines  from  Amino-purines — The 
Physiological  Destruction  of  Uric  Acid — The  Distribution  of  the  Purine 
Ferments — The  Enzymatic  Decomposition  of  Combined  Purines. 


Nucleic  Acids 

WALTER  JOISTES 

BALTIMORE 

/  Chemical  Part 

By  a  tedious  manipulation  it  is  possible  to  isolate  from  animal  and 
plant  tissues  an  organic  acid,  rich  in  both  phosphorus  and  nitrogen,  whose 
decomposition  products  are  so  far  characteristic  that  not  one  of  them  is 
identical  with  any  known  decomposition  product  of  a  carbohydrate,  a  pro- 
tein or  a  fat  (Altman,  1889),  (Osborne  and  Harris,  1002),  (Kossel, 
(a),  (6),  1879,  18S0).  The  substance  has  been  prepared  from  meta- 
morphosed cell  nuclei  (Miescher,  1897),  and  as  the  amount  of  it  that  is 
obtainable  from  a  tissue  is  proportional  to  the  richness  of  the  tissue  in 
cell  nuclei,  it  is  properly  regarded  as  a  nuclear  constituent  and  called 
nucleic  acid. 

Nucleic  acid  cannot  be  prepared  sufficiently  pure  for  chemical  analysis, 
so  that  its  chemical  composition  has  not  been  directly  found.  This  can  be 
inferred,  however,  from  a  summation  of  its  unique  decomposition  products. 
But  chemical  composition,  physical  properties  and  other  considerations 
pertaining  to  nucleic  acid  as  such,  are  matters  about  which,  in  the  present 
state  of  our  knowledge,  physiology  is  little  concerned.  It  is  the  decom- 
position products  that  are  of  importance,  and  these  decomposition  prod- 
ucts are  the  same  whether  they  are  produced  by  chemical  action  outside 
of  the  body  or  by  physiological  agents  present  in  the  tissues;  so  that 
a  discussion  of  the  chemical  decomposition  of  nucleic  acid  will  disclose  its 
metabolic  possibilities. 

Plant  Nucleic  Acid 

It  was  formerly  supposed  that  a  multiplicity  of  nucleic  acids  exist, 
and  that  each  tissue  contains  its  individual  substance  of  this  class.  But 
without  entering  into  the  obscure  and  contradictory  older  contributions, 
it  is  safe  to  state  that  everything  known  is  in  accordance  with  the  assump- 
tion that  there  are  two,  and  only  two,  nucleic  acids  in  nature:  one  is 
obtainable  from  plant  tissues  (yeast  nucleic  acid)  (Kossel,  1893), 
and    the    other    is    obtainable    from    animal    tissues    (thymus    nucleic 

135 


13G  WALTER  JONES 

acid).  (Kossel  and  Xeumau  (a)  (h)  (c),  1893,  1894.)  It  wiJl,  therefore, 
he  necessarv  and  sufficient  to  examine  two  nucleic  acids  in  o,der  to  get  a 
knowledge  of  them  all. 

The  Fundamental  Groups  of  Yeast  Nucleic  Acid. — When  yeast  nu- 
chnc  acid  is  heated  for  a  sliort  time  with  very  dihite  sulphuric  acid,  part 
of  its  molecule  easily  undergoes  hydrolysis  with  the  fonnation  of  pentose, 
phosphoric  acid  and  two  purine  derivatives  (guanine  and  adenine).  But 
when  the  nucleic  acid  is  suhmitted  to  severe  hydrolysis  hy  heating  with 
stronger  sulphuric  acid  in  an  autoclave  at  160°,  a  second  part  of  its  mole- 
cule is  decom}X)sed  with  the  formation  of  pentose  and  phosphoric  acid 
as  hefore,  hut  in  addition,  two  pyrimidine  derivatives  (cystosine  and 
uracil).  So  that  hy  hydrolysis  with  mineral  acid  in  one  Way  or  another, 
yeast  nucleic  acid  produces  six  substances.     / 


1. 

Phosphoric  Acid 

2. 

Pentose 

3. 

Adenine 

4. 

Guanine 

5. 

Cytoslne 

6. 

Uracil 

These  six  substances  constitute  the  fundamental  groups  of  which  yeast 
nucleic  acid  is  composed,  and  as  will  be  seen  later,  the  same  six  substances 
are  formed  when  yeast  nucleic  acid  is  decomposed  by  physiological  agents. 
One  of  them  is  so  simple  as  to  require  no  treatment ;  the  other  five  should 
be  discussed. 

Pentose. — There  are  theoretically  possible,  eight  aldo-pentoses  of  the 
formula  C5H10O5.  The  substance  which  is  obtained  from  yeast  nucleic 
acid  is  that  one  of  the  eight  possibilities  that  has  the  geometrical  config- 
uration called  dextro-ribose.  (Levene  and  Jacobs  (c)  (g)  (A),  1909,  1909, 
1910.)     . 

CHO 

Hcon 

HCOH 
HCOH 
CHoOH 

This  configuration  is  unique,  being  found  very  rarely  in  nature,  and  it 
probably  has  great  physiological  significance,  but  at  present  we  can  only 
refer  d-ribose  to  the  general  metabolism  of  the  carbohydrates;  in  which 
case  it  does  not  properly  fall  into  a  discussion  of  nucleic  acids. 

The  PyHmidine  Derivatives. — Both  cytosine  (Kossel  and  Neuman  (a) 
(&),  1893,  1894),  (Kossel  and  Stendel  (a)(&),  1902,  1903)  and  uracil 


NUCLEIC  ACIDS 


137 


( Ascoli,  1900)  are  chemically  referable  to  hypothetical  pyrimidine.     Cyto- 
sine  is  6-ainino-2-oxypyrimidine  and  uracil  is  2-6-dioxy-pyrimidiiie. 


NH^ 


HO 


V^ 


Cvtosine 
ClHjNaO 


OH 


Uracil 


S^ 


N 


Pvri  midline 


The  two  substances  are  corresponding  oxy-  and  amino-compounds,  so  that 
one  may  pass  into  the  other  by  deaminization 


Cytosine 


Uracil 


in  fact,  cytosine  can  easily  be  converted  into  uracil,  and  will  be  so  con- 
verted in  a  laboratory  manipulation  of  the  material  unless  precautions  are 
taken  against  it.  The  relation  of  the  two  substances  to  each  other  sug- 
gests the  possible  metabolic  conversion  of  one  of  the  compounds  into  the 
other  by  the  deaminizing  ferments  of  the  tissues.  This  is,  of  course,  pos- 
sible, but  the  transformation  has  not  been  shown  either  by  an  organism 
or  by  a  tissue  extract.  In  fact,  very  little  is  known  about  the  metabolism 
of  the  pyrimidine  derivatives,  so  that  of  the  six  fundamental  decomposi- 
tion products  of  yeast  nucleic  acid,  physiological  interest  is  directed  almost 
exclusively  to  the  purine  derivatives. 

The  Pumne  Derivatives. — By  hydrolysis  of  yeast  micleic  acid  with 
dilute  mineral  acid,  it  is  possible  to  obtain  only  the  two  amino-purines, 
guanine  and  adenine ;  but  in  studying  the  metabolism  of  these  two,  it  is 
necessary  to  consider  three  other  purine  derivatives,  viz., .  hypoxanthine, 
xanthine  and  uric  acid.  The  chemical  relation  of  these  ^\e  substances  to 
one  another  is  shown  in  the  following  arrangement,  in  which  the  purine 
ring  is  represented  by  the  letter  P. 

[In  this  article,  purine  formulas  are  used  to  which  the  physician  may 
not  be  accustomed  and  a  word  of  explanation  may  not  be  superfluous. 
There  are  two  tautomeric  formulas  for  purine  derivatives  (enol  formulas 
and  ketol  formulas)  which  are  not  chemically  distinguishable  from  each 
other.  One  of  these  formulas  is  almost  universally  (but  arbitrarily)  used 
by  chemists  and  physiologists.  The  other  formula  has  been  adopted  in  the, 
following  pages  for  its  exceeding  convenience  iu  dealing  with  the  prol)- 
lems  under  consideration.] 


138 


WALTER  JOxXES 


Guanine 

Adenine 

c,nr.N,o 

C5H,N, 

2-araino-H-nxv-purine 

6-amino-piirine 

/Nil, 

/H 

P— OH 

P— NHj 

\ir 

\H 

I'ric  Acid 

Xanthine 

Ilypoxan  thine 

C5H,N403 

C,II,N,0, 

CAN.O 

2-G-S-lii()xv-purine 

2-G-dioxy-pnrinc 

6-ox3'-purinc 

/on 

/OH 

/H 

P— OH 

P— OH 

P— OH 

\OII 

\H 

\H 

Guanine  and  adenine  are  referred  to  collectively  as  the  amino-purines; 
xanthine  and  hypoxanthine  as  their  corresponding  oxy-purines.  The 
amino-purines  may  easily  be  converted  into  the  oxy-purines  by  a  deamin- 
izing  agent  (nitrous  acid). 

C5H3:N'4(^^H2r+H20  -  C5H3:^4(OH)+NH3  (Kossel  (c),  1886) 

adenine  hypoxanthine 

C5H3N,0(NH2)+HoO  ==  C5H3N40(On)+NH3  (Strecker,  1858) 

guanine  xanthine 

and  it  will  be  seen  that  these  transformations  are  actually  brought  about 
by  deaminizing  ferments  present  in  the  tissues.  But  guanine  and  adenine 
cannot  be  directly  converted  into  one  another.  The  one  has  its  amino- 
gi'oup  in  position  two ;  the  other,  in  position  six. 


NM^ 


NH 


By  oxidation,  hypfjxanthine  could  conceivably  be  changed  into  xanthine 
CjH.N.O +0  =  C,H,A^O, 


XUCLEIC  ACIDS  139 

aiul  this  in  turn  could  be  oxidizefl  to  uric  acid 

0,11^402+0=^0,114^403 

but  it  would  be  necessary  to  introduce  the  first  oxygen  atom  into  position 
two,  and  tlie  .-ec<tud,  into  position  ei<^ht.  While  no  chemical  oxidizing 
agent  has  been  found  that  can  effect  this  selective  oxidation,  oxidizing 
ferments  are  pre.-ent  in  tlie  tissues  that  can  direct  the  oxygen  atoms  into 
their  proper  pi^itions,  and  bring  about  the  conversion  of  hypoxanthino 
successively  into  xanthine  and  uric  acid. 

The  converse  reactions  which  involve  the  withdrawal  of  oxygen  can 
bo  effected  in  the  laboratory.  Uric  acid  has  been  successively  reduced  to 
xanthine  and  hypoxanthine.      (Sundwick,  1911.) 

The  Nucleotides  of  Yeast  Nucleic  Acid. — The  older  investigators 
knew  that  by  mild  acid  hydrolysis,  nucleic  acid  is  partly  split  up,  setting 
free  part  of  its  phosphoric  acid,  part  of  its  carbohydrate  and  all  of  its 
purine  bases;  but  that  the  renuiinder  of  its  phosphoric  acid  and  carbo- 
hydrate, together  with  its  pyrimidine  compounds,  are  set  free  only  after 
most  violent  methods  of  hydrolysis.  It  was  therefore  natural  to  assume 
that  nucleic  acid  is  composed  of  four  "complexes,"  all  of  which  produce 
both  phosphoric  acid  and  carbohydrate,  but  each  "complex"  produces  a 
different  one  of  the  four  nitrogenous  compounds.  The  two  purine  "com- 
plexes" evidently  undergo  hydrolysis  with  ease,  while  the  two  pyrimidine 
"complexes"  are  very  stable.  If  the  term  "nucleotide"  be  substituted  for 
the  term  "complex,"  this  becomes  essentially  the  modern  nucleotide  the- 
ory of  the  constitution  of  nucleic  acid.  This  theory  was  originally  pro- 
posed on  the  speculative  grounds  as  outlined  above,  before  any  nucleoside 
or  nucleotide  had  l^en  prepared  from  nucleic  acid;  but  it  has  recently 
received  firm  experimental  support  by  the  preparation  from  yeast  nucleic 
acid  of  the  four  assumed  nucleotides 

H0\ 

O-P-^O.C.IIsO^.CsH.^^O 
110/ 

Guanine  Xucleotide    (Jones  and  Richards,   1014)     (Head,   1017) 

H0\ 
0=P— O .  C^HsOa .  C^H.XjO 

no/ 

Cytosine  Xucleotide  (Thannhauser  and  Dorfmiiller  (fl)  (6),  1018,  1019) 

H0\ 

0=P— O.C5H803.C5H4^5 

HO/ 

Adenine  Xucleotide    (Jones  and  Kennedy,   1918) 


no  WALTER  JONES 

H0\ 

0-P~0 .  C5H8O3 .  C  JI3N2O2 
HO/ 

Uracil  Nucleotide  (Levene  (d),  1919) 


They  are  crystalline  dibasic  acids  which  closely  resemble  phosphoric  acid 
in  their  acidic  conduct.  They  form  crystalline  dibrucine  salts  which  differ 
from  one  another  in  their  solubilities,  thus  making  possible  the  purification 
of  the  nucleotides  and  their  separation  from  one  another. 

The  two  purine  nucleotides  easily  undergro  acid  hydrolysis,  giving  rise 
to  phosphoric  acid  pentose  and  purine  base:  but  the  pyrimidino  nucleotides 
are  very  stable,  and  must  be  treated  severely  before  hydrolysis  is  effected. 
This  explains  the  conduct  of  nucleic  acid  toward  hydrolytic  agents. 

It  will  be  seen  that  a  thermostable  physiological  agent  (a  ferment  ?) 
is  present  in  the  pancreas,  which  at  the  body  temperature  causes  a  decom- 
position of  yeast  nucleic  acid  into  its  four  component  nucleotides. 

The  Nucleotide  Linkages  of  Yeast  Nucleic  Acid. — It  has  been  pointed 
out  that  the  work  of  the  earliest  investigators  indicated  the  nucleotide 
structure  of  yeast  nucleic  acid.  But  this  work  gave  no  suggestion  of  the 
points  where  the  four  nucleotides  are  united  to  one  another  in  yeast  nucleic , 
acid,  or  iii  other  words,  the  location  of  the  nucleotide  linkages.  The  loca- 
tion was  later  assumed,  without  any  evidence,  to  be  through  the  phosphoric 
acid  groups,  but  this  assumption  is  not  coii-ect.  The  nucleotide  linkages 
involve  neither  the  phosphoric  acid  groups,  nor  pfurine  groups,  and  prob- 
ably not  the  pyrimidine  groups.  This  conclusion  is  based  principally  upon 
the  following. 

I.  The  conversion  of  yeast  nucleic  acid  into  simpler  nucleotides  is 
not  attended  ty  an  increase  in  acidity.  (Jones  (e),  1020.)  There  would 
bo  a  marked  increase  in  acidity  if  the  nucleotide  linkages  involved  the 
phosphoric  acid  groups. 

II.  The  laws  governing  the  liberation  of  phosphoric  acid  from  the 
nucleotides  arc  the  same,  whether  the  nucleotides  are  free  or  combined  in 
nucleic  acid.  The  same  is  true  for  the  purines,  and  also  for  the  p^Tim- 
idines,  so  far  as  experiments  with  the  latter  are  possible.  (Jones  {d) 
1920.) 

If  the  nucleotide  linkages  involve  neither  the  phosphoric  acid  gi'oups, 
the  purine  groups  nor  the  pyrimidine  groups,  they  can  only  involve  the 
carbohydrate  groups,  l^ucleic  acid  should  therefore  probably  have'ther 
following  formula  which  represents  the  substances  as  a  polysaccharide. 

[It  should  be  noted  that  this  formula  is  arrived  at  by  exclusion  and  is 
intended  primarily  to  indicate  the  points  at  which  the  nucleotide  linkages 
do  not  exisf] 


KUCLEIC  ACIDS  141 

H0\ 

HO/  I 

O 
H0\  I 

0=P— O .  CsHcO .  CJI^Is^aO 
HO/  I 

O 
H0\  I 

0-::P— O  .  C5H0O.C  JI3:N\02 

HO/  I 

o 

/      H0\  I 

0=:P— O .  CgH.O^ .  C^H^NgO 
HO/ 

Inosinic  Acid  and  Guanylic  Acid. — These  two  substances  were  known 
to  be  constituents  of  animal  tissues  before  the  constitution  of  yeast  nucleic 
acid  had  been  proposed,  and  one  of  them  was  the  subject  of  considerable 
discussion  because  it  was  looked  upon  as  a  peculiar  nucleic  acid ;  but  both 
are  purine  nucleotides  of  the  class  that  has  been  discussed. 

Inosinic  Acid. — This  substance  was  discovered  by  Liebig  (a)  (1847) 
-  in  meat  extract,  and  is  now  known  to  be  a  constant  and  characteristic  con- 
stituent of  niusclo  tissue.     By  mild  hydrolysis  with  mineral  acid,  it  easily 
decomposes  into  phosphoric  acid  pentose  and  hypoxanthine  (Bauer,  1907) 
(Xewberg  and  Brahn  (a)(6)  1907,  1908). 

C10H13N4PO8  +  2H2O  =  H3PO,  +  CsHioOs  +  CsH.X.O 

The  substance  is  marked  by  the  pentose,  which  is  identical  with  the  pentose 
of  yeast  nucleic  acid.  The  muscles  of  animals  contain  a  nucleotide  that 
is  unmistakably  related  to  plant  nucleic  acid.  (Levene  and  Jacobs  (&) 
1909.)  The  relation  is  not  one  of  identity,  for  inosinic  acid  produces 
hypoxanthine,  where  the  nearest  nucleotide  of  yeast  nucleic  acid  produces 
adenine.  If  the  one  nucleotide  originates  from  the  other  (the  plant  food 
of  the  animal),  deaminization  of  the  adenine  group  must  occur  somewhere. 
Inosinic  acid  occupies  a  unique  place  in  a  discussion  of  yeast  nucleic 
acid,  for,  though  it  is  not  a  nucleotide  of  yeast  nucleic  acid,  it  is  the  fii*st 
nucleotide  whose  constitution  w^as  solved,  and  the  method  of  solution  was 
afterward  applied  to  the  purine  nucleotides  of  yeast  nucleic  acid.  Inosinic 
acid  is  composed  of  three  gi'oups,  and  gives  rise  to  three,  and  only  three 
substances  by  acid  hydrolysis,  viz.,  phosphoric  acid,  pentose  and  hypo- 
xanthine. Theoretically,  any  one  of  the  three  gi'oups  may  be  the  central 
group  connecting  the  other  two. 


112  WALTER  J0XE8 

H0\ 

0==P— 0 .  CsHgOa .  C5H3N4O         (1) 
HO/ 

O 

II  ' 

C5HoO,.0-P-O.C5H3N,  (2) 

OH 

/OH 
CJIoO^.C^HolSr^.O— P-:0  (3) 

\0H 

Inosinic  acid  is  a  dibasic  acid,  so  that  foiiiula  (2)  is  excluded.  It 
sets  free  its  hypoxaiithiiie  much  uiore  easilv  than  its  phosphoric  acid. 
This  would  not  be  possible  if  the  hypoxanthine  group  were  internal  to  tho 
phosphoric  acid  gToup;  so  that  formida  (3)  is  excluded.  The  correct 
formula  (1)  remains.  The  order  of  the  gi-oups  in  adenine  nucleotide  and 
guanine  nucleotide  has  been  proven  in  a  similar  way.  (Jones  (d)  1920) 
(Jones  and  Kead,  1017.) 

Of  the  greatest  interest  is  the  hydrolytic  action  of  ammonia  on  in- 
osinic acid  under  pressure.  When  so  treated,  the  substance  loses  its 
phosphoric  acid  completely,  while  the  linkage  between  the  pentose  and 
hypoxanthine  groups  is  not  disturbed,  so  that  a  phosphorus-free  compound 
is  produced  called  inosine.     (Levene  and  Jacobs  (a)  1909.) 

H0\  no\ 

O-rP-O . C5H8O3 .  CsHgN^O+H.O-r    O-P-OH+CgHoO^ .  O^H^^^ 
HO/  HO/ 

Inosine  is  typical  of  a  class  of  compounds  called  nucleosides.  As  from  in- 
osinic acid,  so  also  from  any  nucleotide  a  nucleoside  may  bo  prepared  by 
hydrolysis  with  ammonia. 

GvanijJic  Acid. — This  substance  is  a  strict  analogue  of  inosinic  acid. 
It  is  found  in  animal  tissues  (principally  the  pancreas)  and  doubtless 
originates  from  the  plant  food,  for  it  is  itlcntical  with  gTianine  nucleotide 
prepared  from  yeast  nucleic  acid.  By  mild  acid  hydrolysis,  it  splits  easily 
into  phosphoric  acid  pentose  and  giianine,  setting  free  the  guanine  much 
more  rapidly  than  the  phosphoric  acid.  As  with  inosinic  acid,  giianylic 
acid  ]()?es  its  phosphoric  acid  and  forms  its  nucleoside  by  hydrolysis  with 
ammonia. 

The  chemical  analogy  between  the  two  nucleotides  is  shown  in  the  fol- 
lowing equations: 


NUCLEIC  ACIDS  143 

I.     By  acid  hydrolysis 

H0\ 

0-P-O.C^H803.C5H3N40+2H,0-H,P04+C5H,o05+C5H^N40 
HO/ 

inosinicacid  pentose  hypoxanthine 

H0\ 

0==P-0 .  C^n.Oa .  C5H4N50+2H20-II,PO,+C5H,o05+C,H5N,0 
110/ 

guanylicacid  pentose  guanine 

4 

II.     By  hydrolysis  with  ammonia 

H0\ 

0-P— O .  O^H^O., .  C,n,N40+H20=-H,P04+C5lI^04  .  C5H3K4O 
HO/ 

inosinicacid  inosine 

H0\ 

O-P— O .  C.HgO^ .  CJI.NsO+HoO-H^PO.+CsHoO^  .  CJI.NsG 
HO/ 

guanylicacid  guanosine 

Thus,  inosinic  acid  (from  muscle)  is  h\i)oxanthine  nucleotide,  or 
deaminized  adenine  nucleotide,  one  of  the  purine  nucleotides  of  plant 
nucleic  acid. 

Guanylic  acid  (from  pancreas)  is  guanine  nucleotide,  one  of  the  nu- 
cleotides of  plant  nucleic  acid. 

The  plant  origin  of  hoth  nucleotides  is  shown  by  the  identity  of  their 
characteristic  pentose  (d-ribose). 

The  Nucleosides  of  Yeast  Nucleic  Acid. — ^^Yhen  yeast  nucleic  acid  is 
submitted  to  mild  alkaline  hydrolysis  (as  with  ammonia  at  110°), 
it  easily  decomposes  into  its  four  component  nucleotides..  But  wlien  al- 
kaline hydrolysis  of  the  nucleic  acid  is  effected  at  higher  temperatures 
(as  with  ammonia  at  150°),  the  four  nucleotides  first  formed  lose  their 
phosphoric  acid,  and  are  converted  into  the  corresponding  four  nucleosides. 
(Levene  and  Jacobs  (e)  (/)  (/i),  1901),  1010.) 

[The  logical  order  of  treatment  is  from  nucleotides  to  nucleosides  hut 
this  is  not  the  order  of  discoveiy  as  the  nucleosides  were  discovered  first. 
A  long  period  of  time  elapsed  between  Kossel's  discovery  of  the  funda- 
mental decomposition  products  of  nucleic  acid  and  Levene's  discovery  of 
the  first  partial  decomposition  products  (the  nucleosides).  The  isolation 
of  the  nucleotides  by  Jones  and  by  Thannhauser  came  afterwards.] 


144 


WALTER  JONES 


The  four  nucleotides 


The  four  iiucleosidea 


H0\ 
110/ 

adenine  nucleotide 

i 


H0\ 

0=P— O.  C5H8O3.C4H3N0O2 
HO/ 

uracil  nucleotide 


H0\ 

0-::P  — O.     C5nsO.,.C,H4N30 

110/ 

cytosine  nucleotide 


C5n„o,.c,n,Ns 

adenine  nucleoside 

C5H,04.C4H,X20g 

uracil  nucleoside 
cytoaine  nucleoside 


H0\ 

0_P_0.  C,H803.C5H4N50 
110/ 

guanine  nucleotide 


H 
H 
H 


on 

OH 
OH 


C5H,04.CJI,X50 

guanine  nucleoside 


The  four  nucleosides  were  prepared  from  yeast  nucleic  acid  before  the 
nucleotides  were  known,  and  thus  gave  experimental  probability  to  the 
tetra-nucleotide  structure  of  yeast  nucleic  acid,  which  up  to  that  time  had 
been  simply  speculative. 

The  chemistry  of  the  nucleosides  is  just  what  one  would  suppose  a 
priori,  and  it  follows  closely  that  of  the  simple  nitrogen  derivatives.  They 
offer  two  jM^ssIbilities,  (1)  hydrolysis,  (2)  deaminization.  Thus  by  hy- 
drolysis, adenosine  and  guanosine  are  decomposed  into  pentose  and  tho 
respective  purine  bases. 

CAO.-c^H.x,  +  n,o  =  c„n,oO,  +  caw^ 

adenosine  pentose  adenine 

guanosine  pentose  guanine 


KUCLEIC  ACIDS  145 

Just  as  the  free  amino-purines  (guanine  and  adenine)  are  dcaminized  to 
the  corresponding  oxv-purines  (xanthine  and  hypoxanthine),  so  also  the 
aniino-nucleosidos  (tnuinosine  and  adenosine)  form  the  corresponding  oxy- 
nucleosidc.-;  (xanthosine  and  inosine). 

These  relations  are  shown  in  the  following  diagram.     Horizontal  ar- 
rows indicate  hydrolysis;  vertical  arrows,  deamini^jation. 

C5I  laN.o  ( XII, )        i\]\j\ .  c,H,x/>  { NH2 ;        cji„o, .  c  jr,x,  (  xh,  )        cji^x,  (  xh,) 

guanine        ^^. guanosine  adenosine        — >        adenine 


C- HaX.O  ( OH )            C5H0O, .  C^H.X.O  ( OH )             CH^O^ .  CsH^X,  ( OH )  CsH^N,  (OH ) 

xanthine        < xanthosine  inosine     >      hypoxanthine 

With  the  pyrimidine  nucleosides  the  matter  is  a  little  ditferent.  Deamini- 
zation  converts  the  amino-nucleoside  (cytidine)  into  its  corresponding  oxy- 
nucleoside  (uridine). 

C5H0O3 .  C4lIoX,0(XH2)  C4H3]SroO(XIT2) 

cytidine  cytosine 

I  I 

I  I 

CsHoOj.CJLNoOCOH)  CJIaNjOCOH) 

uridine  '•  uracil 

■  But  the  two  pyrimidine  nucleosides  are  very  stable,  and  are  not  hydro- 
lyzed  by  mineral  acid  into  pentose  and  free  pyrimidine  as  is  the  case 
with  the  purine  nucleosides.  Of  course  it  is  possible  that  animal  ferments 
are  capable  of  effecting  hydrolysis  of  the  pyrimidine  nucleosides. 

One  niiiiht  therefore  suspect  that  the  metabolism  of  yeast  nucleic 
acid  is  a  play  upon  hydrolysis,  deaminization  and  oxidation,  which  ^vill 
produce  various  nucleotides,  nucleosides  and  free  bases,  and  if  continued 
far  enough  must  finally  end  in  the  formation  of  uric  acid.  In  Part  II 
it  will  be  shown  that  such  is  actually  the  case. 

ANIMAL  NUCLEIC  ACID 

The  chemisti'y  of  thymus  nucleic  acid  is  best  appreciated  by  a  com- 
parison of  the  substance  with  yeast  nucleic  acid.  When  thymus  nucleic 
acid  is  boiled  with  dilute  sulphuric  acid  it  easily  sets  free  both  of  the 
aminr>-purines  (guanine  and  adenine),  with  part  of  its  phosphoric  acid  and 
part  of  its  carbohydrate.  But  when  tbymus  nucleic  acid  is  submitted 
to  severe  acid  hydrolysis  (as  with  30  per  cent  sulphuric  acid  at  150°), 
the  two  pyrimidine  derivatives  are  set  free  with  the  remainder  of  the  car- 
bohydrate and  phosphoric  acid.  All  of  these  statements  are  equally  true 
for  yeast  nucleic  acid;  but  it  must  be  noted  that  thymus  nucleic  acid 
yields  thymine  (Kossel  and  Neuman  (a)(&),  (1893,  18D4))  where  yeast 
nucleic  acid  yields  uracil. 


14G 


WALTEK  JOx\ES 

OH  OH 


Another  point  of  ditFerciice  between  the  two  nueleic  acids  is  in  respect 
to  their  carbohydrate  iiroup.  The  carbohydrate  gr<;up  of  yeast  nucleic 
acid  is  a  pentose  group,  and  a  pentose  is  formed  by  hydrolysis  of  the  nu- 
cleic acid;  but  the  carbohydrate  i>roup  of  thymus  nucleic  acid  is  a  hexose 
g-i'oup,  and  tlie  decomposUion  produrts  of  '^  hexose  (formic  acid  and 
levulinic  acidj  are  fonned  by  hydrolysis  of  (lie  nucleic  acid. 

CoHi.Oo  -  CII,CO .  ClIXOsH  +  HCO2H 

levulinic  acid 

The  fundamental  groups  of  the  two  nucleic  acids  are  therefore  as  follows 

Of  Thymus  Xucleic  Acid  Of  Yeast  Nucleic  Acid 

1.     Phosphoric  acid  Phosphoric  Acid 


2.  Guanine 

3.  Adenine 

4.  Cytosine 

5.  Thymine 

6.  ITexoso 


Purine  Derivatives 


Pyrimidine  Derivatives 


Carbohydrate 


Guanine 
Adenine 

Cytosine 
Uracil 

Pentose 


This  fundamental  identity  or  analogy  of  the  two  nucleic  acids  is  very 
striking,  especially  in  connection  with  their  curious  and  parallel  hydro- 
lytic  conduct;  and  it  sti'ongly  suggests  that  the  two  nucleic  acids  have  a 
similar  chemical  constitution.  Such  a  question,  however,  can  only  be 
decided  by  a  study  of  the  partial  decomposition  products  of  thymus  nucleic 
acid,  and  in  such  a  study  one  must  hi  careful  lest  he  fall  into  the  "argu- 
ment in  a  circle/'  Thus,  the  constitution  of  thymus  nucleic  acid  may 
be  assumed  in  the  beginning,  and  from  this  assumed  constitution,  that  of 
its  decomposition  products  may  be  inferred.  The  latter  may  then  be  used 
to  prove  the  constitution  of  the  nucleic  acid.  The  matter  is  mentioned 
here,  not  in  disparagement  of  the  work  that  has  been  done  with  the  prod- 
ucts of  the  partial  bydiolysis  of  thymus  nucleic  acid,  but  because  the 
writer  believes  that  the  logical  fallacy  indic^ated  has  occurred  in  the  orig- 
inal discussion  of  the  sul»ject. 


:XUCLETC  ACIDS  147 

THE  PARTIAL  DECOMPOSITION  PRODUCTS  OF  THYMUS 

NUCLEIC  ACID 

Levfno  and  Mandel  (a)  (11)08)  projmrcMl  an  indcliiiito  substance  from 
thymus  nuflei(f  acid  wliicli  produced  phosphoric  acid,  levulinic  acid  and 
thymine.     'I'hey  conclude  tliat  the  sidsstance  is  thymine-hexa-nucleotide. 

Levene  and  Jacobs  (i)  (1913)  prepared  a  substance  from  th^-nuis 
nucleic  acid  that  forms  guanine  and  levulinic  acid.  It  is  possibly  guanine- 
h&xa-nucleosido. 

If  these  two  substances,  one  a  nuclwside  and  the  other  a  nucleotide, 
indicate  that  thymus  nucleic  acid  is  constructed  throughout  upon  nucleo- 
sides and  nucleotides,  then  the  later  work  of  Levene  and  Jacobs  (/)  (1012) 
suggests  the  strutture  of  thymus  nucleic  acid.  Their  argiiment  is  based 
upon  the  assumed  structures  of  thi'ee  compounds  which  they  obtained  by 
the  mild  hydrolysis  of  thymus  nucleic  acid  with  sulphuric  acid. 

1.  ilexa-thymidine  di-phosphoric  acid 

2.  Hexa-cvtidine  di-phosphoric  acid 

3.  Ilexa-cytosine-thymine-di-nucleotide^       • 

H0\ 
0=:P— OH 
0/ 
H0\  I 

0-:P— 0  .  CcHoOs  .  CsTIp.X.Os 

HO/ 

Thymidine  Di-phosphoric  Acid 

H0\ 

0=P— O .  C  JI,03 . 0  JI,X,02 
HO/  I  • 

o 

H0\  I 

o=p— 0 .  c„Tr»03 .  c  ji^XjO 

HO/ 

Thymine-Cytosine  Di-nucleor.'de 

H0\ 

o=p-o.c„n„03.c,H,X30 

HO/  I 

o\ 

0=P— OH 
HO/ 

Cytidine  Di-phosplioric  Acid 

*In  the  nomenclature  of  the  decomposition  products  of  nucleic  acids  the  prefixes 
'■'penta"  and  "hexa"  liave  reference  to  tlie  carl>ohydrate  groups.  "Hexa"  means  "from 
thymus  nucleic  acid":    "penta"  means  "from  yeast  nucleic  acid." 


148  WALTER  JO.\ES 

If  the  stnictiires  of  these  compounds  ]>e  admitted,  then  the  constitu- 
tion of  thymus  nucleic  acid  is  indicated. 

IIO\ 
O-P-O .  CcH,o04 .  C.H.NsO 
0/ 
H0\  I 

0-:P— O  .  CJ1«0.,  .  C5II0X0O2 

HO/  I 

o 

H0\  I 

0-:P— O  .  CcHsOa  .  O4II4X0O 

HO/  I 

0\ 

HO/ 

Reduced  to  its  siniplest  tenns,  this  complicated  formula  means  the  fol- 
lowing : 

1.  Thymus  nucleic  acid,  like  yeast  nucleic  acid,  is  a  tetra-nucleo- 
tide  composed  of  the  groups  of  four  mono-nucleotides. 

2.  The  linkages  that  join  the  four  mono-nucleotide  gi'^oups  to  one  an- 
other are  differently  located  in  the  two  nucleic  acids. 

With  the  latter  statement  physiology  is  at  present  little  concerned. 
With  the  former  statement  physiology  is  very  much  concerned;  for  the 
decomposition  of  the  two  nucleic  acids  under  the  influence  of  animal  fer- 
ments follows  parallel  lines.  With  reference  to  animal  metabolism  the 
two  nucleic  acids  have  an  "equivalent"  structure.- 


Physioloj^ical  Part 

THE  PHYSIOLOGICAL  DECOMPOSITION  OF  NUCLEIC  ACID 

The  discovery  of  nucleic  acid  in  the  tissues  naturally  prompted  a  host 
of  investigations  to  find  a  physiological  agent  capable  of  decomposing  the 
substance.  It  was  assumed,  without  justification,  that  such  a  decomposi- 
tion would  involve  the  simultaufous  disruption  of  all  of  its  linkages  with 
the  simultaneous  production  of  nil  of  its  fundamental  decomposition  prod- 
ucts.    Of  these  substances,  only  phosphoric  acid  and  the  purine  bases  can 

'While  this  article  was  in  press  Levene  abandoned  the  above  formula  for  thymus 
nucleic  acid  (J.  Biol.  Chem.,  48,  1021,  122^  and  Thannhauser  has  added  an  important 
contribution  to  the  subject.  (Thannhauser  and  Ottenstein,  Zeits.  f.  physiol.  Chera., 
114.    1921.   39.) 


•S'UCLEIC  ACIDS  149 

be  easily  detected,  and  as  free  pliosplioric  acid  is  constantly  present  in 
tissue  extracts,  the  decomposition  of  nucleic  acid  was  generally  consid- 
ered provrn,  when  a  free  purine  base  appeared  during  the  digestion  of 
material  at  the  body  temperature. 

All  of  the  earlier  work  upon  this  subject  was  confused  by  unavoid- 
able sources  of  error.  The  physiolojLiical  decomix>sition  of  nucleic  acid 
could  not  be  clearly  followed  until  after  the  chemistry  of  the  substance 
had  reached  a  comprehensive  stage.  ^lethods  of  isolating  and  separating 
the  decomposition  pi'oducts  were  not  known;  in  fact,  the  identity  of 
the  purine  bases  themselves  was  not  established  until  very  late.  Chemists 
were  limited  to  one  decomposition  product,  and  to  one  reagent  for  its  de- 
tection. Putrefaction  played  an  important  part  that  was  not  taken  into 
account. 

These  are  a  few  of  the  many  circumstances  that  not  only  put  the  ear- 
lier investigators  at  a  great  disadvantage,  but  made  their  work  difficult  to 
luiderstand  and  in  some  cases  impossible  to  interpret.  It  is,  therefore, 
not  in  derogation  of  many  of  these  obscure  investigations,  but  in  the 
interest  of  clearness  that  we  pass  immediately  to  the  work  of  Iwanoff 
(1903). 

He  cultivated  various  molds  (Penicilliura  glaucum  and  Aspergillus 
niger)  on  thymus  nucleic  acid,  and  found  that  both  phosphoric  acid  and 
purine  bases  were  produced  as  the  molds  gi-ew,  although  there  w^as  not 
present  any  ferment  that  could  hydrolyze  a  protein.  Iwanoff  naturally 
concluded  that  he  was  dealing  with  a  specific  ferment,  adapted  to  the 
decomposition  of  nucleic  acid,  and  called  it  "nuclease."  Shortly,  follow- 
ing this  work,  many  researches  were  reported  to  show  the  existence  of  a 
similar  ferment  in  animal  and  plant  tissues,  so  that  the  wide  distribution 
of  nuclease  was  soon  conceded. 

But  it  was  shown  later  that  the  physiological  decomposition  of  nucleic 
acid  is  a  rather  complicated  matter  involving  a  number  of  active  agents, 
and  that  various  gland  extracts  differ  markedly  from  one  another  in  the 
extent  to  which  they  can  carry  this  decomposition.  It  is  certain  that  the 
first  stage  consists  in  the  disruption  of  the  nucleotide  linkages  with  the 
consequent  production  of  simpler  nucleotides,  but  without  setting  free 
either  phosphoric  acid  or  purine  bases.  (Jones  (e),  1920.)  It  would  be 
proper  to  apply  the  term  nuclease  to  this  ferment,  or  to  abandon  the  term 
altogether,  since  it  can  have  no  such  meaning  as  was  originally  ascribed 
to  it. 

Leaving  out  of  consideration  the  two  pyrimidiue  nucleotides  (of 
which  little  is  knowTi),  the  purine  nucleotides  may  undergo  enzymatic 
decomposition  in  either  of  two  "vvays,  depending  on  the  particular  physio- 
logical agent  that  they  encoimter.  The  purine  base  may  be  set  free,  or  the 
phosphoric  acid  may  be  liberated  with  the  production  of  a  nucleoside. 


150  WALTER  JONES 

Eitiallj,  the  nucleosides  under  proper  enzymatic  conditions  decompose  into 
free  purine  and  carbohydrate. 

HO-  H 

no\  Ho\ 

L       O-P— O.C5HSO3.C5H4X5  -=     0:-P— O-C^H^O^+C^HsN/ 
110/  HO/ 

adenine  nucleotide  adenine 


HOH 

iro\  H0\ 

II.  O=P-0 .  CJIsOa .  c,u,y\  =    0=P— On-fCsH^O, .  C^H^Nb 
HO/  i  HO/ 

adenine  nucleotide  adenine  nucleoside 

III.  C  JI„0, .  C,H,N,  +  H,0  =   CbH.oO,  +  C5H5N5 

adenine  nucleoside  adenine 

Purine  bases  are,  therefore,  produced  in  the  nuclein  metabolism  along 
different  lines,  and  their  sub^^equent  conversion  into  uric  also  occurs 
along  different  lines.  The  intention  of  the  following  pages  is  a  disr 
cussion  of  these  various  paths  from  nucleic  acid  to  uric  acid,  and  it  would 
be  logical  to  proceed  from  nucleic  acid,  but  it  is  more  convenient  to  be- 
gin at  the  end,  and  end  at  the  beginning. 

The  Formation  of  Uric  Acid  from  Nucleic  Acid. — Uric  acid  was  for- 
merly supposed  to  be  an  interme'diate  product  in  protein  metabolism,  but 
its  specific  origin  was  clearly  indicated  when  the  purine  gToups  of  nucleic 
acid  were  discovered;  and  endeayoi-s  were  naturally 'made  to  place  this 
indication  on  an  experimental  basis.  Horbaczewski  {b)(c)  (18S0,  1891) 
was  the  first  to  do  this.  His  results  are  fundamental  and  quickly  told. 
Calf's  spleen  was  ground  to  a  pulp  with  water,  and  kept  at  the  body  tem- 
perature until  putrefaction  was  well  advanced.  The  putrid  product  was 
then  sterilized  by  the  addition  of  lead  acetate,  arterial  blood  was  added^ 
and  the  material  was  allowed  to  digest  at  40°  as  a  slow  stream  of  air  was 
passed.  In  the  end,  uric  acid  could  be  found,  while  similar  experiments  in 
which  no  air  was  passed  produced  xanthine  and  hypoxanthine  instead  of 
uric  acid. 

Horbaczewski  did  not  clearly  understand  w^hitt  he  was  doing  and  took 
a  gi-eat  deal  of  useless  trouble.  The  preliminary  putrefaction  and  the 
use  of  arterial  blood  were  superfluous  procedures  while  the  sterilization 
with  lead  acetate  might  have  vitiated  his  results.  Nevertheless,  he  started 
with  nucleic  acid  of  spleen  pulp  and  ended  with  uric  acid. 

Horbaczervvski  also  found  that  in  man  the  ingestion  of  nucleic  acid  pro- 


XUCLEIC  ACIDS  151 

fluced  an  increase  of  uric  acid  in  the  urine,  whereupon  he  formulated  the 
well  know  II  leucocytosis  theory. 

It  is  frequently  stated  that  the  entire  work  of  Horbaczewski  was  "un- 
intelligent";  yet  he  showed  the  physiological  origin  of  uric  acid  from 
luicleic  acid,  and  thus  solvcrl  one  of  the  most  imjwrtant  physiological  prob- 
lems of  his  day. 

The  Formation  of  Uric  Acid  from  the  Oxy-purins.— Of  Tlorbaczewski's 
many  vagaries,  perhaps  the  most  serious  was  his  misconception  of  the 
path  along  which  uric  acid  is  fonncd  from  nucleic  acid.  He  stated  posi- 
tively, that  as  no  one  had  been  able  to  oxidize  either  xanthine  or  hypo- 
xaiithine  to  uric  acid  outside  of  the  body,  these  substances  could  not  be 
intermediate  pro(jucts  in  the  passage  from  nucleic  acid  to  uric  acid,  and 
therefore,  the  purine  groups  of  nucleic  acid  must  have  been  deaminized  and 
oxidized  before  they  were  set  free.  However  this  may  be,  Spitzer  (1890) 
found  that  an  aqueous  extract  of  spleen  can  bring  about  the  required  oxida- 
tion. To  the  extract  he  added  a  weighed  amount  of  oxy-purine  and  digested 
the  mixture  at  40°,  as  a  slow  current  of  air  was  passed.  The  oxy-purine 
disappeared  and  in  its  place  was  found  a  reasonable  equivalent  of  uric  acid. 
The  active  agent  that  brings  about  the  transformation  is  called  xanthine- 
oxidase.  Its  presence  can  be  shown  in  tissue  extracts  that  are  devoid  of 
power  to  bring  about  other  purine  transformations ;  hence  xanthine-oxidase 
is  specific. 

The  Formation  of  Oxy-purines  from  Amino-purines. — In  order  to  pass 
froni  nucleic  acid  to  uric  acid  three  transformations  are  required  (though 
not  necessarily  in  the  order  given). 

1.  Liberation  of  the  purines 

2.  Deaminization 

3.  Oxidation 

Of  these  three,  deaminization  remains  to  be  considered. 

All  gland  extracts  contain  nucleic  acid;  so  that  the  purine  ferments 
may  be  studied  by  examining  the  purine  products  of  autodigestion.  When 
an  aqueous  extract  of  pig's  pancreas  is  allowed  to  digest  at  40°,  free  purine 
bases  soon  make  their  appearance.  They  are  not,  however,  the  amino- 
purines  (guanine  and  adenine)  that  one  would  expect  to  be  formed  from 
nucleic  acid,  but  the  two  corresponding  oxy-purines  (xanthine  and  hypo- 
xanthine).  The  same  results  are  obtained  with  thymus.  These  experi- 
ments lead  to  the  assumption  that  in  the  digestion,  the  amino-purines  are 
first  formed  but  are  subsequently  converted  into  the  oxy-purines  by  a  deam- 
inizing  agent  present  in  the  tissue  extract. 

A  most  unexpected  result  was  obtained  with  pig's  spleen.  The  end 
products  of  the  self-digestion  of  an  aqueous  extract  of  this  tissue  are 
iiuauine  and  hyp)xanthine,  i.f\,  one  amino-purine,  and  one  oxy-purine.  It 
is  reasonable  to  supi>ose  that  initially  l)oth  amino-purines  are  lil)erated  from 


152 


WALTER  JOKES 


the  nucleic  acid  of  the  gland  extract,  but  only  one  of  them  is  subsequently 
deaminized.  This  necessitates  the  conclusion  that  both  thymus  and  pan- 
creas contain  two  independent  deaminizing  ferments  (guanase  and  ade- 
nase),  only  one  of  which  (adenase)  is  present  in  the  spleen. 

An  equally  curious  result  was  obtained  with  pig's  liver.  The  end 
products  of  self-digc-Tioii  are  guanine  and  xanthine.  This  is  easily  ac- 
counted for  by  assuming  that  the  giianinc  set  free  from  the  nucleic  acid 
remains  unchanged,  but  that  the  adenine  is  deaminized  to  hypoxanthine, 
which  in  turn  is  oxidized  to  xanthine. 

Representing  the  purine  ring  wuth  its  three  replaceable  hydrogen  atoms 

by  the  symbol  V—U,  the  results  of  autodigestion  may  be  expressed  as  fol- 
lows : 


/mi. 

/H 

/NH, 

/H 

p— on 

P     XII, 

P— OH 

P— NH 

\H 

\H    ' 

\H 

\H 

guanine 


/on 
p— on 

\H 

xanthine 


adenine 


P— OH 
\H 

hypoxanthine 


guanine 


adenine 


/H 

P— OH 

\H 

hypoxanthine 


Pig's  Thymus  and  Pancreas  Pig's  Spleen 

(Jones  and  Austrian  (a),  1906)    (Jones  and  Winternitz,  1905), 


/OH 

p— on 

\01I 

Uric  Acid 


/XH, 
P— OH 

\n 

guanine 


./OH 
P— OH    <- 

xanthine 


P— KH; 

\H 

adenine 


/H 

P— OH 

\H 

hypoxanthine 


Pig'^s  Liver 
(Jones  and  Winternitz,  1905) 


XUCLETC  ACIDS  153 

But  these  considerations  are  somewhat  speculative.  There  is  hut 
one  way  to  prove  the  presence  of  a  ferment.  The  suhstance  supposed  to 
he  deconip()se<l  must  he  introduced;  as  di.iiestion  proceeds  it  must  disap- 
pear, and  in  its  phice  must  ])e  found  a  reasonahle  equivalent,  of  the  sul>- 
stance  supposed  to  he  formed.  Accordiuiily,  dilute  aqueous  extracts  of 
the  various  tissues  were  prepared  and  }K)rtions  taken  so  small  that  the 
purine  bases  formed  from  the  extract  itself  could  he  iL':nored.  The  purine 
base  in  question  was  then  added  to  the  tissue  extract,  the  material  was 
allowed  to  digest  at  40^  under  antiseptic  conditions,  and  the  product 
was  finally  examined  for  pnrine  bases.  In  this  way  each  of  the  glands 
was  found  to  possess  the  ferments  that  had  been  indicated  by  the  results 
of  autodigestion.  , Thymus  converted  guanine  into  xanthine,  and  adenine 
into  hypoxanthine.  Pancreas  did  the  same.  Spleen  converted  adenine 
into  hypoxanthine,  but  left  guanine  unchanged.  Liver  converted  adenine 
into  hypoxanthine,  and  hypoxanthine  into  xanthine,  but  left  guanine  un- 
changed. Three  independent  factors  of  purine  fermentation  are  thus 
disclosed  (Jones  (a),  1005). 

1.  guanase,  2.  adenase,   ,  3.  xanthine  oxidase 

Dog's  liver  contains  guanase  but  not  adenase;  pig's  spleen  contains  adenaso 
but  not  guanase ;  neither  tissue  contains  xanthine-oxidase.  The  three  fer- 
ments arc  therefore  independent  of  one  another. 


THE  PHYSIOLOGICAL  DESTRUCTION  OF  URIC  ACID 

Many  experimenters  have  observed  that  uric  acid  may  be  made  to  dis- 
appear by  digestion  at  40"^  with  aqueous  extracts  of  certain  glands  in  the 
presence  of  a  sufficient  supply  of  oxygen.  But  the  disappearance  of  uric 
acid  and  its  physiological  destruction  are  two  different  things.  While 
imdoubtedly  an  element  of  truth  permeated  all  of  the  earlier  work,  this 
work  is  so  full  of  error  and  confusion  that  we  nmst  look  upon  much  of  it  as 
a  fortunate  accident.  Uric  acid  was  destroyed  by  laboratory  methods  used 
in  examining  the  products  of  digestion,  or  was  lost  in  coagitla.  Its  de- 
struction product  Avas  incorrectly  stated  to  be  glycocoll,  oxalic  acid  or 
nothing  at  all.  So  that  even  now  a  considerable  amount  of  ingeuuity  is 
required  to  value  the  results  of  the  early  workers.  A  great  deal  of  time 
can  be  saved  and  annoyance  avoided  by  proceeding  directly  to  the  mod- 
ern well-established  conclusion  that  certain  tissue  extracts  are  capable  of 
bringing  about  the  conversion  of  uric  acid  into  the  more  soluble  allantoine 
provided  that  a  sufficient  amount  of  air  be  supplied.  (Wiechow\ski  (a) 
{h){c){d).)  The  gradual  emergence  of  this  truth  from  a  mass  of  ob- 
structing error  is  most  interesting.  While  the  principal  credit  is  given  to 
Wiechow^ski,  it  is  difficult  to  say  who  really  made  the  discovery. 


154 


WALTER  JOXES 


/  \ 

o-:C  c-iVJi\       +  n,o  +  o 

\       II  c^o 

XII~C— XH/ 

Uric  Acid 

NIT— C--0 

/  I 

=       0-c  I      h.:n^\ 

\  I  C-O     +     CO, 

NH— CII— XII/ 

allaiitpine 

Thus  the  purine  feniicntatiou  is  effected  by  four  independent  pliysio- 
loi^ical  agents, 

1.  giianase,         2.  adenasn,         3.  xanthine-oxidase,         4.  uncase. 

Three  of  these  lead  up  to  the  formation  of  uric  acid  and  the  fourth  brings 
about  its  destruction. 


Nucleic  Acid 


guanine 


allantoine     uric  acid     xanthine 

< 0—      < (D—      ^- 


hypoxanthine 


-Or 


A  study  of  the  localization  of  these  ferments  discloses  interesting  and 
important  matter. 


THE  BrSTRIBUTION  OF  THE  PURINE  FERMENTS 

1.  With  very  rare  exceptions,  the  four  ferments  of  the  purine  fer- 
mentation are  not  present  in  any  one  tissue.  The  distribution  character- 
izes the  tissue  and  the  species.  This  variation  of  the  distribution  with 
species,  as  well  as  the  independent  existence  of  giianase,  adenase  and  xan- 
thine-oxidase is  shown  by  an  examination  of  the  livers  of  four  different 
species.  (Jones  and  Austrian  (a)  (190C).)  Ox  liver  forms  uric  acid  from 
both  amino-purines,  pig's  liver  from  only  one  (adenine),  rabbit's  liver  only 


NUCLEIC  ACIDS  155 

from  the  other  (guanine),  and  dog's  liver  from  neither.  The  results  ai'C 
shown  in  the  following  diagrams  which  are  abbreviations  of  the  one  on 
page  1*3H.     The- absence  of  a  ferment  is  indicated  by  a  dotted  line. 


OX  nver 


pl^s  liver  raobits  liver      ^^gs  1  i ver 


t        t 

I 

•        II        * 


2.  The  purine  ferments  do  not  appear  in  an  organ  simultaneously, 
but  are  formed  successively  as  embryonic  development  proceeds;  so  that 
the  distribution  depends  not  only  up(m  the  particular  tissue  and  the  species, 
but  to  a  considerable  extent  upon  the  age  of  the  animal.  None  of  the 
purine  ferments  can  be  demonstrated  in  the  aqueous  liver  extract  of  a 
pig  embryo  less  than  90  mm.  in  length.  As  the  embryo  increases  in  length 
from  90  mm.  to  200  mm.,  adenase  makes  its  appearance,  but  xanthine 
oxidase  appears  only  after  the  birth  of  the  animal.  (Jones  and  Austrian 
1907.) 

3.  The  distribution  of  the  purine  fennents  in  the  organs  of  man  is 
very  characteristic.  Adenase  is  not  present  in  any  human  tissue.  Guanase 
is  irregularly  distributed,  being  present  in  the  kicjney,  liver  and  lung  but 
absent  from  the  spleen  and  pancreas.  (Jones  and  Austrian  (6).)  It  is 
significant  that  human  urine  contains  adenine,  but  not  guanine.  Xanthine 
oxidase  is  profusely  present  in  the  human  liver  but  is  confined  to  the  one 
organ.     (^Miller  and  Jones;  Winternitz  and  Jones.) 

Uricase  is  not  present  in  the  liver,  nor  in  any  other  organ  either  of 
children  or  adults,  nor  is  allantoine  present  in  human  urine,  except  a  trace 
of  the  substance  that  is  ingested  with  the  food.  It  seems  curious  that 
man  should  have  lost  so  useful  a  function  as  ability  to  destroy  uric  acid. 

4.  Uricase  may  be  regarded  as  a  liver  ferment  since  it  is  probably 
present  in  the  livers  of  all  the  lower  animals  except  the  ape  (ox,  dog,  pig, 
sheep,  rabbit,  giiinea  pig,  horse,  rat,  opossum,  monkey),  and  except  for 
an  occasional  occurrence  in  the  spleen  (ox),  the  ferment  is  found  only 
in  the  liver.  Its  location  makes  it  very  elTective,  so  that  allantoine  is 
far  more  abundant  than  uric  acid  in  the  urine  of  the  lower  animals.  This 
appears  in  the  analyses  of  the  urine  of  seventeen  animals,  twelve  of  which 
were  made  by  Hunter  and  his  associates.  They  calculate  a  factor  for 
each  animal  species  called  the  "uricolytic  index,"  which  is  directly  pro- 
portional to  the  allantoine,  and  inversely  proportional  to  the  uric  acid. 
The  following  table,  adapted  from  that  of  Ilunter  and  Givens  (c)(1914), 
shows  the  great  preponderance  of  the  allantoine  over  the  uric  acid  in  the 
urine  of  the  lower  animals,  in  contrast  to  the  urine  of  man  and  the  ape. 


15G  WALTEll  JONES 

Animal  Species.  Uricolytic  Index. 

Opposum    79 

Sheep    80 

Horse 88 

Monkey    89      • 

Goat   92 

Cow    93 

Guinea  pig   94 

Rabbit    95 

Raccoon    95 

Rat    96 

Coyote    97 

Cat    97 

Dog    98 

Badger    98 

Pig   98 

Ape 0 

Man    0 

5.  Xanthine  oxidase,  like  uriease^  is  generally  confined  to  the  liver 
(ox,  pig,  rabbit,  guinea  pig,  opossum,  man),  but  is  not  so  widely  dis- 
tributed as  uricase.  Thus  certain  livers  (rat  and  dog)  are  provided  with 
a  ferment  to  destroy  uric  acid  but  with  none  to  form  it.  This  is  not  an 
uncommon  circunistance.  Rabbit's  liver  is  able  to  oxidize  hypoxanthine  to 
uric  acid,  but  cannot  form  hypoxanthine  from  adenine. 

Perhaps  the  most  active  occurrence  of  xanthine  oxidase  is  in  human 
liver,  which  accords  with  man's  low  output  of  purine  bases,  the  ratio  of 
purine  bases  to  uric  acid  being  thirty-five  times  greater  in  monkey's  urine 
than  in  human  urine. 

The  deficiency  of  xanthine  oxidase  in  the  organism  of  the  monkey  (cer- 
copithecus)  was  noted  by  Hunter.  In  a  haphazard  quantity  of  urine 
he  found 

Uric    ncid .320 

Xantliine    950 

Hypoxanthine    360 

Guanine    .-   .000 

Adenine    000 

Even  subcutaneously  iujectetl  xanthine  was  recovered  unchanged.     (Hun- 
ter and  Givens  (&).) 

Xanthine  oxidase  is  not  present  in  yeast  where  such  a  multitude  of  fer- 
ments occur,  nor  is  uric  acid  to  be  found  in  plants. 

6.  Guana^e  is  the  most  widely  distributed  of  all  the  purine  ferments. 
With  many  animal  spe^ries  it  is  uniformly  present  in  all  of  the  principal 
organs  (rat,  ox,  guinea  pig,  rabbit).  But  pig's  organs  are  peculiarly  de- 
ficient in  the  ferment,  and  the  muscles  of  the  animal  frequently  contain 
deposits  of  guanine,  due  perhaps  to  ^^guanine  gout."  (Virchow  (a)(6), 
1866,  1866.)  Pigs  urine  contains  guanine  and  the  purine  bases  are 
always  in  excess  of  the  uric  acid.      (Pccile;  Alendel  and  Lyman.) 

7.  Adenase,  on  the  contrary,  is  very  rare,  having  a  distribution  that 
is  somewhat  complementary  to  that  of  guanase.  Its  presence  cannot  bo 
shown  in  any  of  the  principal  organs  of  the  rat,  man  or  rabbit.    As  the  two 


XUCLEIC  ACIDS  157 

ferments  are  seldom  associated  with  one  anotber,  it  seems  queer  that  they 
should  ever  have  been  thought  identical. 

^luscular  bypoxanthine,  which  forms  a  considerable  part  of  what 
Bnrian  and  Schur  call  "endogenous"  uric  acid,  is  not  the  result  of  the 
action  of  adenase  on  adenine.  Leonard  and  »Jones  were  not  able  to  observe 
a  transfonnation  of  adenine  into  bypoxantbine  by  aqueous  extracts  of 
muscle,  while  Voegtlin  and  Jones  found  that  perfused  adenine  is  not 
altered  by  surviving  muscle. 

But  the  path  of  adenine  metabolism  does  not  always  pass  through  hypo- 
xanthine.  None  of  the  organs  of  the  rat  exhibit  adenase  (Rohde  and 
Jones),  and  Nicolaier  found  that  in  rats  subcutaneously  injected  adenine 
is  oxidized  but  reaches  the  kidney  without  deaminization  where  it  fonus 
concretions  of  G-amino-2-8-dioxypurine. 


/H 

/OH 

P— NHj 

+ 

20 

=     P— NHj 

\H 

\0H 

adenine 

6-amino-2-8-dioxy-purini5 

Ebstein  and  Bendix  found  a  similar  transformation  of  adenine  in 
the  organism  of  the  rabbit.  But  these  two  are  the  only  authentic  cases 
in  the  literature  w^here  oxidation  of  a  free  amino-purine  was  found  to  oc- 
cur without  deaminization. 

8.  The  distribution  of  the  purine  ferments  is  often  obscure,  because 
a  given  tissue  extract  may  be  able  to  bring  about  the  decompositian  of  a 
combined  purine  but  unable  to  effect  a  similar  decomposition  of  the  free 
base.  Thus,  dog's  liver  cannot  convert  free  adenine  into  hyjx)xauthine, 
but  it  can  fonn  hypoxanthine  from  nucleic  acid  with  the  greatest  ease. 
Human  tissues  do  not  contain  adenase,  yet  the  subcutaneous  injection 
of  adenosine  causes  a  marked  increase  of  uric  acid.  (Thannhauser  and 
Bommes.) 

A  purine  base  may  even  undergo  both  deaminization  and  oxidation 
while  still  combined.  Benedict  (a)  (1015)  has  shown  that  about  00  per 
cent  of  the  uric  acid  of  ox  blood  is  in  combined  form.  It  is  present  only  in 
the  corpuscle  and  is  set  free  by  a  ferment  present  when  the  blood  is  allowed 
to  stand.  This  contrasts  sharply  with  the  uric  acid  of  chickens'  blood, 
which  does  not  have  a  purine  precursor.  Here  the  uric  acid  is  all  free 
and  in  the  plasma. 

Bass  found  that  the  purine  bases  of  human  blood  are  combined,  and 
can  only  be  detected  after  acid  hydrolysis.  He  was  able  to  isolate  adenine 
but  at  most  only  traces  of  guanine. 

9.  The  purine  metabolism  does  not  always  suggest  evolutionary  rela- 
tions, but  it  often  does.  The  proof  that  uricase  is  not  present  in  the 
tissue  extracts  of  either  the  ape  or  man,  and  that  allantoine  is  not  present 
in  the  urine  of  either  species  (Wiechowski  (e)),  surely  justifies  all  the 


158  WALTER  JOXES 

labor  that  lias  been  expended  upon  tlio  purine  metabolism.  Both  species 
also  fail  to  exhibit  adenase,  and  exhibit  giuinase  irregularly  in  the  various 
organs.  (Wells  and  Caldwell.) 

The  gradation  from  man  to  ape  to  monkey  in  relation  to  adenase 
is  interestiiiiT.  Hunter  and  Givens  (b)  found  that  injected  adenine  was 
largely  excreted  unchanged  in  the  urine  of  the  monkey  Cercopithecus,  and 
Hunter  and  Givens  (a )  were  able  to  show  adena<e  in  slight  activity  in  organ 
extracts  of  a  second  monkey  Cehiis  apclla.  With  organ  extracts  of  a  third 
monkey  Macacus  rhesus,  Wells  was  able  to  obtain  a  striking  demonstra- 
tion of  adenase. 

The  distributions  of  the  purine  ferments  in  the  organs  of  the  rabbit 
and  guinea  pig  are  coincident  throughout.     (^litchell.) 

10.  The  purine  metabolism  of  the  rat  is  curious.  Rohde  and  Jones 
found  that  neither  the  individual  organs  nor  the  combined  organs  of  the 
rat  exhibit  xanthine  oxidase  in  spite  of  the  fact  that  they  could  show  the 
plentiful  piesence  of  uric  acid  in  rat's  urine.  They  also  found  that  the 
combined  organs  of  the  rat  could  not  change  hypoxanthine.  This  ap- 
parent contradiction  is  not  different  from  many  similar  cases,  and  could 
be  accoimted  for  by  assuming  that  in  rats,  uric  acid  is  formed  along  a 
path  that  does  not  involve  xanthine-oxidase.  But  Ackroyd  (&)  found  that 
the  injection  of  hypoxanthine  causes  an  increase  in  the  allantoine  of  rat's 
urine.  This  was  a  most  puzzling  matter  until  the  work  of  Benedict  (6) 
appeared. 

11.  Benedict  found  that  the  Dalmatian  coach  hound  excretes  both 
allantoine  and  uric  acid,  and  that  when  the  urine  of  the  animal  is  acidi- 
fied with  hydrochloric  acid,  a  crystalline  deposit  of  uric  acid  is  formed. 
Careful  analyses  of  the  dog's  urine  were  made  for  both  allantoine  and 
uric  acid,  over  a  long  period  of  time^  and  then  uric  acid  was  injected  sub- 
cutaneously.  This  caused  the  expected  rise  in  the  allantoine  but  the  in- 
jected uric  acid  also  appeared,  and  quantitatively.  From  these  results 
Benedict  concludes  that  ^'uric  acid  and  allantoine  are  interrelated  in  metab- 
olism in  other  ways  than  have  heretofore  been  assumed." 

THE  ENZYMATIC  DECOMPOSITION  OF  COMBINED  PURINS 

^^fany  obseiTations  indicate  that  the  organism  treats  combined  purines 
differently  from  free  purines.  The  following  two  experiments  go  to  the 
root  of  the  matter. 

I.  When  adenine  is  digested  for  several  days  with  an  aqueous  extract 
of  dog's  liver,  the  substance  remains  unaltered  and  can  be  recovered. 
Dog's  liver  does  not  contain  adenase.  But  when  nucleic  acid  (yeast  or 
thymus)  is  digested  with  an  aqueous  extract  of  dog's  liver,  hypoxanthine 
is  formed  in  an  amount  corresponding  to  the  adenine  group  of  the  nucleic 
acid  used.    This  is  vory  clear.    Dog's  liver  can  deaminize  combine  adenine, 


:nucleic  acids 


159 


but  not  free  adenine.  The  tissue  contains  l>oth  adenosine  deaminase  and 
inosine  hydrolase  but  neither  adenosine  hydrolase  nor  adenase  (Amberg 
and  Jones),  as  indicated  in  the  diagram: 


adenosine 


C,H3X,  (XH,) 

adenine 


C„H904.C,H,X,(OH) 

inosine  — 


C^H.X.COH) 

liypoxantliine 


In  tlie  nnclein  metabolism  there  are  two  paths  to  hy|x>xanthine,  one  of 
which  cannot  be  used  by  dog's  liver. 

II.  When  an  aqueous  extract  of  pig's  pancreas  is  allowed  to  digest 
at  40°  C,  xanthine  and  hyp<_»xan thine  are  foniied.  This  was  to  be  ex|)ecte«l 
because  the  gland  contains  both  giianase  and  adenase.  But  when  the  di- 
gested extract  is  boiled  with  dilute  mineral  acid  the  free  purines  are  greatly 
increased.     Guanine  and  additional  hypoxanthine  appear. 

These  results  can  be  explained  in  only  one  way.  The  nucleic  acid 
is  first  decomposed  into  its  simple  nucleotides,  as  was  to  be  expected.  Each 
of  the  purine  nucleotides  is  then  decomposed  in  two  ways  by  the  action  of 
two  ferments  present  in  the  gland  extract.  In  one  way,  the  purine  base 
is  set  free  (action  of  purine  nuclease),  and  in  the  other  way,  phosphoric 
acid  is  split  off  leaving  the  nucleoside  (phospho-nuclease).  Thus  in  the 
self-digestion  of  the  pancreas  four  purine  compounds  are  initially  pro- 
duced; guanine,  adenine,  guanine  nucleoside,  adenine  nucleoside. 

The  two  free  purines  are  deaminized  and  we  therefore  find  the  oxy- 
•purines  among  the  products.  The  adenine  nucleoside  is  also  deaminized 
to  hypoxanthine  nucleoside  but  the  guanine  nucleoside  is  not  similarly 
deaminized.  Hence  subsequent  acid  hydrolysis  produces  guanine  and  hypo- 
xanthine. 

Using  the  terminology  of  yeast  nucleic  acid,  the  autolysis  of  pig's  pan- 
creas is  expressed  in  the  following  diagram 

Nucleic  Acid 


guanine 


guanosine  adenosine 


adenine 


xanthine 


I 

inosine 


hypoxanthine 


1(.)0 


WALTEK  JOXES 


The  gland  evidently  contains  adenase,  giianase  and  adenosine  deaminase, 
but  not  pianosine  deaminase  (Jones  (b)   1011.) 

By  similar  experiments  and  similar  reasoning  the  localization  of  the 
nucleic  ferments  of  many  glands  lias  been  shown  but  much  space  would 
be  required  to  consider  the  individual  eases.  The  general  scheme  of  nu- 
elein  metabolism  so  far  as  it  concerns  purine  derivatives,  is  indicated  in 
the  following  diagram  which  shows  the  theoretical  possibilities,  nucleic 
acid  being  represented  as  a  di-purine  di-nucleotide.  The  independent  ex- 
istence of  each  ferment  indicated  by  an  arrow  has  been  fairly  well  shown. 

II0\  /XH, 

0=P— O.CsHjO^CsX,— OH 
110/  ^  \H 


H0\  I  /H 

O=P~0.C5H,O^C,X,— NH, 


HO/ 


nucleic  acid 


\H 


/NH. 

C,N,H— 0>1 

\H 

guanine 

< — 


/OH  /OH 

CsN^H— OH  CsN.H— OH 

\0H  \H 

uric  acid  xanthine 


/XH 

c,HAC.X4— oh' 

guanosinc 


C5H,0,.CsN,— NH, 
adenosine 


/OH 
CsHA.CjN,— OH 

\H 

xanttiosine 


C,H,0,.C5N,— OH 

Inosine 


C,X,H— NH. 

\H    ' 

adenine 

— > 


QNJI— OH 
hypoxanthine 


Urobilin  and  Urobilinogen Louis  Bauman 

Chemistry — ^Occurrence — Mechanism  of  Urobilin  Formation — Determination 


— Clinical  Significance — Resume. 


Urobilin  and  Urobilinogen 

LOUIS  BAUMxVX 

NEW  YORK 

Chemistry 

In  1868  Jaffo  first  described  a  reddish  s>il>stance  vvhicli  he  found  in 
human  and  canine  bile  and  which  resend)led  one  of  the  urinary  pigments. 
Both  absorbed  certain  rays  between  the  B  and  F  lines  of  the  spectrum  and 
both  fluoresced  in  the  presence  of  zinc  salts.  Jaffe  named  the  compound 
urobilin.  It  is  interesting  to  note  that  even  at  that  time  he  was  aware 
that  the  pigment  was  not  preformed,  but  resulted  from  the  oxidation  of  a 
chromogen,  which  is  now  known  as  urobilinogen  (LeNobel). 

Urobilinogen  has  the  empirical  formula,  C33ll4oO(;i^4.  Fischer  and 
Roese  showed  that  it  contained  4  pyrole  nuclei  and  that  its  structural 
formula  closely  resembled  that  of  bilirubin. 

Bilii'uhin. 
HgC^HC-C C-CH3  CH3-C C-CH=:CIIl2 

II      II  li      II 

CO  C        C-OH 

/\  /\  /\  / 

/      Nil      \  /      Nil 
O                         C=C 

\      NH      /  \      Nil 

\/  \/  \/  \ 

HO^C        C  C        C-CII3 

II         II                         II         II 
COOII— Clio— CIT.— C C-CH,  CII3— C C— CHoCIIoCOOH. 

Urobilinogen. 
CII3-CII0-C C-CIIaCHa-C C-CII2CII3 

II  II  II  II 

HC        C  C        C— OH 

\   /\  /\  / 

NH      \  /      Nil 

Q  Q 

NH      /  \      Nil 

/   \X  \X  \ 

HO-0      c  c      c-cirj 

I!      II  II      II 

COOH— CII2— CH.-C 0— OH3  CH,— C C-CIL,CH„COOH. 

163 


164  LOUIS  BAUMAN 

Urobilinogen  is  a  colorless  comix)imd  which  forms  monoelinic  crystals 
melting  at  192*^  C.  Its  molecular  weight  is  600.  It  is  soluble  in  chloro- 
form and  other  organic  solvents  and  is  readily  oxidized  to  urobilin  by  the 
oxyf^cn  of  the  air  and  by  oxidizing  substances. 

II.  Fischer  synthesized  urobilinogen  by  reducing  bilirubin  with  sodium 
amalgam;  he  also  described  some  of  its  physical  and  chemical  properties. 
He  obtained  it  to  the  extent  of  about  46  per  cent  of  the  bilirubin  which 
ho  employed,  and  assuming  that  it  was  derived  from  one-half  of  the 
bilirubin  molecule  he  named  it  hemibilinibin.  Later  Fischer  and  Meyer- 
Betz  (a)  (1911)  proved  that  urobilinogen  and  hemibilinibin  were  identi- 
cal. Fromholdt  obtained  the  same  substance  by  a  somewhat  similar  method. 

When  urobilinogen  is  treated  with  para-dimethylamino-benzaldehyd, 
dissolved  in  hydrochloric  acid,  the  so-called  Ehrlich  reagent,  it  formi  a 
red  compound  which  absorbs  certain  rays  in  the  orange  and  green  regions 
of  the  spectrum  between  the  D  and  E  lines.  The  red  compound  results 
from  the  oxidation  of  a  colorless  chromogen.  A  solution  containing  one 
part  of  urobilinogen  in  640,000  parts  of  water  still  gives  the  Ehrlich 
reaction  (Fischer  and  Meyer-Betz  (a),  1911).  This  reaction  is  not  specific, 
for  it  is  obtained  with  any  pyrole  derivative  that  contains  a  free  hydrogen 
atom  attached  to  one  of  the  carbon  atoms  of  the  ring.  Urine  containing 
indol  derivatives  also  gives  the  color  test  but  does  not  exhibit  the  char- 
acteristic absorption  bands  (Fischer). 

Urobilin  is  easily  obtained  from  urobilinogen  by  oxidation.  It  is  a 
reddish  yellow  or  brown  substance  of  uncertain  composition,  and  probably 
contains  a  number  of  urobilinogen  molecules  that  have  been  oxidized  and 
polymerized.  It  is  soluble  in  aqueous  alkali  and  in  most  organic  solvents 
such  as  alcohol,  ether  and  chloroform.  Urobilin  absorbs  cei-tain  rays  in  the 
region  of  the  B  and  F  lines  of  the  spectrum.  It  forms  a  colored  salt  with 
mercuric  chlorid,  the  so-called  Schmidt  test.  When  an  alkaline  solution 
of  urobilin  is  neutralized  with  copper  sulphate  solution  a  red  compound, 
soluble  in  chloroform,  is  formed.  This  copj>er  compound  exhibits  the 
characteristic  urobilin  absorption  bands  (Bogomolow).  Urobilin  is  pre- 
cipitated from  Vr'atery  solution  by  ammonium  sulphate.  It  can  be  reduced 
to  urobilinogen  by  bacteria  (Chanias).  Fischer  isolated  160  grams  of 
urobilin  from  a  large  amount  of  human  feces.  Ilis  analysis,  carbon  63.46 
per  cent,  hydrogen  7.67  per  cent,  and  nitrogen  4.09  per  cent,  agreed  with 
that  reported  by  Garrod  and  Hopkins  about  14  years  previously.  When 
urobilin  was  subjected  to  dry  distillation  or  reduction  by  glacial  acetic 
acid  aiid  zinc  dust  two  substances  w^ere  obtained.  The  one  c^^ntained 
nitrogen  while  the  other  resembled  cholesterol  or  one  of  the  bile  acids, 
and  did  not  contain  nitrogen. 

Occmrence. — Because  urobilin  and  urobilinogen  have  the  same  clinical 
and  physiological  significance,  and  for  the  sake  of  brevity,  the  tenn  uro- 
bilin w^ill  be  used  to  include  both  substances. 


•       UKOBILIN  AND  UKOBILINOGEiT  165 

Urobilin  occurs  in  normal  bile  and  in  normal  stool  except  in  tbat  of 
the  new-born.  It  is  present  in  the  urine  in  negligible  quantities.  Con- 
cerning its  presence  in  the  blood  there  is  little  definite  information.  If  it 
occurs  therein  it  is  not  demonstrable  by  our  present  methods.  The  writer 
has  frequently  attempted  to  determine  its  presence  in  the  serum  of  patients 
that  were  excreting  considerable  quantities  in  the  urine  and  stool,  but 
without  avail.  When  normal  serum  is  heated  with  strong  hydrochloric 
acid  a  positive  Ehrlich  reaction  is  obtained,  but  this  is  probably  due  to 
decomposition  of  one  of  the  heterocyclic  amino  acids,  such  as  tryptophan. 
Gerhardt  and  otbers  have  obtained  the  reaction  with  serous  fluids  other 
than  blood.  Conner  and  Roper  claim  to  have  found  it  in  the  serum  of 
pneumonia  patients  shortly  before  death.  When  urobilin  is  added  to 
blood  it  rapidly  disappears  probably  as  a  result  of  oxidation  by  oxyhemo- 
globin (Roth  and  Ilerzfeld). 

An  increased  amount  of  urobilin  is  found  in  the  stool,  in  the  bile, 
and  occasionally  in  the  urine,  in  pernicious  anemia  and  other  conditions 
associated  with  a  destruction  of  red  blood  cells,  and  also  in  diffuse  lesions 
of  the  liver.  Urobilin  is  absent  from  the  stool  in  jaundice  due  to  complete 
closure  of  the  common  bile  duct  and  in  severe  diarrhea. 

Mechanism  of  Urobilin  Formation. — The  voluminous  literature  per- 
taining to  this  subject  abounds  in  theoretic  discussion  and  hypotheses. 
The  enterogenous  theory  had  its  chief  exponent  in  Friederich  Mueller  (6) 
(1892).  It  appears  to  be  least  open  to  criticism,  and  is  supported  by 
numerous  clinical  and  experimental  obseiTations.  It  postulates  that  uro- 
bilin results  from  the  reduction  of  bilirubin  by  the  bacteria  of  the  large 
intestine.  The  following  evidence  is  submitted  in  support  of  the  enterog- 
enous theory;  1.  The  transformation  of  bilirubin  into  urobilin  in  vitro 
by  bacteria  (Mueller,  1892  (a) ;  Fischler  (a),  1906).  2.  Urobilin  is  ab- 
sent from  the  stool  and  urine  of  severely  jaundiced  patients  but  appears* 
when  urobil in-free  bile  is  administered  by  stomach  tube  (F.  Mueller  (6), 
1892).  3.  Bilirubin  alone  is  found  in  the  intestine  of  the  new-bora  until  the 
third  day,  when  urobilin  appears  coincident  with  the  development  of  the 
bacterial  flora.  4.  Diarrheal  stools  often  contain  biliinibin  but  no  urobilin. 
This  is  apparently  due  to  the  rapid  propulsion  of  the  intestinal  contents 
— that  is,  the  stool  is  expelled  before  the  bacteria  have  had  an  opportunity 
to  reduce  bilirubin.  5.  Urobilin  is  not  present  in  the  small  intestine  where 
bacteria  are  absent,  but  appears  distally  to  the  ileocecal  valve  (Schmidt). 

Normally  some  urobilin  is  absorbed  from  the  large  intestine  and 
brought  to  the  liver  where  it  is  partly  excreted  into  the  bile  and  partly 
converted  into  another  substance,  probably  bilirubin.  The  liver  does  not 
permit  urobilin  to  escape  into  the  general  circulation.  The  traces  that  are 
normally  found  in  the  urine  may  be  due  to  absorption  from  the  lower 
bowel  by  the  blood  of  the  inferior  hemorrhoidal  plexus. 

When  extensively  diseased  the  liver  may  permit  urobilin  to  escape  into 


166  LOUIS  BAU:\LAJSr 

the  general  circulation  and  then  it  is  excreted  by  the  kidneys.  In  con- 
ditions causing  a  rapid  disintegi'ation  of  red  blood  cells,  as  in  pernicious 
anemia,  hemolytic  jaundice,  internal  hemorrhage,  etc.,  a  large  amount  of 
hematin  is  converted  into  bilirubin,  and  this  permits  an  increased  ab- 
sorption of  urobilin  from  the  intestine.  Under  these  circumstances  some 
urobilin  may  escape  into  the  general  circulation  even  though  the  liver  be 
functionally  intact.  In  recent  years  hematin  and  bilirubin  have  been 
demonstrated  in  the  blood  serum  in  pernicious  anemia  (Schumm). 

While  the  enterogenous  theory  explains  most  of  the  known  facts  it 
does  not  satisfactorily  account  for  all  of  the  experimental  results  recorded 
in  the  literature.  Fischler  («)  (b)  (lOOG,  1908)  has  submitted  evidence 
favoring  the  liver  itself  as  a  site  of  urobilin  fonnation.  The  following  ex- 
periments may  be  cited  in  this  connection :  When  the  common  bile  duct  of 
dogs  is  tied  and  a  biliary  fistula  is  established  it  is  found  that  in  spite  of 
the  deviation  of  the  bile  to  the  exterior  urobilin  persists  in  the  stool  but 
disappears  from  the  bile.  If,  to  such  animals,  poisons  that  exert  a  par- 
ticularly destructive  effect  en  the  liver  parenchyma  such  as  ethyl  alcohol, 
amy]  alcohol  and  phosphorus,  be  administered  there  results  a  large  in- 
crease in  the  urobilin  content  of  the  bile  and  a  lesser  increase  in  the  feces. 
Fischler  maintains  that  under  these  conditions  the  liver  itself  produces 
urobilin  some  of  which  is  absorbed  by  the  blood  and  excreted  into  the 
intestine.  The  disturbing  features  in  Fischler^s  exjxjriments  were  the 
lack  of  uniform  results,  the  licking  up  of  bile  from  the  fistula  by  some 
of  the  dogs  and  the  presence  of  jaundice  in  others.  While  Fischler  believes 
that  the  liver  may  form  urobilin  he  concedes  that  the  intestines  are  the 
usual  site  of  its  s}^lthesis.  Meyer-Betz  criticizes  Fischler's  conclusions 
and  seeks  to  explain  all  of  his  results  by  assuming  that  some  bilirubin 
reached  the  intestine  by  way  of  the  blood  because  of  the  common  occurrence 
of  jaundice  in  bile  fistula  dogs.  Wilbur  and  Addis  have,  in  a  measure, 
substantiated  the  work  of  Fischler.  They  observed  an  increased  excretion 
of  urobilin  in  the  stool  (and  occasionally  in  the  urine)  of  a  dog  that  had 
cirrhosis  of  the  liver.  Further,  they  found  that  wlien  the  common  l'^*> 
duct  was  ligated  the  urobilin  at  first  disappeared  from  the  stool  only  to 
return  later  in  diminished  quantities,  and  that  when  a  biliary  fistula  was 
prodiice<l  in  these  animals  the  urobilin  of  the  stool  decreased  but  did  not 
wholly  disappear. 

The  arguments  in  favor  of  the  so-called  histogeiiic  theory,  which 
ascribes  the  formation  of  iirobilin  to  the  tissues,  appear  to  be  weak  and 
inconcliisive.  The  occurrence  of  urobilinuria  after  internal  hemorrhage, 
for  instance,  is  better  explained  by  the  enterogenous  theory. 

Determination. — The  method  of  Wilbur  and  Addis  is  now  commonly 
employed  in  this  country  for  the  determination  of  urobilin  in  the  stool, 
bile  and  urine.  The  principal  steps  involved  are  as  follows  (the  I'cader 
is  referred  to  the  original  for  all  details)  :     10  c.c.  of  the  24:-hour  volume 


UROBILIN  AND  UROBILINOGEN  167 

of  urine  are  added  to  10  c.c.  of  saturated  alcoholic  zinc  acetate  solution  and 

filtered.     One  c.c.  of  Ehrlicli's  solution  is  added  to  10  c.c.  of  the  filtiitte. 

Tho  reaction  is  allowed  to  progress  in  the  dark  for  one-lialf  hour.     Tlie 

sohition  is  then  dihited  until  tho  respective  spectral  absorption  bands  of 

urobilin  and  urobilinogen  just  disappear.    Tlie  dilutions  required  give  the 

value  for  5  c.c.  of  urine.     If  this  figure  is  multiplied  by  the  factor, 

volume  of  urine  c.c.    .  i         r  ti     .         ^       ,  ,  .      , 

:; •  the  number  of  dilutions  for  the  24  hours  is  obtained. 

o 

The  feces  are  ground  with  water  and  made  to  a  definite  volume.    An 

aliquot  portion  is  extracted  with  3  volumes  of  acid  alcohol  and  then 

treated  with  zinc  acetate  and  Ehrlich's  reagent.     Tho  steps  that  follow  and 

the  computation  are  similar  to  those  describetl  for  the  urine.    The  average 

normal  excretion  in  the  stool  per  day  is  about  6,500  dilutions  (Wilbur 

and  Addis).    Schneider  (a)   (1916)  determines  tho  urobilin  in  the  duo- 

denal  contents  by  mixing  10  c.c.  with  10  c.c.  of  the  zinc  acetate  solution,  and 

then  filtering.     (One  drop  of  ammonia  is  added  to  tho  filtrate  if  it  is  not 

already  alkaline.)     One  c.c.  of  Ehrlich's  reagent  is  added  to  10  c.c.  of 

the  filtrate.    The  dilutions  are  expressed  in  terms  of  1,000  c.c.  of  bile. 


Clinical  Significance 

An  increased  amount  of  urobilin  in  the  urine  is  frequently  observed 
in  diffuse  involvement  of  the  liver  as  a  result  of  fatty  or  paren- 
ch}-matous  degeneration,  cirrhosis,  new  growth,  abscess  or  even  in  the 
congestion  due  to  heart  disease.  Wilbur  and  Addis  record  a  daily 
excretion  of  from  1,100  to  3,000  dilutions  of  urobilin  in  the  urine  of 
patients  suffering  from  cirrhosis,  hemochromatosis  or  liver  abscess.  Owing 
to  the  variability  of  urobilin  excretion  in  the  urine  it  is  desirable  to  con- 

a/ 

tinue  the  determinations  over  several  days.  Urobilinuria  is  quite  common 
in  the  infectious  diseases  that  produce  degeneration  of  the  liver  as  scarlet 
fever,  lobar  pneumonia,  rheumatic  fever,  malaria,  tuberculosis,  etc.  In 
biliaiy  obstruction  the  amount  of  urobilin  in  the  stool  is  proportional  to 
the  degree  of  patency  of  the  common  bile  duet.  Fischer  and  Meyer-Betz  (h) 
(1912)  studied  the  effect  of  administering  fresh  animal  bile  on  the  uro- 
bilin excretion  in  the  urine.  Under  tliese  conditions  the  urine  of  normal 
subjects  contained  little  urobilin  while  patients  suffering  from  liver  disease 
excreted  considerable  amounts.  Similar  results  were  obtained  when  uro- 
bilinogen itself  was  administered.  In  the  writer's  limited  experience  tlie 
excretion  of  urobilin  in  liver  disease  has  been  quite  irregular.  At  times  no 
increase  was  observed;  at  times  an  increase  occurred  in  the  urine  alone 
or  in  the  feces  alone  wdiile  in  some  instances  an  increase  in  both  urine  and 
feces  occurred  (Bauman).  It  is  conceivable  that  in  hepatic  conditions 
an  increase  in  the  urobilin  of  the  stool  may  precede  urobilinuria.     The 


1 


168  LOUIS  BAUMAN^ 

increased  excretion  of  urobilin  in  tlie  stool  of  some  cirrhosis  patients  was 
pointedout'by  :Mueller  (a)  (1892). 

A  disease  or  condition  causing  an  increased  destruction  of  red  cells 
is  usually  if  not  always  accompanied  Ly  an  increased  elimination  of 
urobilin  in  the  bile,  in  the  stool  and  sometimes  in  the  urine  as  well.  In 
secondary  anemia  the  excietion  of  urobilin  remains  normal  or  subnormal 
while  in  pernicious  anemia  it  may  rise  to  15  times  the  normal  amount, 
hence  urobilin  estimations  may  serve  to  differentiate  the  two  conditions. 

Schneider  (a)  (191C)  studied  the  urobilin  in  the  duodenal  contents  of 
pernicious  anemia  patients.  lie  found  over  2,000  dilutions  in  pernicious 
anemia  while  in  secondary  anemia  little  or  no  increase  could  be  detected. 
After  splenectomy  a  (k^crease  of  the  urobilin  occurred.  These  results  have 
been  confirmed  by  Giffin,  Sandford  and  Szk^^-q.  Kobertson  (Z>)  (1915) 
and  McCrudden  emphasize  the  diagnostic  value  ol  Uiobilin  estimations  of 
the  stool,  thus  confirming  the  work  of  Wilbur  and  Addis.  ^Most  recently 
Howard  and  Ilansmann,  working  in  the  writer's  laboratory,  studied  the 
excretion  of  urobilin  in  the  feces,  urine  and  bile  of  a  number  of  pernicious 
anemia  patients.  They  conclude  that  the  estimation  of  tlie  stool  is  more 
reliable  than  that  of  the  bile.  Attempts  to  demarcate  the  2-1-hour  quantity 
of  feces  were  unsuccessful.  In  pernicious  anemia  a  marked  increase  of 
urobilin  in  the  stool  occurred  even  when  the  blood  examination  sliowed  no 
abnormality.  The  urobilin  was  occasionally  diminished  during  the  re- 
missions so  frequently  encountered  in  this  disease. 

Although  obviously  inaccurate  the  "quantitative"  estimation  of  uro 
bilin  in  the  stool  yields  information  which  possesses  considerable  clinical 
value.  On  a  priori  grounds  it  would  appear  preferable  to  approximately 
•letermine  the  total  daily  excretion  than  that  contained  in  a  casual  sample 
•  f  bile;  furthermore,  it  obviates  the  passage  of  the  duodenal  tube,  a  pro- 
cedure which  is  sometimes  disagreeable  to  the  patient. 

The  diagnostic  value  of  urobilin  estimations  is  illustrated  by  the  fol- 
lowing case  report: 

An  Italian,  J.  G.  (history  number  44,031),  entered  the  Presbyterian 
Hospital  in  November,  1910,  complaining  of  gastric  distress  and  constipa- 
tion which  had  lasted  for  2  years  but  which  was  never  accojnpanied  by 
real  pain,  vomiting  or  diarrhea.  13uring  the  2  weeks  prior  to  admission 
lie  had  experienced  a  sudden  attack  of  weakness  and  dizziness  followed 
by  the  appearance  of  tarry  stools  and  shortness  of  breath.  During  tlie 
period  of  illness  he  had  lost  approximately  25  pounds. 

Phj'-sical  examination  showed  evidences  of  neuroretinitis  in  both  eyes 
occurring  in  an  anemic  man  measuring  about  51/2  feet  and  weighing  143 
poimds.  The  remainder  of  the  examination  was  irrelevant.  Radiographic 
examination  and  sigmoidoscopy  were  also  negative. 

The  red  cells  numbered  2,000,000:  hemoglobin  was  40  per  cent ;  white 
blood  cells  6,800,  of  which  58  per  cent  were  polymorphonuclear.     The 


UROBILIN  AND  UROBILIXOGEISr  169 

blood  smear  showed  irregularity  in  size  and  shape  of  the  red  cells,  with 
central  pallor  and  polychromatophilia  on  one  occasion.  The  Wassermanu 
test  was  negative.  The  gastric  meal  contained  no  free  hydrochloric  acid 
and  a  total  acidity  of  32.  Lactic  acid  and  occult  blood  were  absent.  The 
stool  was  repeatedly  examined;  occult  blood  was  found  on  one  occasion 
only.  The  urohilin  content  of  the  stool  was  'persistently  subnormal;  there 
was  none  in  the  urine. 

The  patient  was  given  two  blood  transfusions  and  was  discharged 
after  one  month  wnth  the  diagnosis  of  pernicious  anemia.  This  diagnosis 
was  made  largely  because  of  the  negative  radiographic  examination. 

During  the  following  6  months  the  patient's  weight  gradually  in- 
creased by  15  pounds;  and  his  blood  recovered  to  the  extent  of  about 
5,000,000  red  cells  and  70  per  cent  of  hemoglobin.  He  was  readmitted 
in  June,  1020,  largely  because  of  the  uncertainty  of  the  diagnosis  and 
because  his  gastric  symptoms  had  increased  in  severity.  The  red  cells 
now  numbered  5,200,000,  and  the  hemoglobin  SO  per  cent.  The  24-hour 
stool  contained  1,760  dilxdions  of  urohilin;  the  urine  contained  JfOO  dilu- 
tions on  one  occasion  and  1/)8S  on  another. 

Fluoroscopy  now  showed  a  mass  in  the  region  of  the  cardiac  end  of 
the  stomach,  and  this  was  confirmed  by  an  exploratory  laparotomy,  which 
further  revealed  metastatic  involvement  of  the  liver  and  retroperitoneal 
lymph  nodes. 

In  this  case  the  severe  anemia  during  the  earlier  period  of  the  disease 
was  probably  caused  by  a  profuse  hemorrhage  from  the  tumor.  The  low 
urobilin  content  of  the  stool  militated  against  peraicious  anemia  and 
favored  a  new  growth.  The  late  occurrence  of  urobilinuria  was  due  to 
the  involvement  of  the  liver. 

Our  ignorance  of  the  fate  of  urobilin  in  the  blood  and  tissues  and  its 
irregular  excretion  in  the  urine  in  cases  of  liver  disease  detract  from  its 
value  as  a  functional  test  of  liver  efficiency.  The  interest  aroused  by 
the  work  of  Wilbur  and  Addis  in  this  country,  and  by  that  of  Fischer 
abroad  will  stimulate  investigation  so  that  information  relating  to  this 
phase  of  the  urobilin  problem  will  probably  be  furnished  in  the  near 
future. 

Resume 

ITrobilinogen  and  urobilin  are  almost  exclusively  derived  from  bili- 
rubin by  reduction  by  the  bacteria  of  the  large  intestine.  Urobilin  is  an 
oxidized  and  pohiuerized  urobilinogen. 

The  determination  of  urobilin  in  tlie  feces,  urine  and  hile  may  be  a 
valuable  means  of  estimating  the  rate  of  blood  destruction,  thus  aiding 
in  the  differential  diagnosis  of  primary  from  secondary  anemia;  it  may 
also  serve  to  determine  the  functional  state  of  the  liver. 


Creatin  and  Greatinin .Louis  Bauman 

Chemistry — -The  Creatin  Content  of  Muscle  and  Other  Tissues — The  Origin 
of  Creatin — Creatin  Metabolism — ^luscle — Blood— Urine — Creatinin 
Metabolism — Muscle — Blood — Urine — The  Fat«  of  Administered  Creatin 
or  Creatinin — Resume. 


Creatin  and  Creatinin 

LOUIS  BAUMAX 

NEW  YORK 

Chemistry 

XH2 

r 

C=NH 

I 

Creatin,  methylguanidoacetic  acid  (CII3X — CH2COOH),  was  first 
isolated  from  meat  extract  and  named  by  Chevreul  in  1835.  Twelve 
years  later  Liebig  isolated  it  from  the  muscle  of  various  animals,  analyzed 
it  and  converted  it  into  its  anhydride  which  he  named  creatinin.  Creatin 
was  synthesized  from  sarcosin  and  cyanamid  by  Volhard  (1868),  and 
from  sarcosin  and  guanidin  carbonate  by  Horbaczewski  (a)  (1885). 

Creatin  forms  transparent  prismatic  crystals  which  contain  one  mole- 
cule of  water.  At  room  temperature  it  is  soluble  in  water  to  the  extent 
of  1.35  per  cent.  When  heated  with  water  or  dilute  mineral  acids  it  is 
converted  into  creatinin.  Conversely  creatinin  is  converted  into  creatin 
when  heated  with  calcium  hydroxid  solution. 

NH CO 

I 
C=NH 

)   also  occurs  in  the  form  of  prismatic 

CH,N CH2 

crystals  which  dissolve  in  water  to  the  extent  of  10  per  cent;  it  is  also 
more  soluble  in  alcohol  than  creatin.  Owing  to  its  basic  nature  it  is 
readily  precipitated  by  the  so-called  alkaloidal  reagents. 

In  watery  solution  creatin  is  slowly  transforaied  into  creatinin,  the 
rate  of  transformation  is  slightly  less  than  0.5  per  cent  per  day  at  36"^  C. 
Under  similar  conditions  creatinin  is  changed  into  creatin  so  that  at  the 
end  of  11  months  an  equilibrium  is  established  in  either  case.  When 
these  substances  are  dissolved  in  the  urine  a  similar  change  takes  place 
(Myers  and  Fine  (k),  1015). 

Both  creatin  and  creatinin  reduce  alkaline  copper  solutions.  When 
boiled  with  mercuric  oxid  they  are  oxidized  to  methylguanidin  and  oxalic 

171 


Creatinin   ( 


172  LOUIS  BAU.MAX 

acid  (Dcssai^es).  When  crcatiri  is  oxidized  with  hydrogen  peroxid  in 
the  presence  of  ferrous  sulphate,  glyoxylic  acid  is  formed  (Dakin  (c) ).  lie- 
ccntly  a  new  substance,  methjlguanidoglyoxylic  acid,  was  obtained  upon 
oxidizing  creatin  with  mercuric  acetate  in  watery  solution  (Bauman  and 
TncTaldsen).  The  successive  steps  in  the  oxidation  of  creatin  may  bo 
formulated  as  follows: 

1.  NIl2C(:XH)X(CH3)CH2COOIIl  +  O  =  NH2C(:XH)X 
(CH3)CH01IC00H. 

2.  ]SrH2C(:XH)X(CH3)CHOnCOOIIl  +  O  =  NHaCCiNH)^ 
(CH3)C0C00H. 

3.  NH2C(:XH)X(CH3)COCOOH  +  HgO  =  XH2C(:XIIi)X 
(CH3)H  +  COOHCOOH. 

The  ease  with  which  creatin  is  oxidized  by  metallic  salts  is  noteworthy. 
The  alleged  occurrence  of  methylguanidin  in  the  blood,  muscle  and  urine 
may  in  reality  be  the  result  of  oxidation  of  creatin  by  the  mercuric  or 
argentic  salts  which  are  ordinarily  used  for  the  purpose  of  isolation. 

When  picric  acid  is  added  to  urine  a  characteristic  jx>tassium  creatinin 
picrate  is  precipitated  ( Jaffe  (f),  1886)  ;  this  compound  may  be  readily 
converted  into  the  time-honored  zinc  chlorid  salt  according  to  the  method  of 
Benedict  (a)  (1914).  In  this  manner  relatively  large  quantities  of 
creatinin  (and  creatin)  may  be  prepared  so  that  it  has  become  readily 
accessible  to  most  laboratories  and  is  now  used  to  prepare  standard  solu- 
tions for  its  quantitative  color  imetric  determination. 

Jaffe  (e)  (1880)  first  noted  that  an  alkaline  solution  of  creatinin  re- 
duces picric  acid  to  a  reddish  compound  (probably  picramic  acid).  Folin 
(a)  (1904)  proved  that  the  intensity  of  the  color  was  directly  proportional 
to  the  amount  of  creatinin  and  therefore  that  this  reaction  was  well  adapted 
for  its  quantitative  colorimetric  determination.  The  publication  of  this 
method  proved  to  be  an  incentive  for  numerous  investigations  of  the 
physiological  behavior  of  creatin  and  creatinin,  since  the  foi-mei*  may 
readily  be  converted  into  the  latter  by  relatively  simple  means. 


The  Creatin  Content  of  Muscle  and  other  Tissues 

Creatin  is  a  characteristic  constituent  of  the  muscle  tissue  of  all 
vertebrates.  In  the  skeletal  muscle  of  the  horse,  for  example,  it  fomis 
approximately  one-third  of  the  total  extractive  nitrogen,  the  remainder 
being  formed  by  camosin  and  other  compounds  (Von  Fuerth  and 
Schwartz).  Creatin  is  most  abundant  in  voluntary  muscle;  there  is  less 
in  heart  muscle,  and  least  in  involuntarv'  muscle.  The  following  table 
gives  the  average  percentage  of  creatin  in  the  moist  tissues  of  various 
animals : 


GREAT  FN  AND  CREATININ 


17a 


Tissue 


Voluntary  muscle, 


Liver    

Heart  muscle. 
Uterine    " 


Testes 
Brain 


Kidney 


Brain  . .  , 
Testes  . . . 
Pancreas 


Animal 

Rabbit 

Dog 

Cat 

Kitten^ 

Human 

Horse 

Pig 

Sheep 

Beef 

Rat 

Fish' 

Dog 

Dog 

Dog 

Beef 

Beef 

Beef 

Dog 

Beef 

Dog 

Pig 
Dog 
Dog 
Dog 


Creatm 
mg.  % 


518 

367 

449 

224 

!    393 

I    380 

!    450 

i     410 

I    440 

458 

500 

18 

216 

30 

38 

87 

56 

56 

16 

14 

15 

110 

181 

18 


Author 


Myer«  and  Fine  (1013  (X)) 


**        «« 


Van  Hoogenhuyze  and  \'erploegh  ( 1905 ) 


I     Myers  and  Fine  (1915  (4>) 
to  700       Okuda 
Beker 


•124 


Janney  and  Blatherwick 


*  The  creatin  content  of  kitten  muscle  varies  with  the  age  of  the  animal. 
'  Various  species  of  fish  muscle  were  analyzed.    The  figures  represent  minimal  and 
maximal  values. 

Denis  (e)  (1916)  determined  the  creatin  content  of  a  relatively  large 
number  of  samples  of  human  muscle  and  found  it  to  vary  from  360  to  421 
milligTams  per  cent.  The  muscle  of  children  and  that  of  persons  dying 
of  a  wasting  disease  was  usually  found  to  be  low  in  cz-eatin. 

As  the  creatin  content  of  muscle  is  determined  by  the  Folin  method 
it  was  important  to  know  if  the  color  reaction  was  entirely  due  to  this 
substance.  By  first  transforaiing  the  creatin  in  muscle  extract  into  cre- 
atinin  and  then  quantitatively  removing  the  latter  by  precipitation,  Bau- 
man  and  Ingvaldsen  (a)  (1916)  were  able  to  show  that  creatin  alone  was 
responsible  for  the  Jaffe  reaction. 


The  Origin  of  Creatin 

A  vast  amount  of  experimental  work  has  been  done  on  this  problem. 
The  only  other  guanidin  derivative  which  has  been  found  in  the  animal 
body  is  the  amino  acid,  aroinin  (alpha  amino,  delta  guanido  valerianic 
acid,  (NIL>r(:Xn)XII— CKoCHoCIT^CHXHoCOOH).  Arginin  has 
been  pei-fused  and  administered  in  various  ways  in  order  to  see  if  it  was 
converted  into  creatin.  On  the  whole  the  results  have  not  been  uniform 
or  conclusive.  By  analog}'  one  might  assume  that  arginin  would  first  be 
oxidized  to  guanidoacetic  acid  or  glycocyamin   (KH2C(  :XH)XH-CH2 


174  LOUIS  BAUMAN 

COOII).    Tliis  compouncl  is  converted  into  creatin  when  fed  or  injected 
into  animals  (Czemicki;  Jafto,  1906;  Dorner;  Bauman  and  liines). 

Van  Hoogenliii jze  and  Verploegh  (a)  (1005)  failed  to  observe  an  in- 
crease in  crcatinin  excretion  after  tlic  ingestion  of  proteins  relatively  rich 
in  arginin.  Myers  and  Fine  (1905)  report  that  the  concentration  of 
niusclo  creatin  does  not  appear  to  be  markedly  infiucnced  by  the  feeding 
of  proteins  having  a  high  or  low  content  of  arginin.  Jaffe  (/)  (1906)  did 
not  observe  an  increase  in  creatinin  excretion  after  the  injection  of  arginin 
into  rabbits.  Bauman  and  Marker  also  failed  to  note  an  increase  of 
muscle  creatin  when  arginin  was  circulated  through  dog  muscle. 

Thompson  (a)  (1917)  administered  arginin  to  ducks,  dogs  and  rabbits 
and  observed  an  increase  in  the  elimination  of  creatin  or  creatinin  and  of 
the  creatin  content  of  the  muscle.  Inouye  observed  that  arginin  was  con- 
verted into  creatin  when  perfused  through  the  liver  of  cats.  In  gi-owing 
pigs  the  nature  of  the  protein  in  the  diet  determines  whether  or  not 
creatin  appears  in  the  urine  (McCollum  and  Steenlx)ck).  Denis  (/) 
(1917)  has  shown  that  the  creatin  excretion  in  hyperthyroidism  may  bo 
much  increased  by  the  addition  of  protein  to  the  diet.  In  children  tlie 
creatin  of  the  urine  varies  with  the  amount  of  protein  in  the  diet  (Denis 
and  Kramer).  Creatinuria  in  women  follows  the  ingestion  of  large 
amounts  of  protein  (Denis  and  Minot  (a)). 

Riesser  obseiTcd  an  increase  in  muscle  creatin  and  in  the  creatinin 
excretion  of  rabbits  after  the  injection  of  cholin  and  betain. 

Harding  and  Young  found  that  arginin  was  without  effect  on  the 
creatin  excretion  of  growing  dogs  but  that  a  variation  in  the  cystin  con^ 
tent  of  the  diet  was  followed  by  a  similar  variation  in  the  creatin 
elimination. 

Most  recently  Wishart  observed  an  increase  in  muscle  creatin  follow- 
ing the  injection  of  guanidin  salts  into  cats,  dogs  and  frogs.  The  as- 
sumption is  that  giianidin  is  detoxicated  by  conversion  into  creatin. 

In  the  foregoing  experiments  the  factor  of  creatin  destruction  by  the 
tissues  must  not  be  overlooked.  Creatin  may  be  synthesized  from  a 
precursor  but  subsequently  destroyed. 


Creatin  Metabolism 

Muscle.— Before  discussing  this  subject  it  may  be  well  to  remind  the 
reader  that  the  experimental  results  obtained  by  different  investigators  are 
often  conflicting  and  therefore  hard  to  reconcihf  with  one  another. 

Considerable  evidence  seems  to  show  that  creatin  is  a  product  of  muscle 
metabolism.  Its  preponderance  in  muscle  suggests  that  it  results  from 
metabolic  processes  peculiar  to  this  tissue  (Pckelharing).  jMusele  creatin 
increases  with  an  increase  in  muscle  tonus  and  conversely  paralyzed  muscle 


CREAXm  A¥D  CREATIXIX  '  176 

is  low  in  creatin  ( Pekelhariiig  and  Van  Hoogcnhuyize  (a),  1909;  Jansen 
{h)  ).  Voluntary  nniscle  lias  an  affinity  for  creatin,  for  when  it  is  injected 
into  rabbits  the  creatin  content  of  their  muscles  is  increased  by  5  per  cent 
(Myers  and  Fine  (e),  1913). 

The  constancy  of  the  creatin  content  of  muscle  of  a  given  S£>ecies  of 
animal  under  uniform  conditions  of  diet  was  first  pointed  out  by  Myers 
and  Fine  (c)  (1913).  During  starvation  or  carbohydrate  abstinence  the 
creatin  content  of  nmscle  at  first  increases  and  then  progressively  de- 
creases with  the  length  of  the  fast  (^lendel  and  Rose  (6),  1911).  The 
nuisclo  of  rabbits  that  had  fasted  for  6  days  contained  0.55  per  cent 
of  creatin,  while  that  obtained  from  rabbits  that  had  been  starved  for  24 
days  contained  0,36  per  cent  (Myers  and  Fine  (d)  1913).  The  decrease 
in  creatin  is  explained  by  the  loss  of  this  substance  through  the  urine. 

Benedict  and  Osterberg  maintained  phlorhizinized  dogs  in  approximate 
nitrogen  equilibrium  by  feeding  creatin  free  protein.  Under  these  con- 
ditions the  excretion  of  creatin  continue<l  unchanged,  and  in  spite  of  the 
relatively  large  quantity  lost  in  the  urine  the  muscle  of  these  animals 
actually  contained  more  than  that  of  normal  dogs.  The  authors  conclude 
that  the  creatin  excreted  in  the  urine  is  not  dependent  on  the  amount  of 
body  tissue  destroyed,  that  it  is  not  derived  from  muscle  creatin,  and 
further  that  creatin  is  probably  formed  in  large  amounts  and  is  noi-mally 
utilized  or  destroyed  for  the  gi-eater  part.  The  creatinin  of  the  urine 
can  only  account  for  a  small  part  of  the  creatin  that  is  normally  katabol- 
ized.  Folin  and  Denis  (/i)  (1914)  found  that  when  creatin  was  injected 
into  cats  it  was  absorbed  by  the  muscles  to  an  extraordinary  degree.  They 
believe  that  living  muscle  does  not  contain  free  creatin  and  that  that  found 
on  analysis  is  a  post-mortem  product.  The  vital  combination  must  be  a 
very  loose  one  to  be  sure. 

According  to  several  authors  creatin  is  not  destroyed  during  aseptic 
or  antiseptic  autolysis  of  muscle  (Denis  (e),  1916 ;  Mellanby  (a)  ).  Myers 
and  Fine  (k)  (1915)  find  that  no  destruction  of  creatin  or  creatinin  occurs 
when  rabbit  muscle  is  pennitted  to  autolyze  (under  aseptic  conditions)  at 
body  temperature.  On  the  other  hand  the  work  of  Iloagland  and  McBryde 
seems  to  show  that  during  aseptic  autolysis  of  beef  muscle  creatin  at  first 
increases  and  then  decreases. 

Blood. — N"ormal  blood  contains  between  3.5  and  6  milligTams  of 
creatin  per  100  c.c.  (Folin  and  Wu).  In  nephritis  as  much  as  31.7  mgs. 
have  been  observed  (Myers  and  Fine(^),  1915 ).  Though  the  concentration 
of  creatin  in  the  blood  is  higher  than  that  of  creatinin  the  former  is  usually 
not  excreted  by  the  kidney  while  the  latter  is  a  normal  constituent  of  the 
urine.  In  other  words  the  renal  threshold  for  creatinin  is  low^er  than  for 
creatin.  The  concentration  of  creatin  in  the  plasma  is  lower  than  in 
whole  blood  (Hunter  and  Campbell  (?>)). 


176  LOUIS  BAU.AIAX 

Urine. — Under  normal  conditions  creatin  is  absent  from  tlie  urine  of 
men  when  living  on  a  creatin  free  diet;  it  is  constantly  present  in  the 
urine  of  children  and  frequently  occurs  in  the  urine  of  women.  Powis 
and  Raper  have  shown  that  children  eliminate  more  creatin  during  the 
day  than  at  night.  In  the  young  the  supply  of  carbohydrate  and  fat 
appears  to  be  unable  to  meet  the  demands  of  gi*owth  and  maintenance, 
and  as  a  consecjuence  muscle  tissue  disintegTates,  creatin  is  liberated  and 
appears  in  the  urine.  The  frequent  occurrence  of  acetonuria  in  childi-en 
and  the  rapidity  with  which  the  glucose  content  of  their  blood  is  lowered 
during  starvation  are  further  indications  of  a  limited  supply  of  glycogen 
(Sawyer,  Stevens  and  Bauman).  The  occurrence  of  creatin  in  the  urine 
of  children  may  also  be  due  to  a  diminished  ability  to  destroy  it  (Krause 
(&),  1913;  Gamble  and  Goldschmidt  (a),  1919).  In  infants  the  in- 
creased excretion  of  creatin  when  they  are  on  a  pure  milk  diet  may  be  due 
to  the  creatin  present  in  the  milk  and  not  to  the  protein  therein  (Gamble 
and  Goldschmidt  (6),  1919). 

Sawyer,  Stevens  and  Bauman  observed  that  the  increased  excretion  of 
creatin  which  occurs  in  children  when  deprived  of  carbohydrates  is  usually 
followed  by  a  period  of  creatin  retention  upon  resumption  of  the  normal 
diet.  It  appears  as  if  the  body  retained  creatin  with  gi*eat  regularity 
under  these  circumstances. 

The  alleged  occurrence  of  creatinuria  after  menstruation  (Krause  (a), 
1911)  has  not  been  confirmed  by  M.  S.  Rose,  who  found  no  definite  rela- 
tion between  the  creatin  output  and  the  sexual  cycle,  nor  w^as  creatin 
excretion  affected  by  protein  feeding.  In  normal  pregnancy  the  excretion 
of  creatin  is  usually  less  than  20  per  cent  of  the  creatinin  excretion  (Van 
Hoogenhuyze).  A  pregnant  woman  excretes  about  170  mgs.  of  creatin 
and  the  same  woman  during  the  lying-in  period  eliminates  about  470  mgs. 
(Van  Hoogenhuyze  and  ten  Doeschate).  After  cesarean  section  an  in- 
creased elimination  of  creatin  occurs  even  when  the  uterus  has  been  re- 
moved at  the  time  of  operation  (Mellanby  (h),  1913 ;  Morse).  F.  G.  Bene- 
dict (c),  and  F.  G.  Benedict  and  Diefendorf  first  noted  the  occurrence  of 
creatin  in  the  urine  of  starving  men  and  women.  Mendel  and  Rose  (a) 
(1911)  found  creatin  in  the  urine  of  adult  animals  when  they  were  de- 
prived of  carbohydrates  and  began  to  break  down  their  body  proteins. 
Certain  animals  having  small  reserves  of  glycogen  and  fat,  as  the  rabbit, 
will  excrete  creatin  after  a  short  fast,  while  others  with  large  stores  of  fat, 
as  the  pig,  can  be  fasted  for  from  14  to  16  days  without  excreting  creatin 
(McCollum  and  Steenbock).  In  this  respect  the  human  being  and  dog 
occupy  intermediate  positions.  Mendel  and  Rose  (a)  (1911)  found  that 
rabbits  began  to  excrete  creatin  on  the  second  day  of  starvation  and  that 
the  amount  excreted  gradually  rose  until  death.  Depriving  the  tissues  of 
carbohydrates  by  means  of  phlorhizin  poisoning  also  leads  to  creatinuria 
(Mendel  and  Rose  (a),  1911;  Cathcart  and  Taylor). 


CREATIX  xVXD  CliEATINIX  177 

From  the  foregoing  one  might  conclude  that  creatinuria  regularly 
accompanies  nmlernutrition,  whatever  the  cause.  This  is  actually  the  case. 
Diabetes,  carcinomatosis,  hyperthyroidism,  fevers,  incessant  vomiting  and 
other  wasting  conditions  are  usually  accompanied  by  the  appearance  of 
creatin  in  the  urine.  Feeding  thyroid  substance  increases  the  metabolic 
rate  and  leads  to  the  eliminarion  of  creatin  (Krause  and  Cramer).  Shaffer 
(a)  (11)08)  found  that  of  10  cases  of  hyperthyroidism  8  exhibited  creatin 
in  the  urine.  I  )enis  (/)  ( 1  '.♦IT )  has  shown  that  the  creatin  excretion  in  this 
condition  is  increased  by  feeding  a  high  protein  diet.  As  hydroxbutyric  and 
acetoacetic  acids  often  accompany  creatin  in  the  urine  it  has  been  supposed 
that  a  causal  relationship  exists  between  acidosis  and  creatin  excretion. 
Underbill  (k)  (191G)  noted  that  rabbits  began  to  excrete  creatin  when  they 
were  fed  on  acid  pi*oducing  diets  or  when  hydrochloric  acid  itself  was 
administered.  In  both  series  of  experiments  the  supply  of  carbohydrates 
was  sufficient  and  the  protein  per  se  was  without  influence.  Underhill  (I) 
(1916)  also  found  that  the  administration  of  alkalies  diminished  the 
creatin  output  during  the  early  days  of  starvation.  In  phlorhizin  glyco- 
suria, however,  alkali  administration  was  without  effect  (Underhill  and 
Baumann).  McCollum  and  Hoagland  (a)  (1013)  observ^ed  that  pigs  elim- 
inated creatin  when  fed  on  fats,  w^ater  and  neutral  salts,  but  failed  to  da 
so  when  the  salts  were  alkaline.  Considering  all  the  known  facts  per- 
taining to  this  phase  of  the  subject  it  appears  unwise  at  present  to  assume 
a  causal  relationship  between  acidosis  and  creatinuria. 


Creatinin  Metabolism 

Muscle. — Skeletal  muscle  contains  from  5  to  15  mgs.  of  creatinin  per 
100  grams  of  moist  tissue  Olyera  and  Fine  (t),  1915 ;  Folin  and  Denis  (g), 
1914),  that  is,  from  5  to  10  times  the  amount  which  is  present  in  the 
blood  which  circulates  through  it.  Shaffer  (h)  (1914)  holds  that  this  is  an 
argument  in  favor  of  the  view  that  creatinin  is  formed  in  muscle  tissue. 
The  rate  of  conversion  of  creatin  into  creatinin  in  autolyzing  muscle  is 
proportional  to  the  temperature  and  is  3  times  more  rapid  than  in  watery 
solution. 

Blood. — The  blood  of  normal  individuals  contains  from  1  to  2  mgs. 
of  creatinin  per  100  c.c.  (Folin  and  Denis  (^),  1914).  In  nephritis  rela- 
tively large  quantities,  as  much  as  33  mgs.  have  been  reported.  In  patho- 
logic conditions  of  the  kidney  uric  acid  and  urea  are  retained  before  crea- 
tinin and  elevations  of  the  last  above  5  mgs.  indicate  a  grave  prognosis 
except  in  acute  renal  inflammations  (flyers  and  Lough). 

Urine. — In  a  classical  article  published  in  1905,  Folin  showed  that  the 
excretion  of  creatinin  on  a  meat  free  diet  was  constant  for  each  individual 


178  LOUIS  BAU.MAX 

aiid  inrlepeiuleiit  of  the  exogenous  metabolism  ainl  the  total  nitrogen  ex- 
cretion. Shail'er  (a)  (1008)  confirmed  these  observations  and  found  that 
tlie  hourly:  excretion  of  creatinin  was  also  uniform.  This  constancy  of  cre- 
atinin  elimination  has  l)een  used  to  control  the  accuracy  of  the  21:-hour 
urine  collection.  The  daily  creatinin  excretion  for  an  adult  man  lies 
l>etween  1  and  2  grams.  From  the  viewpoint  of  (juantity  it  is  second  in 
importance  to  urea.  A  normal  man  excretes  between  7  and  11  nig-s.  of 
creatinin  nitrogen  per  kilo  of  body  weight ;  this  has  been  named  the 
creatinin  coefficient  by  Shaffer  (a)  (1908).  It  is  apparently  a  function  of 
the  mass  of  active  muscle  tissue  for  stout  and  elderly  j>eople,  and  women 
often  have  values  below  7.  The  coefficient  of  the  dog  averages  8.4.  ^Fyers 
and  Fine  (c)  (1913)  have  studied  the  relation  of  the  creatinin  coefficient  to 
the  total  creatin  content  of  the  body.  In  the  case  of  the  rabbit  this  is 
quite  constant,  averaging  44.7  mgs.  of  body  creatin  to  1  of  creatinin  in 
the  urine.  The  daily  output  of  creatinin  represents  a  conversion  of  about 
2  per  cent  of  the  total  creatin  present  in  the  lx>dy.  The  creatin  content 
of  the  rabbit  per  kilogram  is  about  one-third  higher  than  that  of  man,  and 
its  creatinin  coefficient  is  proportionately  higher,  that  is,  14. 

The  creatinin  excretion  of  wcmien  is  lower  than  that  of  men.  Tracy 
and  Clark  found  the  average  creatinin  coefficient  of  26  women  to  be  5.8. 
According  to  these  authors  the  low  coefficient  of  women  is  due  to 
their  relatively  inferior  muscular  development.  Hull  found  the  average 
creatinin  excretion  to  range  between  070  and  880  mgs.  Muscular  activity 
has  no  effect  on  creatinin  excretion  (Van  Iloogenhuyze  and  Verploegh  (&), 
1908;  Shaffer  (a),  1908). 

During  starvaticm  there  is  a  gradual  decrease  in  creatinin  in  the 
urine  along  with  an  increase  in  creatin  (Cathcart  (a),  1907;  How^e,  Mat- 
till  and  Hawk  (h)  ;  Hunter,  1914),  Pigs  that  were  fed  on  a  liberal  amount 
of  carbohydrate,  salts  and  water  reached  a  stage  when  the  creatinin  ac- 
counted for  18  per  cent  of  the  total  nitrogen  in  the  urine  (^rcCollum  and 
Hoagland  (a),  191J3).  Fevers  cause  an  increase  in  urinary  creatinin 
(Van  Iloogenhuyze  and  Verploegh  (6),  1908 ;  Klercker  (c),  1909 ;  Leathes 
(a)).  Myers  and  Volovic  observed  that  the  increase  was  proportional  to 
the  height  of  the  temperature. 

Creatin  is  often  present  in  the  urine  in  conditions  associated  with 
dissolution  of  nmscle  tissue,  and  then  the  creatinin  is  usually  found 
to  be  decreased  (Levene  and  Kristeller).  Spriggs  reported  a  very  low 
creatinin  excretion  in  2  cases  of  muscular  dystrophy  and  also  in  a  case 
of  amyotonia  congenita.  In  progressive  muscular  dystrophy,  McCrudden 
and  Sargent  obseiTcd  large  quantities  of  creatin  in  the  urine  with  a  con- 
stant creatinin  elimination. 

In  wasting  or  atrophy  of  muscle  the  creatin  eliminated  in  the  urine 
is  probably  derived  from  the  disintegrated  muscle  fibres. 


CKEATIN  AND  CEEATIXIX  170 


The  Fate  of  Administered  Creatin  or  Creatinin 

A  niniiLcr  of  investigators  liavo  attacked  this  problem.  The  experi- 
ments of  flyers  and  Fine  (e)  (11)13)  are  fairly  representative.  These  ob- 
servers found  that  when  creatin  was  injected  into  rabbits  a  small  portion 
was  deposited  in  the  nuiscles,  and  from  2.")  to  SO  [>er  cent,  depending  on 
the  amount  injected,  could  bo  recovered  from  the  urine.  When  creatinin 
was  administered  an  average  amount  representing  80  per  cent  of  that 
injected  was  found  in  the  urine  and  the  remainder  was  deposited  in  the 
muscles.  When  creatin  was  fed  to  man  a  .slight  increase  in  creatinin 
elimination  occurred  which  accounted  for.  from  3  to  4  per  cent  of  the  in- 
gested substance;  from  0  to  30  per  cent,  again  dojK^nding  upon  the  amount 
administered,  appeared  in  the  urine  unchanged  (Myers  and  Fine  (/i), 
1915).  Many  of  the  other  investigators  obtained  similar  results.  See 
Folin  (e)  (1906),  Klercker  (a)  (&)  (1906,  1907),  Wolf  and  Shaifer,  Van 
iroogenhuyze  and  Verploegh  {b)  (1908),  Pekelharing  and  Van  Hoogen- 
huyze  (6)  (1910),  Foster  and  Fisher,  Towles  and  Voegtlin,  Folin  and 
Denis  ((i)   (1912)  and  Krause. 

Summarizing,  it  may  be  said  that  when  creatinin  is  administered  it  is 
excreted  almost  quantitatively,  whereas  creatin  is  only  partly  excreted, 
the  major  portion  being  probably  destroyed  in  the  body.  Only  a  small 
percentage  of  the  administered  creatin  is  excreted  as  creatinin.  There 
is  no  evidence  that  creatin  is  converted  into  urea.  On  a  high  protein 
diet  a  smaller  amount  of  administered  creatin  is  retained  than  on  a  low 
diet.  According  to  Krause  (b)  (1913)  children  are  less  able  to  destroy 
creatin  than  adults. 

Gibson  and  ^lartin  observed  that  creatin  was  promptly  excreted  when 
administered  to  patients  suffering  from  progTcssive  muscular  atrophy. 


Resume 

The  creatin  content  of  muscle  is  fairly  constant  for  a  given  species  of 
animal  nnder  uniform  conditions  of  diet. 

Muscle  creatin  is  diminished  during  carbohydrate  privation.  This 
change  is  ascribed  to  the  loss  of  creatin  in  the  urine. 

The  normal  excretion  of  creatin  by  children  and  young  animals  in 
general  is  probably  due  to  their  relatively  high  planes  of  metabolism  and 
their  small  reserves  of  glycogen.  In  the  absence  of  carbohydrate,  fat, 
and  protein  to  a  lesser  extent  are  called  tipon  to  supply  the  body  require- 
ments; under  these  circumstances  muscle  tissue  is  disintegi-ated,  creatin 
is  libei'ated  and  excreted  in  the  urine. 

The  precursor  of  creatin  has  not  been  definitely  established.    Creatinin 


180  LOUIS  BAU^lAiS^ 

is  probably  derived  from  creatiii,  that  is,  a  definite  percentage  of  the 
body  creatin  is  daily  converted  into  creatinin.  The  crcatinin  excretion  is 
projK)rtional  to  the  bulk  of  active  muscle  tissue.  The  daily  amount  of 
crcatinin  excreted  by  a  given  individual  is  constant  under  widely  varying, 
conditions.  It  is  increased  during  fever  and  diminished  during  starvation 
and  during  periods  of  muscle  disintegration. 

Creatinin  is  eliminated  by  the  kidneys  with  great  facility  and  is  only 
retained  in  the  blood  in  advanced  disease  of  the  kidneys.  When  creatinin 
is  fed  or  injected  it  is  almost  quantitatively  eliminated,  whereas  creatin 
under  similar  circumstances  is  largely  destroyed  in  the  body. 


n 


Normal  Fat  Metabolism w.  R.  Bioor 

Introductory — The  Lijjoids — Simple  Lipoids — Compound.  Lipoids — Derived 
Lipoids — Simple  Lipoids — Compound  Lipoids — Derived  Lipoids — Fat 
Digestion  and  Absorption — The  Stomach — The  Intestines — Factors  in 
Fat  Digestion  and  Absorption — Summary — Fat  in  the  Blood — Alimen- 
tary Lipemia—Lipoids  of  the  Blood — Fat  in  the  Tissues — Storing  of  Fat 
— Changes  in  Fat  in  the  Tissues — The  Liver  in  Fat  Metabolism — Later 
Stages — /3-ox idation — Fat  Excretion. 


Normal  Fat  Metabolism 


BERKELEY 

Introductory 

In  the  course  of  the  great  developineut  whicli  has  taken  place  in  bio- 
chemistry during  tlie  last  few  years  our  knowledge  of  metabolism  has  been 
greatly  extended,  esix-cially  in  the  fields  of  the  pr(;teins  and  the  carbo- 
hydrates. Comparatively  little  has  been  added  to  that  of  the  fats,  for 
which  the  main  reason  is  the  ditKculty  of  chemical  examination  and  de- 
termination. The  fats  are  relatively  inert  substances  which  do  not  leml 
themselves  readily  to  reactions  wdiich  may  be  used  as  a  basis  for  their 
study,  and  as  a  result  there  is  not  the  same  backgi'ound  of  exact  chemical 
knowledge  as  in  the  case  of  the  proteins  and  carbohydrates.  Another  rea- 
son is  that  in  their  function  as  stored  material,  the  part  which  they  and 
their  derivatives  play  in  the  life  processes  of  the  cells  has  been  obscured, 
and  all  the  more  so  since  the  comparative  inertness  of  the  fats  would  seem 
to  render  them  unfit  to  take  part  in  the  delicately  balanced  reactions  of 
living  protoplasm.  Just  the  opposite  may,  however,  be  said  of  certain 
of  their  derivatives  such  as  the  phospholipoids,  members  of  which  group 
are  among  the  most  reactive  sul)stanees  found  in  living  beings.  In  fact, 
so  great  is  their  tendency  to  break  up,  to  oxidize,  to  c()nd)ine  with  a  great 
variety  of  substances  that  it  is  with  extreme  difficulty  that  they  can  be 
prepared  pure  enough  for  analysis.  In  recent  years  methods  have  l)een 
devised  for  the  study  not  only  of  the  fats  but  of  the  more  important 
related  substances  in  living  organisms,  and  the  result  has  been  an  aroused 
interest  in  the  whole  field.  With  the  accui.iulation  of  data  has  come  the 
realization  that  the  study  of  the  metabolism  of  the  fats,  meaning  essentially 
that  of  the  fatty  acids,  involves  many  if  not  all  of  the  compounds  of  the 
fatty  acids,  and  that  only  by  a  consideration  of  the  whole  gi-oup  of  com- 
pjunds  can  a  true  picture  of  the  metab(;lism  of  fat  l)e  obtained.  For  this 
reason  it  has  apjx^arcd  necessary  to  reclassify  the  fats  and  rclated  sulv 
stances  on  the  basis  of  their  relationship  to  the  fatty  acids  in  metalioiism, 
and  a  brief  outline  of  such  a  classification  with  a  short  description  of 
some  of  the  more  important  members  is  given  below.    For  a  more  detailed 

183 


184  W.  R.  Bl.OOR 

discussion  of  the  cla.ssiticatiou  and  of  the  ineinhors  the  reader  is  referred 
to  other  sources  (RJoor  {/),  1920;  Leathes  (c),  1010). 

The  Lipoids 

Xatiirally  occurriiiii  coiiip<>iiii(ls  of  the  fatty  acids,  too-ether  with 
certain  suhstances  found  naturally  in  chemical  association  with  them. 

The  i^roup  is  characterized  in  general  hy  insoluhility  in  water  and 
soluhility  in  **fat  solvents/'  chloroform,  henzol,  etc. 

Simple  Lipoids. — Esters  of  the  fatty  acids  with  various  alcohols. 

Fats. — Esters  of  the  fatty  acids  with  glycerol.  (Eats  which  are  liquid 
at  ordinary  teniijcratures  are  called  oils.) 

Waxes. — Esters  of  the  fatty  acids  with  alcohols  other  than  glycerol. 
Beeswax,  lanolin,  cholesterol  oleate. 

Compound  Lipoids. — Compounds  of  the  fatty  acids  with  alcohols  but 
containing  other  groups  in  addition  to  the  alcohol. 

FhosphoUpoids, — Substituted  fats  containing  phosphoric  acid  and 
nitrogen.     Lecithin,  eephalin,  etc. 

Glycolipouls. — Compounds  of  the  fatty  acids  with  a  carbohydrate  and 
nitrogen  but  containing  no  phosphoric  acid.     Cerebron. 

(Amino  lipoids,  Sidpho  lipoids,  etc. — Various  gi'oups  which  may  be 
added  as  soon  as  they  are  sufficiently  well  characterized.) 

Derived  Lipoids. — Substances,  derived  from  the  above  groups  by 
splitting,  which  have  the  general  properties  of  the  lipoids. 

Fatty  acids  of  various  series. 

Sterols. — Alcohols,  mostly  large  molecular  solids,  found  naturally  in 
cond)ination  wdth  the  fatty  acids  and  which  are  soluble  in  *^fat  solvents." 
Cetyl   ah3t>hol    (CieHg.OH;,   myricyl   alcohol    (CaoH^iOH),    cholesterol 

(c^^n^.oii). 

Simple  Lipoids.— T/^e  Fats. — Esters  of  the  triatomic  alcohol  glycerol. 
They  are  commonly  called  fats  when  they  are  solid  at  ordinary  temjxjra- 
tures  and  oils  when  liuuid.  Of  the  lipoids  these  are  the  most  widely 
distributed  in  nature,  the  most  imjwrtant  from  the  point  of  view  of  nu- 
trition and  the  best  understood  chemically.  As  ordinarily  occurring,  they 
are  triatomic  esters,  i.  e.,  all  three  of  the  hydroxyl  groups  of  the  alcohol 
are  replaced  by  fatty  acids.  Diatomic  and  monatomic  esters  are  occa- 
sionally found  but  usually  only  where  metabolic  processes  are  in  active 
progress  as  in  germinating  seeds  and  during  fat  digestion.  The  fatty 
acids  in  combination  \yith  a  single  glycerin  molecule  may  be  either  all  the 
same — producing  simple  glycerides — or  may  be  different,  producing  mixed 
glycerides.  As  the  knowletlge  of  the  chemistry  of  the  fats  increases  it 
becomes  evident  that  mixed  glycerides  are  of  much  more  frequent  oc- 
currence than  was  previously  sup^xjsed — a  fact  which  is  of  considerable 


NOR:\rAL  FAT  :\rETABOLTSM  185 

intoiT'st  from  a  l)iocliciiiical  pf;int  of  view  because  of  the  potential  optical 
aftivity  <.('  iiumy  of  tlie.-:('  mixed  enters,  since  optical  activity  is  recagiiized 
as  a  prnjrt'ity  closely  connected  with  life  processes.    Thus 

n  H 

IK-O-Ri  IIC-O-R^ 

j  I 

H(— O— Ti  IIC— ()— R..  ^^^  ^•-  ^*  ^>^'i"?:  different 

j  I                 "  far ry  acid  radicals) 

HC-O-R.  IIC-O-R, 

11  II 

should  from  the  structure  he  optically  active.  Up  to  the  present  time  no 
optically  active  fats  have  been  found  in  nature  or  been  prepared  syn- 
thetically, which  may  mean  merely  that  present  day  methods  of  prepara- 
tion and  .separation  of  isomers  are  not  adequate  for  the  purpose.  On  the 
other  hand  many  of  the  pho^pholipoids  are  optically  active  and  contain 
different  fatty  acids  in  combination,  and  since  there  is  good  reason  to 
believe  that  the  phospholipoids  are  staiies  in  the  metabolism  of  the  fats 
and  are  known  to  be  constituents  of  living  tissues,  the  inference  is  that 
while  the  fats  themselves  may  not  take  part  in  life  processes  they  are 
readily  changed  into  substances  Avhich  do. 

TVrt.res.-— Distinguished  from  the  fats  by  the  fact  that  the  alcohol  in 
combination  is  not  glycerol.  These  are  substances  widely  distributed  in 
nature  but  in  amounts  much  smaller  than  the  fats.  They  are  characterized 
in  general  by  great  chemical  inertness;  tbey  are  much  more  difficult  to 
oxidize  or  to  hydrolyze  either  by  enzymes  or  other  agents.  The  con- 
stituents of  the  waxes  have  been  completely  worked  out  in  but  few  cases, 
so  that  our  knowledge  of  the  chemistry  of  these  substances  is  very  frag- 
mentary. The  alcohols  found  in  combination  in  the  waxes  are  mostly  of 
large  m«:leeule  (see  under  Sterols),  and  the  fatty  acids  are  also  generally 
large  mohcular  and  either  saturated  or  containing  hydroxyl  groups.  Com- 
mon examples  of  the  waxes  are: 

Beeswax. — ^A  mixture  of  many  substances  of  which  the  best-known 
ones  are  esters  of  myricyl  (C;.oir,;,OII)  and  ceryl  (Csc.IIs.jOII)  alcohols 
with  palmiric  (C-^(.^l:.20._>)y  cerotic  (CVH^oOs)  and  melissic  (CaoH^joOg) 
acids  and  nmch  free  cerotic  acid. 

Cetin. — The  ester  of  cetyl  alcohol  (CioHna^H)  and  palmitic  acid. 

Wool  Wax  (Lanolin). — Contains  esters  of  cholesterol  derivatives  with 
various  fatty  acids. 

Cholesterol  esters  of  palmitic  and  oleic. acids  are  present  in  blood. 

Compound  Lipoids. — Phospholipoids. — -Compounds  of  the  fatty  acids 
and  alycciol  containing  phosphoric  acid  and  nitrogen.  They  are  widely 
distrihutod  in  nature,  being  constant  constituents  of  living  cells.     They 


180  W.  E.  BLOOR 

may  l)o  rogarckMl  as  pliospliorizcd  fats — ^glycerides  in  which  one  fatty  aci«l 
lias  hcon  replaced  hy  a  substituted  phosphoric  acid.  On  hydrolysis  they 
yield  fatty  acids,  g]ycerop!ios}>horic  acid  and  a  basic  substance,  which  in 
tho  case  of  lecithin  is  mainly  choiin  and  in  eephalin  probably  aminoethyl 
alcohol. 

In  Cuorln,  a  phospholipoid  from  heart  muscle,  the  proportion  of  phos- 
phoric acid  to  fatty  acid  is  i»reater  than  in  lecithin. 

Since  satisfactory  chemical  characterization  and  identification  of  most 
members  of  this  group  has  not  yet  been  made  reference  will  be  made  to 
only  a  very  few. 

In  general  they  are  very  active  chemically,  undergoing  rapid  changes 
in  air  and  light,  Ix'coming  colored  and  rancid.  They  are  not  soluble  in 
water  in  the  ordinary  sense,  but  mix  with  it,  forming  opalescent  colloidal 
suspensions.  They  are  readily  hydrolized  by  many  reagents  as  well  as  by 
the  lipases  and  esterases  and  even  by  boiling  with  alcohol  (Erlandsen). 
They  form  combinations  readily  with  many  substances,  as,  for  example, 
with  proteins  and  carbohydrates,  but  these  combinations  are  unstable 
and  of  inconstant  composition,  so  that  it  is  doubtful  whether  they  are  true 
chemical  compounds.  The  similarity  in  chemical  composition  indicates  a 
close  relationship  to  the  fats;  the  constant  occurrence  in  quantity  in  living 
active  cells,  the  ready  reactivity  to  oxidation,  hydrolysis  and  combination 
with  other  tissue  constituents  and,  al:)0ve  all,  the  miscibility  with  the  uni- 
versal solvent,  water,  indicate  that  the  phospholipoids  are  the  intennediato 
step  through  which  the  fats  pass  before  being  finally  utilized.  Tho  fatty 
acids  obtained  from  the  phospholipoids  were  thought  by  the  earlier  investi- 
gators (Hoppo  Seyler,  etc)  to  be  the  same  as  those  in  ordinary  animal 
fats,  i.  e.,  stearic,  palmitic  and  oleic,  but  recent  work,  particularly  that  of 
Leathes  (c),  1910,  Hartley  (a),  1907-08,  Erlandsen  and  MacLean  have 
shown  that  the  earlier  su])position  is  not  correct  and  that,  if  care  be  taken 
to  avoid  oxidation,  mainly  unsaturated  fatty  acids  are  obtained. 

The  Lecithins. — The  best  known  of  the  phospholipoids.  They  are  char- 
acterized by  their  insolubility  in  acetone — a  property  which  is  made  use 
of  in  their  separation.  They  are  readily  soluble  in  other  fat  solvents  and 
form  a  colloidal  solution  with  water.  Most  members  of  this  group  are  very 
sensitive  to  chemical  change,  so  that  it  is  almost  impossible  to  prepare 
them  in  pure  form.  In  addition  to  their  chemical  sensitiveness  they  pos- 
sess, in  a  higher  degree  than  most  other  organic  compounds,  the  power  of 
uniting  with  other  substances  such  as  salts  (NaCl),  compounds  of  the 
heavy  metals  as  Pt  and  Cd,  and  with  many  organic  substances  such  as 
alkaloids,  toxins  (snake  venoms),  carbohydrates  and  proteins.  These 
cond)i nations  are  not  of  constant  composition  and  are  broken  up  by  rel- 
atively gentle  treatment,  e.  g.,  boiling  with  neutral  solvents,  and  it  is 
therefore  a  question  whether  they  are  true  chemical  compounds  or  merely 
physical  (adsorption)  mixtures.     This  power  of  combination  is  of  great 


XOILMAL  FAT  ^LETABOLIS^E  187 

significance  in  the  consideration  of  these  lipoids  as  constituents  of  living 
matter. 

Tiie   cljeniii.-al    formula    of   a    typical    lecithin    which    embodies    o\ir 
knowledge  of  its  composition  at  the  present  time  is: 

CITo— O— Rj  As   indicated   by  the   fornnila 

I  the  fatty  acid  groups  (Ri  and  R^) 

I  arc  generally  different  and  tliecom- 

I  pounds  are  optically  active.     The 

CII — 0 — Rg  fatty  acids  are  often  unsaturated, 

particularly  in  the  lecithins  from 

O  the  active  organs  as  heart,  liver, 

//  etc. 
CH.-0-P-OII 

I 
O 

I  . 

I 

I 
o 

I 

•  H 

Cephallns. — These  differ  from  lecithins  in  being  difficultly  soluble  in 
alcohol  and  in  containing  a  different  basic  gi'oup,  the  exact  nature  of 
which  is  unknown,  but  which  is  believetl  to  be  amino-ethyl  alcohol.  They 
are  widely  distributed  in  the  body  and,  according  to  Thudicum,  are  the 
main  phospholipoids  of  the  brain.  They  have  recently  received  a  good 
deal  of  attention  because  of  their  connection  with  blood  coagulation 
(Howell).  MacLean  has  sho^^^l  that  they  are  formed  rather  easily  from 
lecithin  and  that  one  of  the  difficulties  in  preparing  pure  lecithin  is  its 
tendency  to  lose  its  methyl  groups  and  pass  over  into  cephalin. 

Glycolipoids. — These  substances,  characterized  by  their  content  of  car- 
bohydrate, are  less  understood  than  the  phospholipoids.  The  only  one 
which  has  been  well  studied  is  the  cerebrone  of  Thierfelder,  a  constituent 
of  brain  tissue.  The  carliohydrate  is  galactose,  the  fatty  acid  a  higher 
isomer  of  stearic  acid,  and  there  is  also  a  basic  substance^  known  as 
sphingosine. 

Derived  Lipoids. — Fatti/  Acids, — The  fatty  acids  found  combined  in 
tlio  fats  include  practically  all  the  known  fatty  acids  of  the  various  series 
which  contain  even  uuiiil)ers  of  carbon  atoms  arranged  in  straicrht  chains. 
Fatty  acids  of  odd  numbers  r;f  carbon  atoms  are  so  rare  that  their  natural 
origin  is  questionable,  while  branched  chains  are  unkno^^^l.     A  few  acids 


188  W.  K.  BLOOIi 

of  the  benzene  series  should  perhaj^s  he  included  sine©  they  arc  found  in 
certain  natural  oils  (cludmougi-a  oil,  etc.).  The  fatty  acids  most  fre^ 
quently  found  in  animals  are  palmitic,  oleic  and  stearic  acids.  In  active 
tissues  fatty  acids  of  tlie  linoleic  and  possibly  of  still  more  unsaturated 
series  are  to  be  found,  while  in  the  brain  hydroxy  acids  are  present,  to- 
gether with  a  gTcat  variety  of  unsaturated  fatty  acids. 

In  milk  are  to  be  found  all  known  even  nundjered  members  of  the 
.acetic  acid  series,  beginning  with  butyric  and  ending  with  aracliidic. 

Sterols. — -This  group  inchules  the  alcohols  fcnmd  naturally  in  com- 
bination with  the  fatty  acids  in  the  waxes.  They  are  generally  inert 
substances  of  large  molecule,  mainly  of  the  straight  chain  monatomic  group 
of  alcohols.  The  notable  exceptions  to  this  rule  are  cholesterol  and  related 
substances, — secondary  alcohols  belonging  to  the  terpene  series;  most 
sterols  occur  in  the  free  as  well  as  in  the  combined  form.  The  more  im- 
|X)rtant  members  of  this  group  are  cetyl  (C\oH:{40)  and  octodecyl 
(CigH^gO)  alcohols  in  spermaceti,  ceryl  alcohol  (CgoHg^O)  in  Chinese 
wax,  myricyl  alcohol  (CaoHooO)  in  beeswax,  cocceryl  {C^ifyTTf-^Oo)  iii 
cochineal  wax  and  the  cholesterol  gi'oup  containing  cholesterol  (C27H44O) 
in  most  animal  tissues  and  fluids,  the  isomeric  phytosterol  similarly  dis- 
tributed in  plants,  isocholesterol  (CorJIic^)  and  a  number  of  others  more 
or  less  well  characterized.  Of  these,  the  only  one  which  calls  for  extended 
discussion  is  cholesterol.  According  to  our  present  information  it  is  a 
monatomic  secondary  alcohol  with  a  terminal  vinyl  gTOup.  The  nucleus 
pi'obably  contains  four  to  six  carbon  rings  and  belongs  in  the  general 
gi'oup  of  terpenes.    The  details  of  structure  are  illustrated  in  the  foi-mula: 

CII3 
\ 
CH .  Clio .  CI  I. .  —  C,  ,Ho.CH  :  CII.^ 

CH3  HoC  CIIo 

CH(OH) 

In  the  free  form  or  as  esters  with  the  fatty  acids  it  is  widely  distributed 
in  animal  tissues  and  fluids  and  either  as  such  or  as  various  derivatives 
(the  bile  acids  have  been  so  regarded)  it  is  probably  of  great  importance 
in  animal  metabolism. 

Of  the  fatty  acids  those  most  frecpiently  found  in  combination  with 
cholesterol  are  oleic  and  palmitic  acids. 

Cholesterol  is  a  colorless,  odorless  substance  crystallizing  in  thin 
plates,  insoluble  in  water,  soluble  in  fats  and  fat  solvents,  melting  at 
148.5^  C,  and  is  optically  active.  Specific  rotation  [a]  ^  =^  —  20.92. 
The  corresponding  alcohol  in  plants  is  phytosterol  which,  accoi'ding  to 
Gardner,  changes  to  cholesterol  during  intestinal  absorption  in  animals. 


XOmiAL  FAT  :META HOLISM  180 

Closely  *'elated  substances  found  in  animals  and  probably  derived  from 
eliolestcrul  are  copro;«terol  in  feces  and  isocliolesteroi  in  skin  and  hair 
waxes. 

Fat  Dij^estion  and  Absorption 

The  Stomach. — Digestion, — Fat  splitting  enzymes  (lipases)  may  ap- 
pear in  the  stomach  from  either  of  two  sources — as  part  of  the  gastric 
secretion  or  by  regurgitation  from  the  intestine.  The  presence  in  the 
stomach  of  secretions  from  the  small  intestine,  especially  bile,  has  been 
known  clinically  for  many  years,  and  while  the  tendency  has  l)een  to 
minimize  the  influence  of  these  secretions  on  fat  digestion  it  is  realized 
that  under  suitable  conditions  splitting  of  fats  in  the  stomach  may  assumo 
considerable  proportions.  Cannon  has  shown  that  fats  slow  the  emptying 
of  the  stomach  by  inhibiting  the  production  of  acid,  also  that  the  pylorus 
is  kept  closed  by  the  presence  of  acid  on  the  intestinal  side  of  the  sphincter. 
In  the  absence  of  acidity  the  pylonis  may  relax  or  open  and  allow  regurgi- 
tation of  intestinal  contents  including  lipases  by  reverse  peristalsis,  and 
under  the  conditions  of  low  gastric  acidity  considerable  lipolysis  would 
take  place.  Boldyreff  found  that  after  a  meal  rich  in  fat  there  is  a  reflux 
of  pancreatic  secretion  into  the  stomach. 

Quite  aside  from  the  regurgitated  intestinal  material  the  stomach  has  a 
lipase  of  its  own,  a  fact  which  was  claimed  many  years  ago  by  Ogata  and 
other  observers.  Their  work  received  little  attention  until  it  was  confirmed 
by  Volhard  and  his  pupils.  Volhard^s  work  stimulated  investigation  and 
discussion  and  the  existence  of  a  gastric  lipase  has  been  a  much  debated 
topic  since  that  time.  One  difliculty  has  been  to  rule  out  the  possibility  of 
intestinal  lipase,  and  when  this  has  been  successfully  accomplished  the  low 
values  obtained  for  lipolysis  by  pure  gastric  juice  have  thrown  doubt  on 
its  existence  in  amounts  w^orthy  of  consideration.  Volhard  foimd  un- 
doubted dig-estion  of  the  emulsified  fat  of  milk  and  egg-yolk  both  by  gastric 
juice  obtained  by  siphon  and  by  glycerin  extract  of  the  mucous  membrane 
of  the  fundus,  and  his  findings  have  been  confirmed  by  several  workers 
since  (Davidsohn,  1012),  while  London  and  others  were  unable  to  dem- 
onstrate lipase  in  gastric  juice  from  a  Pawlow  stomach.  Davidsohn  has 
compared  the  properties  of  gastric  and  of  pancreatic  lipase  and  found 

diflerences  in  their  optimum  reaction.    For  pancreatic  lipase  the  optimum 

+ 
reaction  w^as  H  =  1  X  10"^,  while  for  stomach  lipase  it  was  2  X  10~® — 
also  that  pancreatic  lipase  was  much  more  sensitive  to  sodium  fluoride. 

The  probable  reason  for  the  conflicting  results  regarding  gastric  lipase 
has  recently  been  found  by  Hidl  and  Keeton,  who  studied  the  lipase  in 
gastric  juice  obtained  from  Pawlow  stomachs  and  in  noi-mal  stomachs, 
of  which  the  pylorus  had  been  ligated  and  the  flow  of  secretion  stinmlated 
by  gastrin  and  by  food.     They  found  that  the  gastric  lipase  was  sensitive 


190  W.  Tl.  BLOOK 

to  acid,  Leiiig  destroyed  by  a  fifteen  mimites'  exposure  to  0.2  per  cent 
hydrochloric  acid,  and  tliat  if  the  acidity  was  reduced  cither  by  ordinary 
neutralization  with  alkali  or  by  protein  a  fairly  good  lipase  action  could 
be  denionstratctl  (about  five  times  as  great  as  that  of  the  succus  entericus). 
The  practical  bearing  of  their  work  was  to  indicate  that  after  a  meal  anrl 
before  the  stomach  acidity  had  reached  a  value  high  encjugh  to  destroy 
the  lipase  (being  kept  down  by  the  proteins  of  the  food)  considerable 
fat  splitting  might  take  place,  at  least  of  emulsihed  fats. 

The  sum  of  the  work  to  date  leaves  little  doubt  that  a  lipase  is  secreted 
by  the  stomach.  Whether  there  is  much  fat  splitting  will  depend  on  a 
immber  of  factors  among  which  are  the  following:  (a)  The  acidity  of  the 
stomach  contents — high  acidity  destroying  and  lower  acidity  down  to  a 
certain  point  inhibiting  the  activity  of  the  gastric  lipase.  The  degree  of 
acidity  is  dependent  on  the  amount  of  aci(l  secreted  and  on  the  amount 
of  neutralizing  substance  (mainly  protein)  present.  The  presence  of  fat 
inhibits  acid  secretion,  (b)  The  state  of  division  of  the  fat.  Since  the 
lipase  and  the  fat  have  no  mutual  solvent,  the  splitting  can  take  place 
only  at  the  surface  of  the  fat  particles,  and  unless  these  are  very  small  and 
the  surface  correspondingly  great  (as  in  an  emulsion)  not  much  splitting- 
is  likely.  The  acidity  of  the  stomach  is  probably  rarely  weak  enough 
to  permit  the  formation  of  soap  emulsions  so  that  the  lipcdytic  activity  of 
the  gastric  juice  would  be  confined  to  natural  emulsions  as  milk,  etc.  The 
splitting  of  the  fat  in  these  emulsions  may  be  very  considerable  (Volhard). 
(c)  The  length  of  time  the  fat  remains  in  the  stomach.  The  presence 
of  much  fat  slows  the  passage  of  food  from  the  stomach  (Cannon),  giving 
more  time  for  the  gastric  lipase  (and  also  the  regurgitated  pancreatic 
lipase)  to  act. 

Absorption, — Klem]>erer  and  Scheuerlen,  by  ligating  the  intestine  of 
dogs  below  the  pylorus  and  weighing  fat  before  and  after  3  to  G  hours  in 
the  stomach,  found  that  none  had  been  absorbed.  The  objection  might 
be  raised  in  this  case,  as  in  many  similar  ones,  that  the  operative  pro- 
cedures were  responsible  for  the  failure.  Histological  observations  from 
von  Kolliker  onwards  have  demonstrated  fat  droplets  in  the  gastric  epi- 
thelium although  none  were  seen  in  the  lymphatics.  Weiss  believed  that 
absorption  iiito  the  epithelia  was  confined  to  young  animals,  in  which 
belief  he  is  opposed  by  Greene  and  Skacr,  who  found  absorption  (into 
the  epithelium)  in  both  young  and  old  animals  and  also  that  the  amount 
of  absorbed  material  (observed  by  staining)  and  the  depth  of  penetration 
depended  on  the  length  of  stay  of  the  fat  in  the  stomach.  The  histological 
picture  was  found  by  these  observers  to  resemble  strongly  the  appearance 
of  the  intestinal  mucosa  during  fat  absorption.  After  the  fat  left  the 
stomach  the  cycle  reversed  and  the  fat  disappeared  (back  into  the 
stomach?). 

Jklendel  and  Baumann  studied  the  absorption  of  fat  by  the  stomach 


KOTLMAL  FAT  METABOLISM  191 

liistolof^ically  and  clicniically,  and  confinncd  in  general  the  work  of  Greene 
and  Skaer,  althongh  in  some  animals  they  found  no  penetration.  They 
found  no  change  in  the  fat  content  of  the  blood  a5  a  result  of  the  presence 
of  fat  in  the  stomach,  but  they  point  out  that  the  absorption  would  bo 
necej^sarily  slow  and  that  the  fat  may  have  been  removed  from  the  blood 
as  fast  as  absorbed.  That  absorption  of  other  substances  went  on  normally 
in  those  same  animals  was  shown  by  tests  with  iodids.  On  feeding  fat 
stained  with  Sudan  III  no  color  could  be  observed  in  the  lymph  or  in 
the  blood. 

The  Intestines. — Passage  from  the  Stomach, — When  the  amount 
of  fat  in  the  food  is  small  it  probably  does  not  affect  appreciably  the  rate 
)f  emptying  of  tlio  stomach,  which  proceeds  nonnally  as  described  by 
Cannon — the  pylonis  opening  under  the  stimidus  of  a  sufficient  acidity 
of  the  food  on  the  gastric  side  and  closing  when  the  acid  food 
reaches  the  intestinal  side  of  the  opening  valve.  When  the  amount  of  fat 
ill  the  food  is  large  the  gastric  secretion  is  inhibited,  the  amount  of  acid 
produced  is  lessened,  and  it  therefore  takes  longer  for  the  food  to  reach  the 
degree  of  acidity  necessary  to  bring  about  the  opening  of  the  pylonis. 
The  rate  of  emptying  of  the  stomach  is  thus  slowed  and  the  rate  at  which 
the  fat  reaches  the  intestine  is  lowered.  When,  however,  the  fat  is  taken 
in  liquid  form  (as  oil)  or  suspended  in  a  liquid,  as  in  milk,  it  may  pass 
immediately  through  the  stomach  like  other  liquids. 

Thus  in  all  cases  except  where  the  fat  is  taken  in  quantity  in  the  form 
of  oil  (an  unusual  condition)  it  is  passed  into  the  intestine  in  small  por- 
tions. When  it  reaches  the  intestine  in  large  quantities  diarrhea  may  bo 
produced  either  through  action  of  the  fat  itself  or  more  probably  as  the 
result  of  irritation  produced  by  the  abnormally  large  amounts  of  soaps 
formed.  One  result  of  the  normal  functioning  of  the  gastric  mechanism 
is  therefore  the  delivery  of  the  fats  to  the  intestine  in  small  amounts,  which 
has  a  direct  bearing  on  the  question  as  to  the  form  in  wdiich  it  is  absorbed 
from  the  intestine,  since  under  these  circumstances  the  chances  are  that 
the  fat  Avill  be  completely  hydrolyzed  in  the  presence  of  the  relatively 
large  amounts  of  pancreatic  and  intestinal  lipases  which  it  encounters. 
When  the  amount  of  fat  in  the  food  is  so  large  that  there  is  gTeat  in- 
hibition of  gastric  secretion  the  pylorus  appears  to  lose  its  tone  after  somo 
hours  and  allows  the  passage  of  intestinal  contents — bile  and  pancreatic 
secretion  with  its  lipase — to  pass  into  the  stomach,  where  considerable 
hydrolysis  of  the  fats  may  take  place.  Boldireif  has  shown  that  this  re- 
gurgitation may  be  made  to  take  place  readily  in  humans  by  feeding 
fat  containing  fatty  acid. 

Natural  food  fat  always  contains  some  free  fatty  acid  and  the  amount 
is  increased  during  the  processes  of  cooking  and  by  whatever  lipolytic 
action  occurs  in  the  stomach,  so  that  by  the  time  the  fat  reaches  the 
intestine  there  is  probably  always  a  considerable  quantity  of  free  fatty 


102  W.  R.  BLOOK 

acid  present  which,  uniting  with  tlie  alkali  of  the  intestinal  secretions,  pro- 
duces soap  eiiong-h  to  eniiilsify  the  whole  amount  and  thus  prepare  it  for 
the  action  of  tlic  intestinal  lipases. 

The  Lipases  of  the  Intestinal  Tract  and  Digestion. — Lipases  are  se- 
creted into  the  intestine  mainly  hy  tlie  pancreas,  alth«»ii-h  noklirefF  has 
found  that  the  intestinal  secretions  contain  a  lipase  actiiiii"  un  enmlsified  fat 
which  is  (liferent  from  pancreatic  lipase  in  that  its  action  is  not  accelerated 
hy  hile.  J>oIdireff  tested  lipolytic  action  with  monohutyrin,  milk  and 
olive  oil  (Jansen  ohjects  to  the  use  of  monohutyrin  because  it  is  split 
hy  water  alone  and  because  in  all  probability  a  different  ferment,  mono- 
butyrinase  fan  esterase]  is  involved).  The  lipolytic  activity  of  intestinal 
juice  is  ordinarily  slight,  and  in  the  presence  of  normal  pancreatic  secre- 
tion is  pnjbably  not  an  important  factor  in  fat  digestion.  Bile  increases 
its  activity.  The  flow  of  secretion  in  fasting  is  small  and  is  increased  by 
the  presence  of  food,  secretin,  acids  and  soaps.  In  general,  the  amount 
of  secretion  is  less  the  farther  away  from  the  duodenum  it  is  collected. 

The  excitants  for  the  secretion  of  pancreatic  juice  are  normally  acids 

+ 

(H),  fats  and  water;  alkalies  have  a  retarding  action.  Acids  act  prob- 
ably by  the  formation  of  secretin,  rather  than  by  reflex  action  on  the 
intestine,  as  Pawlow  believed,  although  stinmlation  of  the  nerve  supply 
will  cause  secretion.  Fats  are  found  to  act  as  excitants  only  when  partially 
saponified,  and  soap  is  prol)ably  therefore  the  active  substance — which  is 
rendered  tlie  more  likely  since  soap  has  been  found  by  Pleig  to  produce  a 
secretion.  By  tlie  time  it  reaches  the  intestine  food  fat  normally  contains 
enough  free  fatty  acid  to  form  a  considerable  amount  of  soap  with  the 
alkali  of  the  intestinal  secretions.  Water  acts  mainly  indirectly  by  stim- 
ulating acid  gastric  secretion.  The  nervous  system  undoubtedly  also 
plays  an  important  part  in  pancreatic  secretion  not  only  as  a  regulator 
but  also  in  the  production  of  the  secretion  (Bylina,  1911). 

The  amount  of  pancreatic  juice  secreted  in  a  24r-hour  period  has  been 
found  to  vary  gToatly,  the  average  from  normal  dog>  (Pawlow  and  co- 
workers) obtained  by  pancreatic  fistula  being  about  22  c.c.  per  kilo  per 
24  hours.  For  human  beings  the  amount  is  reported  to  be  about  600  c.c. 
per  day. 

The  pancreatic  lipase  (steapsin)  hydrolyzes  the  fats  to  fatty  acids  and 
glycerol,  an  action  which  is  reversible,  as  was  first  reported  by  Pottevin, 
later  confirmed  by  Taylor  and  Ilamsik  (a)  (1009),  and  finally  more  con- 
clusively by  Foa  (a),  who  determined  the  exact  conditions  by  which  an  ex- 
cellent synthesis  may  be  accomplished.  By  using  oleic  acid  homogenized 
with  glyceiij]  and  mixed  wifh  glycerol  extract  of  pancrea?  (therefore  with 
excess  of  glycerol)  he  was  able  to  get  a  synthesis  of  about  02  per  cent  of  the 
oleic  acid  used  in  50  hours  at  38"  C.  The  compound  formed  was  mainly 
the    triglycerid.      Armstrong    and    Gosney    have    made    an    exact    study 


N0R:\[AL  fat  METABOLISl^f  19S 

of  the  reaction,  using  castor  bean  lipase.  They  found  that,  proceeding  in 
either  direction  witli  the  glycerid  or  with  glycerol  and  oleic  acid  in  the 
proix>rtious  found  in  the  natural  glycerid  the  eipiilihriuni  j>oint  was 
reached  when  about  40  per  cent  of  the  acid  was  cond)inrd.  IJuring  the 
synthesis  the  compounds  formed  were  apparently  mainly  diglycerids. 
During  the  h\drolysis  with  excess  of  water  and  near  the  l)eginning  a 
small  amount  of  a  lower  glycerid  was  present,  but  as  the  action  continuetl 
the  molecule  was  completely  hydrolyzed.  When  only  a  small  proix>rtion 
of  water  was  present  a  greater  projxjrtion  of  mono-  and  diglycerids  was 
produced.  Conversely  when  the  synthesis  is  effected  in  the  presence  of 
water  more  of  the  triglyccrid  is  formed.  Synthesis  in  the  presence  of 
extra  glycerol  results  as  would  be  expected  in  a  proportionately  greater 
combination  of  fatty  acids  with  the  formation  cf  more  of  the  lower  types 
of  glycerid  although  the  diglycerid  is  probaldy  still  the  main  pro<luct. 

The  pancreatic  lipase,  although  secreted  with  the  pancreatic  juice  in 
water-soluble  form,  is  with  difficulty  extracted  from  the  gland  by  water. 
Glycerol  is  generally  used  for  the  purpose  and  the  result  is  a  suspension 
which  may  become  inactive  on  filtration,  indicating  that  the  lipase  is 
probably  not  in  true  solution. 

Pancreatic  lipase  is  secreted  mainly  in  the  active  fonii,  and  its  activity 
is  increased  by  the  presence  of  bile  (bile  salts)  and  by  many  other  sub- 
stances as,  for  example,  blood  sennn,  soaps,  saponins,  alcohol,  etc. 
Its  action  is  inhibited  by  cholesterol.  Kosenheim  has  succeeded  in  sepa- 
rating from  the  lipase  of  pancreatic  extracts  (glycerol)  a  co-enzyme  with- 
out which  the  enz;^Tne  is  inactive.  As  is  generally  the  case  with  co-enz^Tnes 
this  one  is  heat-stable.  Since  the  inactive  enzyme  is  activated  by  blood 
serum  the  assumption  is  made  that  the  activating  substance  is  a  hormone 
produced  by  the  pancreas  and  secreted  into  the  blood. 

formally  the  provisions  for  the  digestion  of  the  fats  in  the  intestine 
are  such  as  to  insure  practically  complete  splitting.  Fat  is  delivered 
to  the  intestine  in  small  amounts — wdien  there  is  little  fat  in  the  food  this 
follows  as  a  matter  of  course;  when  fat  is  present  in  large  proportion 
emptying  of  the  stomach  is  slowed,  whereby  the  same  result  is  effected. 
Lipase  is  abundant,  being  found  both  in  the  gastric  secretion  and  in  tlic 
pancreatic  and  intestinal  secretions.  The  amount  in  the  pancreatic 
secretion  alone  is  sufficient  to  digest  quickly  several  times  the  amount 
of  fat  supplied  in  the  ordinary  diet.  The  gastric  lipase,  under 
favorable  conditions,  can  digest  considei»able  quantities,  and  even  the 
intestinal  lipase  can  probably  affect  splitting  of  the  daily  quota  of  fat, 
since  in  cases  where  the  pancreatic  secretion  is  lacking  very  little  imsplit 
fat  is  found  in  the  feces.  Emidsification  by  soap  is  an  important  factor  in 
the  hydrolysis,  and  there  is  normally  abundant  provision  for  the  forma- 
tion of  soap.  There  is  always  some  free  fatty  acid  in  natural  fats,  and 
the  amount  is  increased  by  cooking  and  by  the  action  of  the  gastric  lipase, 


194  W.  E.  BLOOPt 

so  that  bj  the  time  the  fat  reaches  the  intestine  a  considerable  amount  of 
free  fatty  acid  is  present.  The  free  fatty  acid  is  neutralized  by  tlie  alkali 
carbonates  of  the  various  secretions  that  find  their  way  into  the  intestine, 
forming  soaps  which  quickly  and  completely  emulsify  the  remaining 
fat,  thus  preparing  it  for  rapid  digestion  by  the  lipases.  Addcnl  to  the 
other  factors  is  the  contiimous  absorption  which  removes  tlie  products  of 
hydrolysis  from  the  field  of  acticm,  thereby  in  a  balanced  reaction  like 
the  hydrolysis  of  a  fat,  providing  the  best  conditions  for  rapid  and  com- 
plete action.  Under  these  conditions  it  is  probahle  that  the  amount  of 
fat  which  escapes  digestion  is  negligibly  small. 

The  Absorption  of  Fat  from  the  Intestine, — The  manner  in  which 
the  fat  leaves  the  intestine  has  received  its  share  of  experimentation  and 
speculation.  The  earlier  belief  was  that  the  fat  was  absorbed  as  such  in 
enmlsified  form,  based  largely  on  the  observation  that  enmlsions  are  often 
found  in  the  intestine  during  fat  absorption  and  that  the  fat  in  the  chyle 
is  also  in  the  emulsified  form.  While  it  was  known  that  the  chyle  fat 
was  in  general  much  more  finely  divided  than  the  intestinal  fat,  that 
objection  might  be  explained  away  by  the  assumption  that  the  particles 
were  absorbed  only  as  they  reached  a  fine  state  of  division.  Further  evi- 
dence believed  to  point  in  the  same  direction  is  that  large  amounts  of 
characteristic  food  fat  may  be  laid  down  in  the  fat  depots  of  animals  wdtb 
slight  change.  Another  argument,  later  shown  to  be  faulty,  was  that  if" a 
stained  fat  were  fed  similarly  stained  fat  appeared  in  the  chyle.  An 
additional  bit  of  evidence  in  favor  of  absorption  of  unchanged  fat  was 
the  observation  of  Ravenel  that  bacteria  may  be  carried  through  the 
intestinal  wall  if  fat  is  fed  along  with  them  when  they  do  not  pass  through 
otherwise.  The  fact  that  other  foodstuffs  such  as  the  carbohydrates  and 
proteins  were  knovai  to  be  absorbed  in  water  soluble  form  and  that  much 
free  fatty  acid  and  soap  were  to  be  found  in  the  intestine  during  fat  diges- 
tion led  Kiihne  to  put  forward  the  hypothesis  that  fats  also  were  absorbed 
in  w-atcr  soluble  form,  being  first  split  in  the  intestine  and  then  re- 
sjTithesized  in  passing  through  the  intestinal  w^all.  This  hypothesis 
brought  forth  a  large  amount  of  experimental  w^ork  which  finally  resulted 
in  practical  adoption  as  the  most  satisfactory  explanation  of  the  method 
of  tratisference  of  fat  from  the  intestine  to  the  blood. 

The  earliest  conclusive  work  on  the  subject  was  that  presented  by 
Mimk  (a)  (1891),  who,  making  use  of  a  human  patient  with  a  chyle  fis- 
tula, was  able  to  show  that  fatty  acids  and  esters  of  the  fatty  acids  with 
alcohols  other  than  glycerol  wxa-e  absorl^d,  appearing  in  the  chyle  not  as 
these  substances  but  as  iieutral  triglycerids.  He  was  followed  by  v.  Wal- 
ther,  who  confirmed  his  results  with  fatty  acids  or  soaps,  and  more  recently 
by  Frank  (c)  (1S9S),  with  ethyl  esters  of  the  fatty  acids  and  Bloor  (a) 
(1913)  with  an  optically  active  mannite  ester  of  a  fatty  acid.  In  all  these 
cases  the  evidence  indicated  that  no  trace  of  the  substance  fed  appeared  in 


KOKMAL  FAT  ^METABOLISM  195 

the  cliyle  but  alwav.s  Mie  glycerol  triosters  of  the  fatty  acids  involved.  The 
presence  of  the  glycerids  in  tlie  chyle  presupposed  a  splitting  of  the  esters 
fed  and  a  synthesis  of  the  fatty  acids  with  glycerol  which  if  not  supplied 
with  the  fatty  acids  by  the  experimenter  must  have  been  furnished  by  the 
organism.  Further  details  on  this  interesting  point  have  been  furnished  in. 
recent  work  by  Bang  (a)  (1918),  who  found  that  fatty  acids  alone  pro- 
duced but  little  lipeniia  while  when  these  are  fed  with  glycerol  there  is 
marked  lipemia,  indicating  that  the  ability  of  the  organism  to  supply  gly- 
cerol is  limited.  One  experiment  which  he  reported  in  which  lie  fed  50 
grams  of  fatty  acid  to  a  dog  and  recovered  only  2  grams  in  the  chyle  would 
indicate  that  absorption  in  this  case  was  dircn^tly  into  the  blood. 

Direct  evidence  against  the  absorption  of  fat  in  emulsified  form  has 
also  been  forthcoming.  Connstein,  experimenting  with  lanolin,  a  wax 
which  emulsifies  well  with  water  and  has  a  melting  point  (40^-42'^  C.) 
only  slightly  above  body  temperature,  showed  that  when  this  substance 
was  fed  about  08  per  cent  of  it  could  be  recovered  in  the  feces,  showing 
that  neither  emulsifying  power  nor  melting  point  was  the  criterion  for 
absorption.  The  same  fact  was  more  strikingly  shown  by  Henriques  and 
Hansen,  who  dissolved  vaselin  in  lard  and  fed  the  well  emulsified 
mixture  to  rats  and  were  able  to  recover  practically  all  (98  per  cent)  of 
the  vaselin  fed  while  the  lard  was  completely  absorbed.  The  com- 
panion test  to  this  one — the  attempt  to  recover  the  substance  from  the 
chyle — was  carried  out  by  Bloor  (a)  (1913)  with  negative  results.  In  this 
experiment  a  liquid  paraffin  was  dissolved  in  olive  oil,  the  wdiole  well  emul- 
sified and  fed  to  dogs.  A  suitable  time  after  the  feeding  chyle  was  collected 
from  the  thoracic  duct,  the  contained  fat  extracted  and  examined  for  the 
paraffin  oil.  None  was  found.  Thus  though  all  conditions  were  favorable 
for  the  absorption  of  unchanged  emulsion  which  would  have  included  the 
mineral  oil,  no  trace  of  it  could  be  demonstrated  while  the  food  fat  was 
completely  absorbed.  Summing  up  all  the  evidetice  then,  the  hypothesis 
of  Kiihne  appears  to  be  very  well  supported.  Facilities  are  provide^l 
for  complete  splitting  of  the  fats  in  the  intestine,  fatty  acids  and  soaps 
are  absorbed  and  appear  in  the  chyle  as  triglycerids,  esters  of  the  fatty 
acids  which  are  hydrolyzable  by  the  intestinal  lipases  are  absorbed  but 
always  as  triglycerids,  while  non-hydrolyzable  esters  of  the  fatty  acids 
and  other  fat-like  substances  which  cannot  be  made  water  soluble  are 
rejected.  Altogether  it  seems  likely  that  fats  are  no  exception  to  the  rule 
that  substances  pass  from  the  intestine  only  in  water  solution,  and  since 
solubility  in  water  appears  to  be  a  necessary  prereqTiisite  for  use  in  living 
cells  the  intestine  acts  as  a  barrier  against  the  admission  of  substances 
that  cannot  be  made  soluble.  The  fact  that  fats  appear  in  the  blood 
stream  largely  in  the  insoluble  suspended  form  is  probably  only  an 
apparent  exception  since  they  are  readily  and  quickly  transformed  in  the 
blood  into  soluble  phospholipoid. 


lOG  W.  K.  ELOOll 

Synthesis  of  the  Fats  During  Absorption. — It  is  a  necessary  corollary 
of  the  foregoing  that  the  splitting  of  the  fats  which  takes  phice  in  the 
intestine  is  followexl  hy  a  rosynthesis  before  the  fat  reaches  the  thoracic 
duct.  Direct  proof  of  the  synthesis  ha>,  however,  not  been  satisfactorily 
furnished.  Ewald  thouglit  that  he  had  demonstrated  a  synthesis  by  the 
surviving  intestinal  mucous  niend)raue^  as  did  also  Ilandnirger,  but  Frank 
and  Ritter,  on  repetition  of  their  experiments,  were  unable  to  get  posi- 
tive results,  and  pointed  out  that  their  results  were  irregular  and  that 
such  positive  findings  as  were  obtained  win-o  due  to  faulty  technique.  Sim- 
ilarly Moore  failed  to  demonstrate  synthesis  in  vitro  using  mixtures  of 
sodium  oleate  and  glycerol  with  hashed  intestinal  mucous  membrane. 
On  the  other  hand,  Moore  showed  that  during  fat  absorption  the  fatty 
acid  in  the  mucous  membrane  of  the  intestine  amounted  to  15-35  per 
cent  of  the  total  fat,  while  in  the  mesenterial  glands  and  lymph  vessels 
it  amounted  to  only  about  4  per  cent,  which  facts  they  believed  to  show 
that  the  synthesis  took  place  in  the  mucous  membrane  and  not  in  the 
lymph  glands. 

Paths  of  Absorption  of  Fat. — The  thoracic  duct  is  probably  not  the 
only  channel  by  which  fat  reaches  the  blood  stream.  ^lunk  and  Eosenstein 
in  chyle  fistula  experiments  with  a  human  being  were  able  to  recover  not 
more  than  60  per  cent  of  the  total  fat  fed.  In  experiments  with  dogs 
Mimk  and  Friedenthal  were  able  to  show  an  absorption  of  32  to  48  per 
cent  of  the  fat  fed  after  tying  off  all  the  neck  and  arm  veins  of  both 
sides.  The  blood  fat  increased  from  0.5  per  cent  to  2.92  per  cent,  with 
notable  increases  of  fat  in  the  corpuscles.  Others  have  found,  on  the 
contrary,  that  tying  off  the  thoracic  duct  prevented  any  increase  in  blood 
fat.  Munk  also  noted  the  accumulation  of  fat  droplets  in  the  liver  during 
normal  fat  absorption  ("physiological  fat  infiltration"),  which  ho  be- 
lieved to  originate  from  fat  directly  absorbed  into  the  portal  vein — 
although  it  could  equally  well  be  ascribed  to  fat  Avhich  had  reached  the 
blood  stream  by  the  thoracic  duct.  v.  Walther  found  in  the  chyle  not 
more  than  1/10  of  the  fat  which  had  disappeared  from  the  intestine  of 
dogs.  A  similar  observation  is  reported  by  Frank  (1898).  Attention  should 
be  directed  to  the  fact  that  in  these  thoracic  duct  experiments  the  operative 
procedure  is  severe  and  the  results  found  may  not  represent  what  happens 
normally.  Aside  from  the  thoracic  duct  there  is  left  the  path  of  absorption 
taken  by  other  foodstuffs,  i.  e.,  directly  into  the  circulation  by  the  intestinal 
capillaries  and  the  portal  vein,  but  there  is  very  little  direct  evidence  of 
absorption  by  this  channel.  D'Errico  showed  that  during  fat  absorption 
the  fat  content  of  the  portal  vein  was  always  higher  than  of  the  jugular  and 
concluded  that  fat  was  normally  absorbed  directly  into  the  circulation  like 
other  food  substances.  Very  recently  Zucker  has  reported  negatively  on 
repetition  of  this  work. 

Changes  in  Fats  During  Absorption. — In  spite  of  the  fact  that  large 


NORMAL  FAT  MP:TAE0LI8.M  197 

amounts  of  food  fat  may  by  certain  treatment  be  transported  without  con- 
siderable change  directly  to  the  fat  depots,  evidence  is  available  to  show 
that  nnder  normal  con<litions  where  the  animal  has  free  choice  of  food 
and  where  the  amount  of  fat  ingested  is  not  too  large,  the  fat  in  the  chyle 
may  ])e  noticeably  different  from  the  fat  in  the  intestine.     Two  factors 
aj>poar  to  be  at  work  in  the  production  of  the  differences:  (a),  selection 
from  the  food  fat  of  the  more  desirable  or  useful  ix)itions  (generally  the 
lower  melting),  and  (b)  other  changes  either  of  the  nature  of  additions 
or  of  chemical  changes — saturation   or   desaturation — which   may  alter 
the  compositicm  considerably.    With  regard  to  the  first  factor — selection — 
^lunk  has  found  that  in  dogs  fed  with  lard  the  feces  fat  had  a  considerably 
higher  melting  point  than  the  fat  fed.    With  regard  to  the  second  factor — 
admixture  or  alteration — during  the  passage  from  the  intestine,  INFunk 
and    Rosenstein   after  feeding  cetyl  palmitate  found   the   chyle  fat   to 
consist  of  one  part  of  triolein  and  six  parts  tripalmitin,  with  a  melting 
point  of  30=^  C.     Frank  (1808),  after  feeding  ethyl  palmitate,  found  36 
per  cent  of  olein  in  the  chyle  fat,  and  after  feeding  mutton  tallow  (m.p. 
51.7°  C.)  obtained  a  chyle  fat  melting  at  38°  C.    In  these  cases  there  was 
an  alteration  in  the  direction  of  obtaining  a  lower  melting  fat.     Bloor 
(1913-14)  obtained  evidence  of  an  alteration  in  the  other  direction,  i.  e., 
the  chyle  fat  having  a  higher  melting  point  than  the  fat  fed.    After  feed- 
ing olive  oil  of  which  the  constituent  fatty  acids  had  a  melting  point  of 
16°  C.  and  an  iodin  number  of  S6,  chyle  fat  was  obtained  with  a  melting 
point  of  30°  C.  and  iodin  numbers  down  to  72.   Other  evidence  corroborat- 
ing the  above  findings  was  furnished  by  Raper  (1912-13).     In  most  of 
these  cases  the  influence  of  lipoids  present  in  the  fasting  chyle  was  excluded 
so  that  we  may  conclude  that  the  fat  may  be  considerably  modified  during 
the  process  of  absorption.     The  modifications  as  found  appear  to  be  pur- 
posive in  that  in  all  cases  the  tendency  appears  to  be  toward  the  production 
in  the  chyle  of  a  fat  approximating  the  properties  of  the  body  fat  of  the 
animal.    As  to  the  significance  of  these  changes  Frank  was  of  the  opinion 
that  there  is  an  addition  of  body  fat  either  by  way  of  secretion  into  the 
intestine  or  after  the  fat  leaves  the  intestine.  It  has  been  shown  by  Leathes 
(1909)  that  the  liver  has  probably  the  power  of  desaturating  the  fatty 
acids — a  power  which  all  living  cells  may  possess  to  some  degree,  and 
there  is  a  possibility  that  the  intestinal  cells  can  desaturate  or  saturate  the 
fatty  acids  during  their  passage  through.     The  mechanism  would  allow 
adaptive  changes  in  the  fats  during  absorption. 

Factors  in  Fat  Digestion  and  Absorption. — Pancreaiic  Secretion, — 
The  pancreas  is  the  main  source  of  lipase  in  the  intestine.  The  amoimt 
of  secretion,  generally  given  at  oOO  to  000  c.c,  is  sufTicient  for  the  rapid 
hydrolysis  of  at  least  its  own  weight  of  emulsified  fat,  and  since  the 
amount  of  fat  in  the  daily  human  diet  does  not  often  exceed  100  grams, 
is  greatly  in  excess  of  the  needs.     In  the  absence  of  pancreatic  secretion. 


108  W.  II.  BLOOR 

the  amount  of  fat  absorbed  falls  off,  but  not  to  the  extent  that  would  be 
expected  from  the  loss  of  such  an  imp<ii-tant  secretion.  Also,  as  has 
heen  noted  many  times,  the  fat  which  is  found  in  the  feces  in  these  cases 
is  almost  entirely  present  as  fatty  acids,  indicating  that  the  other  hydro- 
lytic  agents  present  (see  previous  discussion,  pages  181)-192)  and  also  prol>- 
al)ly  hacteria  very  etfectiv^ely  take  (m  the  work  of  the  pancreatic  lipase. 
Complete  extirpation  of  the  gland  produces  much  more  marked  etl'ects 
than  exclusion  of  the  secretion.  Emulsific^l  fats  are  hetter  utilized  than 
non-emulsified  and  feeding  of  pancreas  improves  the  utilization  of  lx>th. 
AVith  regard  to  complete  extirpation  various  factors  complicate  the  situa- 
tion, such  as  shock  of  operation,  deprivation  of  the  internal  secretion, 
h(5th  of  which  are  severe  in  their  effects  on  the  animals,  the  inability  to 
digest  and  utilize  other  foodstuffs,  which  results  secondarily  in  a  failure 
to  utilize  fat,  the  efficiency  of  the  pancreatic  secretion  in  forming  enuilsions 
which  are  stable  in  the  faint  acidity  found  in  the  intestine,  the  disturbance 
in  the  intermediary  metabolism  of  fat  which  results  in  an  accumulation 
of  fat  in  the  liver  and  other  tissues  and  the  slowing  of  the  emptying  of  the 
stomach  in  the  absence  of  pancreatic  secretion. 

Taking  all  the  evidence  together  there  can  be  no  question  that  the 
intestinal  secretion  of  the  pancreas  is  an  indispensable  factor  in  the  proper 
digestion  and  absorption  of  fat.  Whether  its  internal  secretion  is  of 
equal  importance  cannot  be  stated  at  the  present  time.  Lombroso  found 
that  fat  absorption  was  not  much  affected  by  stopping  the  pancreatic 
secretion  or  on  extirpation,  if  a  small  portion  of  the  gland  were  left  in 
place,  from  which  he  reasons  that  it  is  the  internal  secretion  which  is  of 
imjx)rtance.  On  the  other  hand,  it  is  well  known  that  in  sevei'e  diabetes 
where  the  carbohydrate  tolerance  is  very  low,  that  fats  are  readily  digested 
and  absorbed,  and  indeed  in  such  amounts  that  they  cannot  be  taken  care 
of  in  the  blood,  resulting  in  the  extreme  and  lasting  li|)emia  which  is 
occasionally  reported.  The  lipemia  may  be  the  direct  result  of  the  absence 
of  internal  secretion,  resulting  in  failure  of  the  intermediary  fat  metab- 
olism or  a  secondary  effect  of  the  failure  to  utilize  carbohydrate. 

The  Bile. — The  importance  of  the  bile  in  the  digestion  of  the  fats 
has  been  extensively  studied.  Early  experiments  by  Claude  Bei-nard  and 
Dastre  demonstrated  the  probable  necessity  of  both  bile  and  pancreatic 
secretion  for  effective  fat  absorption.  Work  by  Bidder  and  Schmidt, 
Rohmann  and  others  have  sho\ni  that  exclusion  of  the  bile  from  the  in- 
testine may  result  in  fat  losses  up  to  85  per  cent  of  the  fat  fed.  In 
icterus  with  complete  exclusion  of  bile  there  is  considerable  loss  of  fat, 
but  not  to  the  extent  observed  in  operative  exclusion.  The  importance  of 
bile  in  fat  absorption  seems  thus  to  be  well  establishe<l.  As  to  its  function 
in  this  relation  evidence  has  been  brought  forward  by  Moore  and  Rock- 
wood  to  show  that  one  very  important  part  which  it  plays  is  in  increasing 
the  solubility  of  the  fatty  acids  and  soaps  produced  by  hydrolysis  of  the 


XOR^VFAL  FAT  METABOLISM  1^9 

fats.  It  also  iiiorrasos  tlie  foniiafion  of  soaps  from  the  fatty  acids  as 
>Iiowii  hy  riliiiior,  and  later  by  Kingsbiny.  Tlieso  effects  arc  partly  duo 
to  the  })ilo  salts  hut  fo  a  considerable  extent  toother  substances,  e.  g.,  mucin 
and  lecithin. 

Tiio  accelerating;'  or  activating  effect  of  bile  on  the  pancreatic  lipjise 
has  heen  shown  hy  Kachford  and  by  von  Fi'irth  and  Schiitz,  who  found 
that  the  fat  splittlnii'  {)Ower  of  pancreatic  juice  was  increased  several  fold 
liy  the  presence  ai  hile.  The  active  substance  in  the  bile  which  produces 
the  accelerati(m  has  been  shown  by  both  investigators  to  be  the  bile 
salts.  Aside  from  any  positive  action  of  the  bile  the  mere  exclusion  from 
the  intestine  of  a  pint  or  more  of  alkaline  colloidal  secretion  nmst  have  a 
jnofound  effect  on  intestinal  processes.  As  regards  further  and  unknown 
functions  of  the  bile  mention  should  be  made  of  the  important  findings  of 
Hfxjper  and  Whi}>[>le  that  dogs  cannot  long  survive  complete  exclusion 
of  bile  from  the  intestine  unless  liver  is  included  in  their  diet. 

In  the  absence  of  both  bile  and  pancreatic  secretion  very  little  fat  is 
absorbed,  probably  not  over  20  per  cent  of  emulsified  fat,  is  in  milk, 
and  much  less  of  non-emulsified  fat,  although  splitting  is  generally  good — 
^<>  to  00  per  cent  of  the  rejected  fat  consisting  of  free  fatty  acids.  Traces 
only  of  soaps  are  present,  which  would  point  to  the  lack  of  alkali  ordi- 
narily furnished  by  the  pancreatic  secretion  and  the  bile  as  the  significant 
factor  in  absorption. 

The  Nature  of  the  Food  Fat. — Lipase  can  act  only  on  the  surface  of 
the  fat,  hence  the  necessity  as  a  preliminary  step,  of  breaking  up  the 
fat  masses  to  as  fine  a  state  of  division  as  possible  as  in  emulsions, 
so  as  to  increase  the  available  surface.  For  ready  emulsification  the  fat 
must  be  liquid  or  at  least  semi-solid  at  body  temperature,  and  we  find 
that  the  utilization  of  a  food  fat  depends  largely  on  its  fluidity  at  Ixxly 
temperature.  Thus  v.  Walther,  in  feeding  experiments,  found  that  various 
fats  which  were  liquid  at  body  temperatures  were  absorbed  to  the  extent 
of  07  to  98  per  cent,  while  tristearin  (m.p.  60^  C.)  was  absorbed  to  the 
extent  of  only  14  |K>r  cent.  Dissolving  tristearin  in  almond  oil  so  as  to 
l>ring  the  meltinir  point  down  to  55^  increased  its  absorption  to  80  per 
cent,  indicating  the  importance  of  the  liquid  fats  and  esjx'cially  of  triolein 
as  a  solvent  for  the  harder  fats,  making  it  jwssible  to  deal  with  them  in  tlve 
organism  both  in  hydrolysis  and  in  transjx^-t.  On  the  other  hand,  experi- 
ments with  ethyl  stearate  (m.p.  30^  C.)  have  showTi  that  melting  point  in 
the  intestine  is  not  the  only  factor  in  absorption,  since  this  substance  is 
very  little  better  absorbed  than  tristearin,  although  it  is  liquid  at  body 
temperature.  Also  when  it  reaches  the  thoracic  duct  (as  tristearin)  it 
was  found  mixed  with  enough  softer  fat  to  bring  its  melting  point  down 
to  near  body  temj>erature.  It  seems  from  these  experiments  that  the 
organism  is  able  to  protect  itself  against  the  absorption  of  high  melting 
fat  which  it  would  have  difficultv  in  dealing  with,  first  by  limiting  the 


200  W.  R.  BLOOH 

amount  absorbed  and  second  by  mixing  it  with  enough  low  melting  fat  to 
bring  tbe  melting  point  of  the  mixture  to  somewhere  near  body  tempera- 
ture, (liecent  work  by  Lyman  indicates  tliat  available  glycerol  may  be  a 
limiting  factor  in  absorption  of  the  simple  esters,  just  as  it  is  with  the 
fatty  acids.) 

Aside  from  the  high  melting  fats  and  excepting  certain  ones  like 
castor  oil  which  are  eith(»r  irritating  to  the  intestine  or  which  form  irritat- 
ing soaps,  there  appears  to  l)e  little  dill'erence  in  the  extent  of  utilization 
of  fats  of  whatever  origin,  animal  or  vegetable,  a  result  which  might  have 
been  foretold  since  the  fatty  acids  in  combination  in  fats  from  various 
sources  are  largely  the  same,  the  main  ditrerence  being  in  the  relative 
amounts  of  each  constituent  of  the  mixture. 

Eynulsification  in  Fat  Dir/estioii  and  Absorption, — It  is  generally 
assumed  that  fats  must  be  enudsified  in  the  intestine  before  they  can  be 
digested  and  absorbed,  for  the  reason  that  Avhile  the  lipases  found  in  the 
intestinal  secretions  are  always  in  water  solution  the  fats  are  insoluble 
in  water  and  lipolysis  can  take  place  only  at  the  sui'face,  which  emulsifica- 
tion  greatly  increases.  The  assumption  has  the  support  of  a  large  number 
of  observations  on  fat  in  the  intestine  during  digestion.  That  emulsions 
are  not  always  present  in  the  intestine  unrlcr  these  conditions  is,  however, 
attested  by  observations  of  Moore  and  Rockwood,  who  found  in  many  cases 
no  emulsion  but  a  brownish  liquid  with  an  acid  reaction.  Xo  examination 
was  made  as  to  Avhether  this  liquid  contained  fat  and  it  is  possible  that  it 
consisted  of  a  bile  solution  of  the  fatty  acids.  Where  conditions  for  diges- 
tion are  exceptionally  good  the  emulsion  may  be  only  transitory.  The 
conditions  for  the  emulsification  of  the  food  fat  on  its  entry  into  the  in- 
testine arc  ordinarily  very  favorable.  There  are  present  free  fatty  acid 
in  the  fat,  alkali  in  the  secretions,  and  other  substances  such  as  proteins, 
lecithin,  etc.,  wdiicli  are  either  emulsifiers  themselves  or  which  act  to 
stabilize  emulsions.  The  acidity  of  the  intestine  which  many  observers 
have  found  need  not  be  a  hindrance  since  it  is  due  mainly  to  carbonic  acid 
and  emulsions  formed  with  the  aid  of  pancreatic  secretion  and  bile  are 
knoAvii  to  be  stable  in  solutions  of  carbonic  acid. 

Smnmary. — It  will  be  seen  that  no  definite  answer  can  yet  be  given 
as  to  the  way  in  which  fat  passes  through  the  intestinal  wall. 
Emulsification  is  probably  at  least  an  early  if  temporary  ste}).  Hydrolysis 
undoubtedly  takes  place  in  large  measure  and  would  therefore  seem 
to  be  a  necessary  preliminary  to  absorption.  Soap  formation  under  the 
conditions  of  reactions  of  the  intestinal  contents  (faint  acidity)  and 
the  presence  of  bile  prolnibly  takes  place  to  a  considerable  extent.  Soap 
being  water-soluble  is  assumed  by  many  to  be  the  form  in  which  the  fats 
are  finally  absorbed,  but  it  should  be  borne  in  mind  first  that  soap 
is  a  difficultly  diffusible  substance  and  second  that  in  water  solution 
it  hydrulyzes,  forming  aggregates  of  free  fatty  acid  which  would  be  still 


XOl^MAL  FAT  :trETABOLISM  201 

less    diffusible.      On    the    other   hand,    the    earlier    theory    of    absorp- 
tion of  fat  as  such  has  secured  some  additional  sup}x>rt  from  the  observa- 
tions of  Green  auil  Skaer  that  fats  can  penetrate  for  considerable  distances 
into  the  stomach  walls  of  animals,  confirming  on  animals  the  much  earli»T 
observation    of    Schmidt    that    fat    penetrates    readily    into    plant    cells, 
especially  if  it  contain  a  little  free  fatty  acid.    The  ability  of  certain  ty[>es 
of  animal  tissue  t'clls  to  engulf  foreign  particles,  including  fats,  has  been 
shown  by  Evans,  just  as  the  phagocytic  white  blood  cells  are  known  to  d<). 
(The  part  which  these  same  white  blood  cells  take  in  fat  absorption,  while 
known  to  be  large  for  the  individual  cell,  is  not  believed  to  be  important 
in  the  aggregate.)      However,  even   in  plants  a   preliminary  hydrolysis 
would  seem  to  be  necessary  since  in  fat  se^ds,  such  as  the  castor  bean, 
hydrolysis  is  known  to  take  place  before  tl;o  fat  is  utilized.     Even  so, 
hydrolysis  produces  another  kind  of  insoluble  substance — the  fatty  acid — 
which,  however,  is  different  and  probably  essentially  so  in  that  in  the 
presence  of  alkali  it  becomes  water  soluble.     To  what  extent  fat  passes 
the  intestinal  walls  as  fatty  acid — bile  being  the  ferry,  as  has  been  sug- 
gested by  Mathews — cannot  be  determined.     Xeither  can  it  be  said  what 
factors  determine  whether  the  digested  fat  shall  pass  directly  into  the  blood 
by  w^ay  of  the  portal  system  or  indirectly  by  way  of  the  thoracic  duct.    In 
the  former  case  it  passes  directly  to  the  liver,  and  in  the  latter  it  avoids  it. 
It  seems  quite  certain  that  esters  of  the  fatty  acids  which  cannot  be 
hydrolyzed  in  the  intestine  and  so  rendei'ed  water-soluble  and  also  oily 
substances  of  other  kinds  which  cannot  be  made  water-soluble  are  rejected 
no  matter  what  their  other  properties  may  be  nor  how  intimately  they  may 
bo  mixed  with  the  fats.     Water  solubility  of  the  absorbed  products  seems 
to  be  as  essential  for  the  fats  as  for  other  focxl  substances.    The  mechariisni 
for  excluding  substances  which  are  not  water-soluble  is  i>erfect,  presumably 
because  such  substances  could  not  possibly  be  handled  in  the  organism. 


Fat  in  the  Blood 

Alimentary  Lipemia. — The  study  of  the  blood  brings  us  one  step 
nearer  to  the  actual  seats  of  metabolism  than  that  of  the  urine  and  other 
waste  products.  It  is  the  great  distributing  system  of  the  body.  The 
recognition  of  these  facts  has  turned  the  attention  of  most  investigators 
to  the  blood,  with  the  result  that  thereby  much  has  been  added  to  our 
knowledge  of  metabolism.  Because  of  the  greater  difficulty  of  their  study 
the  discoveries  regarding  the  fats  have  as  usual  rather  lagged  behind  those 
of  the  other  foodstuff's,  although  a  good  deal  has  been  accomplished. 
Methods  for  fat  detei'mination  in  foods  and  tissues  have  been  adapted  for 
use  with  blood,  and  new  methods  have  l)een  devised  especially  suited  to 
use  with  small  amounts  of  blood,  so  that  processes  can  be  followed  in 


202  W.  K.  BLOOK 

the  livinp:  animal  with  considerable  exactness.  The  result  has  heen  an 
accunmlation  of  data  from  which  we  can  now  begin  to  get  an  insight  into 
the  history  of  the  fats  after  thev  leave  the  intestine.  After  absorption 
that  part  of  the  food  fat  which  has  passed  into  the  lacteals  finds  its  way 
into  the  blood  stieani  by  way  of  rlie  thoracic  duct  in  the  form  of  a  sus- 
pension of  very  tine  particles  (generally  less  than  1  fi  in  diameter)^  in 
which  the  Brnwnian  movement  is  marked  and  which  give  the  chyle  and 
the  blood  plasma  their  milky  appearance.  The  milkiness  persists  for  some 
time  but  has  generally  disappeared  in  from  eight  to  fourteen  hours  after 
the  fat  is  eaten.  According  to  present  observations  milkiness  persisting 
fourteen  hours  after  a  meal  indicates  an  abnormality  in  fat  metaboli^n. 
Emulsified  fat  (particles  2  to  5  f.t  in  diameter)  injected  directly  into  tlio 
veins  disappears  within  a  few  'minutes,  the  difference  from  alimentary 
lijxjmia  being  due  probably  to  the  larger  size  of  the  fat  particles,  although 
there  is  a  [X)ssibility  that  the  relatively  small  amount  injected  would  be 
quickly  removed  and  stored  while  a  larger  amount  would  not,  Rabbeiio 
found  that  homogenized  fat  (particles  up  to  2  (x  in  size)  injected  in 
quantity  disappeared  rather  slowly  (7  hours).  The  extent  and  duration 
of  the  increase  of  the  blood  fat  following  a  meal  depends  on  the  amount 
of  fat  fetl  and  also  apparently  on  the  level  of  the  blood  lipoids  at  the 
time  of  feeding.  When  the  blood  lipoid  level  is  high  the  maximum  in. 
the  blood  is  reached  sooner  and  the  fall  from  the  maxinuim  is  slower  than 
is  the  case  when  the  li]K)id  level  in  the  blood  is  low.  The  amount  of  extra 
fat  in  the  blood  does  not,  however,  at  any  time  represent  the  amount 
which  has  disappeared  from  the  intestine  so  that  absorption  by  the  tissues 
from  the  blood  must  normally  be  rapid.  The  extent  of  alimentary  lipemia 
varies  greatly  in  different  animals.  In  rabbits  it  is  very  diflicult  if  not 
im|>ossible  to  produce.  In  geese  stuffed  with  rye  values  as  high  as  6  per 
cent  have  been  recorded.  This  is  probably  a  cumulative  value,  since  under 
these  conditions  fat  absorption  must  l>e  continuous.  In  dogs  the  bhx>d 
fat  values  larely  exceed  three  i)er  cent,  and  in  humans  two  per  cent.  In 
human  beings  with  diabetes,  lipemia,  which  is  j>rol)ably  primarily  of  ali- 
mentary origin,  witli  values  of  over  20  per  cent,  has  been  recorded,  and 
while  this  is  an  extreme  instance,  high  values  are  not  unconmion  in  un- 
treated eases.  The  passage  of  fat  from  the  bhx)d  is  probably  inhibited 
in  these  cases,  since  on  a  low  calorie  low  fat  diet  it  may  take  a  month  for 
values  to  get  down  to  normal. 

The  mechanism  of  the  disappcii ranee  of  fat  from  the  blood  is  uncertain. 
Stained  or  otherwise  distinguishable  fat  injected  into  the  circulation  dis- 
appears promptly  as  indicated,  and  is  found  to  have  accumulated  in  the 
liver,  bone  marrow,  spleen  and  muscles  in  the  order  named — which  is  true 
also  of  other  finely  su£|>ended  material  of  other  kinds.  During  fat  diges- 
tion the  fine  fat  particles  are  found  to  have  accumulated  in  various  places 
along  the  endothelial  lining  of  the  blood  vessels.     Vai-ious  theories  have 


NOiniAL  FAT  METABOLISM  203 

been  advanced  to  exj)lain  the  way  in  wliicli  the  material  passes  across  the 
vessel  walls  into  the  tissues.  One  of  the  earliest  was  that  there  is  the 
same  process  of  hydrolysis  and  resynthesis  as  takes  place  in  the  passage  of 
the  intestinal  wall,  which  fx>stulates  the  presence  of  lipases  in  the  nciglibov- 
h(Jod  of  where  the  transfer  takes  place.  In  this  connection  much  confusion 
has  resulted  from  the  failure  to  distinguish  between  '^esterases*' — enzymes 
which  can  hydrolyzc  simple  esters  such  as  ethyl  butyrate  and  also,  though 
more  slf»wly,  glycerids  of  the  lower  fatty  acids,  as  for  example  tributyrin, 
but  cannot  hydrolyzc  ordinary  fats  (or,  at  least,  only  very  slowly),  and 
true  lipases  such  as  are  found  in  the  pancreatic  secretion,  which  split  fats 
readily;  and  still  further  uncertainty  has  been  caused  by  the  failure  to 
exclude  cells  or  portions  of  cells  from  the  extracts  used  for  testing.  Es- 
terases appear  to  be  quite  widespread  in  the  blood  and  tissues,  although 
generally  in  small  amounts  and  of  slight  activity,  while  lipases  in  sig- 
nificant amounts  apjwar  to  be  confined  to  the  pancreas.  Even  in  the 
mammary  gland  and  the  fat  deix)ts  where  the  exchange  of  fat  would 
presumably  be  most  active  no  significant  amount  of  lipase  can  be  demon- 
strated. So  that  the  primary  requisite  for  hydrolysis  and  resynthesis,  an 
adequate  supply  of  lipase  at  the  tissue  cell  wall  is  missing.  On  the  other 
hand,  esterases  which  are  capable  of  splitting  lecithin  are  found  to  be 
quite  widely  distributed  (Thiele,  1912-13)  and,  for  reasons  which  will 
appear  later  in  the  discussion,  are  believed  to  be  of  importance  in  fat 
metabolism. 

Coincident  with  or  immediately  following  the  rise  of  fat  in  the  blood 
during  fat  absorption  certain  changes  have  been  noted  in  the  other  blood 
lipoids  wliich  appear  to  be  of  importance  in  fat  metabolism.  A  consid- 
erable increase  of  lecithin  is  noted  by  all  workers.  A  similar  increase  of 
cholesterol  is  found  by  some  but  not  by  others,  which  may  be  explained  by 
the  fact  that  it  apparently  comes  later.  It  is  becoming  more  and  more 
evident  that  these  three  substances — fat,  cholesterol  and  lecithin — are 
closely  conne^jted  in  fat  metabolism,  and  when  one  is  increased  the  others 
are  very  generally  also  found  to  be  similarly  high.  The  period  during 
which  fat  is  abnormally  high  in  the  blood  during  fat  absorption  (about 
eight  hnurs)  is  apparently  long  enough  to  produce  increases  of  lecithin, 
which  follow  quickly  the  increases  in  fat,  but  may  not  be  long  enough  to 
bring  about  increases  of  cholesterol  which  take  place  later  and  more  slowly. 
The  close  relation  of  lecithin  and  cholesterol  to  fat  would  indicate  that 
these  are  stages  in  metal)olism  through  which  the  fats  may  or  must  pass 
before  they  are  utilized,  a  supposition  which  is  supported  in  the  case  of 
lecithin  by  the  close  similarity  in  composition  and  in  the  case  of  cholesterol 
by  the  constant  relation  in  the  blood  serum  between  cholesterol  and  its 
fatty  acid  esters. 

The  blood  corpuscles  appear  to  take  a  considerable  part  in  the  changes 
in  the  blood  lipoids  during  alimentary  lipemia.     The  old  observation  of 


204  W.  R.  BLOOR 

Munk  and  Friedenthal  that  the  fat  content  of  tlie  corpuscles  increased 
durinc^  fat  al)Sorption  has  been  recently  confirmed  and  it  was  also  shown 
that  tho  increase  of  fat  was  accompanied  hy  incn.'ases  of  lecithin,  from 
which  tho  inference  was  drawn  that  the  corjmsck'S  take  np  the  suspended 
fat  from  the  phisma  and  transform  it  into  Iwithin.  Scmie  snpjx^rt  is 
given  to  this  inference  hy  the  observations  of  Thiele  and  of  Foa  (1015), 
who  found  that  tlie  blood  esterase  decom|K)ses  lecithin  only  when  corpuscles 
are  present,  indicating  that  this  esterase,  which  presumably  also  synthesizes 
lecithin,  is  present  only  in  the  corpuscles.  On  the  other  hand,  later  work 
in  this  laboratory  has  shown  that  in  certain  dogs  lecithin  does  not  markedly 
increase  in  the  corpuscles  but  does  in  the  plasma.  As  has  been  recently 
jjointed  out  by  Bang  (lOlSj,  animals  show  great  individuality  in  their 
blood  reaction  to  ingested  fat.  Some  can  dispose  of  large  amounts  without 
showing  much  effect  on  the  blood  lipoids;  others  react  strongly.  He 
makes  some  suggestions  to  explain  the  differences — habituation  to  fat  food 
and  the  presence  of  carbohydrate  in  the  food  or  of  much  stored  glycogen 
being  in  his  opinion  important  factors.  As  regards  lecithin  formation  in 
tho  blooil  it  is  not  likely  that  it  is  confined  to  the  corpuscles  but  probable 
that  other  cells  with  which  the  suspended  fat  comes  in  contact  have  the 
same  function.  Furthermore,  the  failure  to  find  increased  lecithin  values 
in  the  corpuscles  of  certain  animals  does  not  necessarily  mean  that  it  is 
not  fonned  there.    It  may  be  formed  and  pass  at  once  into  the  plasma. 

Lipoids  of  the  Blood. — A  gi-eat  deal  of  investigative  work  has  been 
done  on  the  lipoids  of  the  blood  both  in  the  normal  and  in  various  path- 
ological conditions,  the  results  of  which  in  general  bear  out  the  nde  just 
enunciated,  that  when  one  of  the  constituents  (fat,  cholesterol,  lecithin), 
is  found  abnormal  the  other  two  will  also  be  abnormal  and  in  the  same 
direction.  It  has  been  sho\\Ti  how  feeding  fat  increases  the  blood  lecithin, 
and  while  there  is  some  question  as  to  whether  blood  cholesterol  is  in- 
creased in  tho  lipemia  produced  by  a  single  fat  feeding  there  is  none  at  all 
where  tlie  lipemia  persists.  Feeding  cholesterol  produces  not  only  increase 
of  blood  cholesterol  but  also  of  blood  lecithin.  Whether  feeding  lecithin 
would  produce  increases  in  the  other  two  constituents  has  not  been  re]X)rted 
and  probably  cannot  be  determined  since  lecithin  is  largely  hydrolyzed 
in  the  alimentary  tract  and  probably  absorbed  as  fat  although  some  may 
apjxmr  as  such  in  the  chyle.  While  there  are  not  enough  data  available 
to  justify  the  statement  that  there  is  a  constant  relation  between  the 
three  -constituents  in  normal  and  in  most  pathological  conditions,  the 
tendency  seems  to  be  in  that  direction  and,  at  any  rate,  it  apj>ears  reason- 
ably certain  that  the  three  substances  are  interdependent,  and  also  that  all 
are  concerned  in  the  metabolism  of  the  fatty  acids. 

The  concentration  of  fat,  cholesterol  and  lecithin  in  the  blood  is  fairly 
constant  for  the  same  species  but  varies  greatly  in  different  species,  the 
variation  being  noticeable  mainly  in  the  plasma.     The  concentration  in 


KOmiAL  FAT  METABOLISM  205 

the  plasma  and  the  corpuscles  of  the  same  animal  is  clifFerent.  In  general, 
the  lipoid  level  in  the  plasma  is  higher  in  the  carnivora  than  in  the 
herhivora,  hoing  iindouhtedly  infincnced  hy  the  amount  of  fat  ha]>itually 
present  in  the  diet.  There  is  no  such  difference  between  the  concentration 
of  the  lipoid  constituents  in  the  c<n-puscles  of  the  various  species,  the 
tendency  being  rather  to  a  similarity  of  composition  in  all. 

The  level  of  the  blood  iijioids  may  be  affected  by  various  conditions, 
the  most  frequent  being  alimentary  lipemia  as  discussed  above.  Other 
foods  than  fat  ajjparently  do  not  affect  the  level,  at  least  not  unless  the 
diet  is  continued  for  some  time.  Fasting  for  short  periods  may  or  may 
not  raise  the  level  of  the  blood  lipoids  (dogs),  depending  probably  on  the 
nutritional  condition  of  the  animal.  After  the  first  two  weeks  of  fasting 
there  is  generally  a  slow  fall,  although  here  again  the  nutritional  condition 
of  the  animal  at  the  beginning  of  the  fast  is  probably  im|X)rtant.  Nar- 
cotics— chloroform,  ether  and  alcohol  (especially  the  two  latter) — if  long 
continued  generally  cause  an  increase  of  the  blood  lipoids.  Chloroform 
may  not  produce  any  effect  during  or  immediately  after  the  narcosis,  but 
the  effects  may  appear  two  or  three  days  later.  As  reasons  for  the  effects 
may  be  given  the  increase  in  the  lipoid  solvent  power  of  the  blood  due  to 
the  dissolved  narcotics  and  also  their  poisonous  effects  on  the  tissues, 
especially  the  fatty  tissues — which  absorb  these  substances  selectively — 
producing  more  or  less  disintegration  of  the  cells.  Poisoning  Avith  phos- 
phorus or  phlorizin  will  sometimes  produce  an  increase  of  the  blood  lipoids, 
but  the  reaction  is  not  constant.  In  late  pregnancy  in  mammals  there  is 
often  a  rise  in  blood  lipoids,  due  probably  to  preparation  for  lactation. 
It  has  been  found  that  there  is  a  relation  between  the  level  of  blood  lipoids 
and  the  amount  of  fat  secreted  in  the  milk  of  lactating  animals,  also  that 
the  lipoid  phosphorus  is  higher  in  lactating  animals  than  in  dry  ones. 


Fat  in  the  Tissues 

storing  of  Fat. — Lipoid  material  exists  in  the  tissues  in  two  states  or 
conditions:  (a)  stored,  or  inactive,  consisting  of  almost  pure  fat  ^vith  not 
more  than  traces  of  other  li}»oids;  and  (b)  cell  lipoid,  *^built  in"  or  active, 
forming  part  of  the  living  tissue  and  taking  an  active  part  in  life  processes. 
Of  this  latter,  phospholipoid  is  the  one  present  in  largest  amount  and 
widest  distribution,  then  cholesterol  and  its  compounds  followed  by  the 
series  of  more  or  less  well  characterized  substances  which  include  most 
of  the  knoAvn  lipoids.  The  cell  lipoids  are  relatively  constant  in  com- 
position and  appear  to  be  characteristic  of  the  tissue. 

Stored  fat  is  found  in  various  parts  of  the  animal  body,  mainly  in 
more  or  less  v/ell  defined  fat  depots  such  as  the  abdominal,  subcutanetais 
and  inteiTTiuscular,  and  around  the  organs.     It  is  not  normally  found 


20G  W.  E.  BLOOR 

in  more  than  small  amounts  in  active  tissues  such  as  the  heart,  kidney  and 
muscles,  although  considerable  li}>»i<l  material  of  other  kinds  is  present 
there.  The  stored  fat  has  its  origin  in  part  directly  from  the  fat  of  the 
food  and  in  part  indirectly  by  synthesis  from  other  food  substances,  mainly 
carl)ohydrate.  Synthesis  from  protein  probably  does  not  ordinarily  take 
place  to  any  considerable  extent.  Under  certain  circumstances — stuffing 
of  an  animal  with  fat,  espe^'ially  after  starvation — food  fat  may  be  laid 
down  in  the  fat  depots  with  but  little  if  any  change,  but  under  ordinary 
conditions  where  the  animal  has  a  normal  choice  of  foo<l  there  is  a  marked 
tendency  to  produce  a  fat  characteristic  of  the  animal ;  for  example,  beef 
fat  has  certain  definite  characteristics  which  distinguish  it  from  hog  fat  and 
both  from  human  fat.  The  laying  down  of  a  characteristic  body  fat  by 
an  animal  fr<uu  its  food  must  involve  several  factors  such  as  choice  from 
the  food  fat  as  to  which  jx)rtion  is  to  be  immediately  consumed  and  which 
stored,  tlio  nature  of  the  fat  synthesized  from  carbohydrate,  also,  in  case 
the  stored  fat  is  used,  choice  as  to  whether  the  harder  or  softer  constituents 
are  to  be  used  first,  since  there  is  some  evidence  to  show  that  the  fat  of  a 
starvefl  animal  has  a  higher  melting  point  than  the  normal  body  fat  of 
the  animal.  Although  the  laying  up  of  a  characteristic  fat  is  partly  the 
resultant  of  these  factors,  their  activity  is  limited  and  in  the  end  the  fat 
stored  is  gi-eatly  influenced  by  the  food  fat  especially  if  it  forms  a  large 
proportion  of  the  diet.  The  question  has  a  considerable  economic  interest 
in  connection  with  the  fattening  of  animals,  e.  g.,  hogs  for  market,  since 
it  has  been  found  that  if  too  much  liquid  fat  is  inclndal  in  the  diet  the 
result  is  a  soft  meat  from  which  the  fat  oozes  out  on  standing. 

Changes  in  Fat  in  the  Tissues.— If  the  stored  fat  is  thus  markedly 
influenced  by  the  fowl  fat,  the  built  in  fat  or  cell  lipoid  is  just  as  notably 
characteristic  of  the  tissue  and  uninfluenced  by  the  food  fat,  and  since  the 
fatty  acids  found  in  combination  in  the  cell  ]ijx)ids  are  often  different 
from  thoso  ordinarily  found  in  the  food,  the  question  arises  as  to  the  power 
of  the  tissues  to  alter  for  various  pur]X)ses  the  fat  presented  to  them. 
The  differences  between  the  fatty  acids  of  the  active  tissues  and  those  of 
the  food  consist  mainly  in  (a)  their  degree  of  satuititiou,  (b)  the  groups 
with  which  they  are  combined.  They  are  in  general  much  more  un- 
saturated, the  iodin  absorption  value  of  the  fatt}^  ae$ds  of  the  tissues  is 
found  to  be  in  the  neighborhood  of  1*30,  while  that  ©f  the  stored  fat  is 
from  35  to  TO.  The*  iodin  value  of  the  blood  li}X>ids  in  normal  human 
beings  is  about  QQ  (calculated).  The  fatty  acids  in  8^he  tissue  cells  are 
largely  combined  as  phospholipoids,  although  there  amtr  also  a  number  of 
other  combinations  of  the  fatty  acids  to  be  found  in  the  organs  and  in  the 
brain  and  nervous  tissue.  These,  with  few  exceptions,  are  not  well 
understood  chemically,  and  since  they  apparently  take  Imt  a  small  part  in 
ordinary  fat,  metabolism  they  will  not  l)e  considered  lueaie-  The  ])i'esence 
of  compoimds  of  the  unsaturated  fatty  acids,  esjx'ciallnr  jiSiospholipoids,  in 


NOR^IAL  FAT  :\IETABOLISM  207 

]i\rp:o  amount  (up  to  15  per  cent)  in  the  cells  of  continuously  active  organs 
like  the  heart  and  kidney  as  well  as  in  lesser  ix?rcentages  in  the  muscles 
furnish  a  hasis  for  the  theory  that  they  constitute  the  form  in  which  the 
fats  are  utilized,  and  that  food  fat  must  undergo  these  changes — desatura- 
tion  and  plusphorization — before  it  can  Ih*  utilized.  The  theory  is  given 
sui>|X)rt  from  the  fact  already  discusse<l  that  whenever  there  occurs  a 
large  accumulation  of  fat  in  the  blood,  most  frequently  in  alimentary 
jipemia,  there  is  accompanying  it  a  marked  increase  in  the  amount  of 
lipoid  phosphorus  present. 

The  Liver  in  Fat  Metabolism. — That  the  liver  plays  an  important 
part  in  fat  metabolism  is  indicated  by  the  work  of  many  investigator?. 
Alunk  (1002 )  found  that  the  liver  was  loaded  with  fat  during  fat  absorp- 
tion. Leathes  and  ^leyer-Wedell,  by  the  use  of  a  fat  with  high  iodin  num- 
ber, found  not  only  that  the  accumulated  fat  of  the  liver  after  feedinjr  was 
food  fat  but  that  the  liver  was  the  only  organ  in  which  such  marked  accu- 
mulation occurred.  In  various  abnormal  conditiuns,  such  as  poisoning  with 
phosphorus,  chloroform  or  phloridzin,  in  diabetes,  in  starvation,  etc.,  great 
increases  of  the  fat  in  the  liver  may  occur  which  are  believed  to  be  the 
result  of  mobilization  of  stored  fat  since  the  fat  found  in  the  liver  at  these 
times  has  the  properties  of  stored  fat  rather  than  of  normal  liver  fat. 

The  accumulations  of  fat  in  the  liver  whenever  fat  is  being  extensively 
moved  by  the  blood  stream  indicate  that  the  liver  must  have  an  important 
function  in  fat  metabolism.  Is  it  a  temjDorary  storehouse  by  means  of 
which  the  fat  in  the  blood  is  kept  within  limits  as  is  the  case  with  the 
carbohydrate,  or  does  the  fat  undergo  some  essential  change  there  ? 
Leathes'  theory  of  the  function  of  the  liver  in  fat  metabolism  is  that 
mobilization  of  fat  to  the  liver  is  a  normal  process,  that  the  fat  is  brougnt 
there  for  two  purposes:  (a)  introduction  of  double  bonds  (desaturation) 
which  paves  the  way  for  breaking  the  long  fatty  acid  chains  into  shorter 
ones,  and  (b)  phosphorization  of  the  fat,  changing  it  into  phospholipoids 
which  increasing  evidence  seems  to  show  is  the  initial  stage  in  the  inter- 
mediary metabolii^m  of  fat.  The  desaturation  he  believes  to  be  specific  for 
the  liver,  but  phosphorization  may  be  accomplished  in  other  places.  His 
theory  is  based  on  the  following  evidence:  The  fatty  acids  ordinarily 
f(nind  in  the  liver  differ  from  those  of  the  stored  fat  in  being  much  more 
unsaturated.  The  liver  is  the  only  point  of  mobilization  of  fat  from  the 
intestine  or  the  fat  stores.  The  inference  is  that  the  liver  desaturates 
the  fatty  acids  which  are  brought  to  it.  Since,  however,  similar  un- 
saturated fatty  acids  are  found  in  other  organs  like  the  heart  and  kidney 
it  might  with  equal  correctness  be  inferred  that  desaturation  occurs  in 
these  also.  Some  work  by  ^Fcttram  with  the  plaice  in  which  he  found 
tliat  the  fatty  acids  of  the  liver  had  a  lower  iodin  number  than  those  of 
cither  the  food  or  the  muscles,  w^ould  indicate  that  the  liver  may  not  always 
have  the  function  of  desaturation.     But  as  it  is  the  only  place  where 


20S  W.  K.  BLOOE 

temporary  aeciimiilatioiis  of  fat  occur  and  is  tlie  most  important  glarul  in 
tlio  oriraui.-in  tlio  probable  cornx^tness  of  I^cathes'  hypothesis  as  regards 
desaturation  must  Ix)  admitted.  That  phosphorizatiou  takes  phace  iu  other 
locations  than  the  liver  is  indicated  hy  work  on  changes  in  fat  in  the 
lijood  in  which  it  is  shown  that  the  blood  cells  may  have  this  function. 
Allowing  the  correctness  of  the  assumption  that  phospholipoid  ('^lecithin") 
is  the  e-sential  interiije<liate  step  in  fat  metabolism,  the  questions  of  fat 
trans]X)rt  in  the  blood  and  in  and  out  across  cell  walls  after  it  enters  tho 
blood  stream  as  well  as  its  further  utilization  are  greatly  simplified,  since 
lecithin  is  soluble  in  the  blood  plasma  and  since  tliei-e  are  present  in  all 
organs  and  tissues  esterases  which  hydrolyze  lecithin  readily  but  which 
have  little  effect  on  the  fats.  That  blood  lecithin  may  be  a  source  of  fat 
in  the  living  organism  is  well  shown  by  the  w^ork  of  ^Eeigs  and  coworkers, 
who  found  that  milk  fat  could  be  satisfactorily  acc^nmted  for  by  decreases 
in  lecithin  in  the  blood  passing  through  the  mammary  gland. 

Later  Stages— P-oxidation. — As  regards  later  stages  in  the  inter- 
mediary metabolism  of  the  fats  little  is  definitely  known.  The  fatty  acids 
ordinarily  disappear  in  m(»tabolism  without  leaving  any  traces  in  the  w^ay 
of  intermediate  stages  by  which  the  process  of  breakdown  may  be  followed. 
In  certain  cases,  however,  as  in  severe  diabetes  and  even  in  short  periods 
of  fastings  acids  appear  in  the  urine  which  are  now  believed  to  be  late 
stages  of  fatty  acid  combustion.  These  unbunied  residues  are  P-oxy- 
but^Tic  and  diacetic  acids  which  with  their  derivative  acetone  constitute 
the  '"acetone  bodies.'^  That  these  substances  are  actually  stages  in  the 
breakdo\\Ti  of  the  fatty  acids  is^  strongly  indicated  by  the  work  of  Ivnoop, 
wdiose  hypothesis  of  p-oxidation  seems  to  account  satisfactorily  for  the 
final  stages  in  the  prcce3s  of  oxidation  and  breakdown  of  the  fatty  acids. 
For  the  stages  between  we  can  only  surmise.  As  pointed  out  hy  Loathes 
the  introduction  of  double  bonds  produces  points  of  weakness  in  the  long 
chains  where  oxidation  with  subsequent  breaking  readily  takes  place,  pro- 
ducing shorter  chain  mono-  and  dicarboxy  acids.  (In  this  connection  it 
is  interesting  to  note  that  in  such  a  process  of  oxidation  and  breaking 
down,  only  one  monocarboxy  acid  would  be  produced  from  a  long  chain 
fatty  acid,  the  other  fragments  being  dicarboxy  acids.  Thus  from  an  un- 
saturated fatty  acid  of  the  linoleic  series  such  as  Hartley  finds  in  the  liver, 

II    H         H    n 

CH. .  (CII>)^ .  C  =  C  .  dig  .  C  =  0  .  (CHg)^  .  COOH 

there  would  be  formed, 

CHo .  (CTIo)4 .  COOH       CH2  .  (C00II)2       (CIIo)^  .  (COOH)^ 

caproic  acid  malonic  acid      and      azelaic  acid 

of  which  the  dicarboxy  acids  would  presumably  have  a  different  type  of 
metabolism  from  the  monocarboxy  acids.) 


JS'OEMAL  FAT  METABOLISM  200 

Knoop's  hypothesis  that  the  fatty  acid  chains  are  broken  down  two 
carbon  atoms  at  a  time  is  supported  by  the  following  evidence  (Knoop,  F. 
(a)  11)04-05.  ]\raking  use  of  benzol  derivatives  of  the  fatty  acids  which  are 
utilized  with  much  more  difficulty  in  the  organism  than  the  fatty  acids 
tlicnij^elves,  he  found  that  the  fatty  acid  side  chains  on  the  benzol  nucleus 
are  l)roken  down  two  carbon  atoms  at  a  time  and  that  the  bi-eaking  is  pre- 
ceded by  oxidation  at  the  P-carbon  atom.  Oxidation  of  the  fatty  acids  in 
vitro  usually  takes  place  at  the  a-carbon  atom,  and  Kn<K)p's  theory  was  re- 
ceived skeptically  by  chemists  until  further  work  by  Dakin  confinned  his 
results  both  on  animals  and  in  vitro,  and  indicated  that  |3-oxidation  is  pro1>- 
al)ly  the  common  type  of  oxidation  of  the  fatty  acids  in  the  animal  organ- 
ism. The  theory  adequately  explains  the  appearance,  in  diabetes  and  other 
conditions,  of  P-oxybutyric  and  its  derivatives,  which  are  regarded  mainly 
as  residues  of  the  fatty  acids  which  have  escaped  complete  combustion 
because  of  an  abnormality  in  metabolism.  Later  work  has  shown  that 
certain  gToups  in  the  protein  molecule  may  also  form  "acetone  bodies," 
but  it  is  believed  that  this  source  is  relatively  unimportant. 

The  fact  that  the  fatty  acids  are  broken  down  two  atoms  at  a  time 
and  the  fact  that  naturally  occurring  fatty  acids  contain  even  numbers 
of  carbon  atoms  would  render  it  probable  that  they  were  built  up  two 
carbon  atoms  at  a  time,  affording  a  basis  for  a  theory  of  fatty  acid  syn- 
thesis from  carbohydrates  in  support  of  which  there  is  considerable  experi- 
mental evidence.  That  fat  is  formed  from  carbohydrate  has  Ions:  been 
known  empirically  since  farm  animals  are  ordinarily  fattened  on  a  diet 
which  consists  mainly  of  starch ;  and  scientifically  acceptable  proof  was 
furnished  by  Lawes  and  Gilbert  many  years  ago.  The  probable  mechanism 
of  the  synthesis  has  been  indicated  by  changes  which  take  place  readily 
in  carbohydrates.  Thus  sugars  readily  yield  lactic  acid  by  various  treat- 
ment— action  of  bacteria,  of  weak  alkalies,  etc.,  and  lactic  acid  in  turn 
breaks  down  readily  to  acetaldehyd.  The  acetic  aldehyd  by  aldol  con- 
densation may  be  made  to  forai  (3-hydroxybutyric  aldehyd,  which  by 
shifting  of  the  oxygen  atom — simultaneous  oxidation  and  reduction — 
yields  butyric  acid.  The  butyric  acid  femientation  of  dextrose  or  lactic 
acid  observed  by  Pasteur  may  probably  be  explained  iu  this  way.  The 
likelihood  of  this  procedure  being  the  true  method  of  synthesis  of  the 
fatty  acids  is  rendered  probable  by  the  work  of  Kaper  (1006-07),  who 
showed  that  in  addition  to  butyric  acid,  caproic  and  caprylic  acids  are 
formed,  and  that  the  synthesis  of  higher  fatty  acids  may  be  brought  alx>ut 
ii-i  vitro  from  aldol  and  therefore  from  acetaldehyd.  Smedley  has  raised 
objections  to  the  assumption  that  the  higher  fatty  acids  are  formed  from 
acetaldehyd  by  aldol  condensation,  basing  her  objection  on  the  fact  that 
the  aldol  condensation  when  applied  to  the  higher  aldehyds  m  vitro  pro- 
duces branched  chains  instead  of  straight  chains,  also  that  no  free  aldehyds 
(except  sugars)   are  found  in  the  living  organism.     She  suggests  as  the 


210  W.  Jl.  BJ.OOJt 

probable  intermediate  stage  between  carbohydrate  and  fatty  acid,  pyruvic 
acid  CIIj . CO . COOII,  which  she  lias  shown  to  produce  straight  chain 
higher  fatty  acids  iri  vitro  by  condensation  with  fatty  aldehyds.  To  get 
around  her  own  objection  that  aldehyds  are  not  found  in  living  organisms 
she  postulates  that  cond>ination  is  affected  with  aldehyds  in  the  ^'nascent'' 
condition.  The  earlier  suggestion  of  Emil  Fischer  that  the  higher  fatty 
acids  are  formed  by  direct  condensation  of  sugar  molecules  with  reduction 
and  oxidation  has  neither  chemical  nor  bioloj^ical  evidence  to  support  it, 
but  is  nevei-theless  interesting  since  the  most  widely  distributed  fatty 
acids,  stearic,  oleic,  linoleic,  etc.,  are  those  containing  eighteen  carbon 
atoms  in  tlio  chain,  while  the  sugar  most  commonly  present  is  a  hexosc. 
It  seems  likely  that  the  higher  fatty  acids  may  be  synthesized  in  more 
than  one  way  and  that  the  intermediate  ones  may  be  formed  either  by 
synthesis  from  the  lower  ones  and  the  elementary  substances  or  by  de- 
gradation from  the  higher  members. 


Pat  Excretion 

Probably  no  one  of  the  foodstuffs  is  completely  burned  in  the  animal 
organism.  The  occurrence  in  the  urine  of  residues  of  the  protein  molecule 
which  still  have  some  caloric  value — urea,  uric  acid,  traces  of  amino 
acids,  etc. — is  well  known.  The  much  debated  question  of  the  presence 
of  sugar  in  normal  urine  has  recently  been  convincingly  answered  in  the 
affirmative  by  Benedict.  Traces  of  fatty  acids  are  present  in  normal 
urine  but  except  in  rare  conditions  the  amounts  found  are  not  impor- 
tant. Fatty  material,  mainly  in  the  fomi  of  fatty  acids,  is  always 
present  in  the  feces  in  considerable  amounts.  This  fat  may  come  from 
at  least  three  sources:  (a)  undigested  material  from  the  food,  (b)  from 
the  cellular  material  of  the  gastro-intestina]  tract — epithelial  cells,  bodies 
of  bacteria,  etc.,  and  (c)  a  true  excretion  of  wnused  or  unusable  fat.  To 
what  extent  food  fat  passes  the  tract  unabsorl>ed  under  normal  conditions 
cannot  be  stated,  but  it  seems  likely  from  considerations  discussed  earlier 
in  the  chapter  that  fats  suitable  as  regards  consistency  and  composition 
are  completely  digested  and  absorbed.  Some  of  the  feces  fat  undoul)tedly 
arises  from  cellular  nuiterial,  •  but  there  is  also  considerable  evidence  to 
show  that  there  is  a  true  excretion  of  fat  into  the  intestine.  In  fasting, 
fat  is  present  in  the  feces  to  the  extent  of  abomt  %  »f  the  total  dry  matter. 
Isolated  rings  of  intestine  with  their  bloo«i  supply  intact  fill  up  with 
material  similar  to  feces  containing  about  35  per  cent  of  their  content  of 
fat,  an  amount,  when  calculated  for  the  wl«o3e  intestine,  agreeing  with 
the  figure  for  fat  in  fasting  feces  (Hennaim,  1880-00).  Loops  of  intestine 
with  one  or  both  ends  opening  outside  the  aMominal  wall  secrete  a  fluid 
which  contains  fattv  material.    In  some  animiak  the  excretion  flows  freely 


KOinrAL  FAT  METABOLISM  211 

;ni<l  may  ])e  collected  from  the  fistula;  in  others  it  is  viscous  and  must  he 
washed  out.  lu  one  doi;  used  hy  the  writer  in  which  the  fistula  (ahout  14 
inches  of  jejunum)  had  heen  estahlished  for  ahout  a  year,  a  total  of  0.72 
i:m.  of  fatty  material,  mainly  soaps,  was  collectefl  from  the  fistuhi  in  live 
(hiys.  At  least  two  kinds  of  soap  were  present,  one  in  the  fonn  of  soft 
lumps,  being  probably  palmitate,  and  tlie  otlier  in  solution  yieldin«r  a  li(|uid 
fatly  acid  and  lieini»;  probably  oleate.  Exi»erimenfers  from  rime  to  time 
have  reported  cases  in  which  more  fat  appeared  in  the  feces  than  was 
present  in  the  food. 


The  Carbohydrates  and  Their  Metabolism 

A,  L  Ringer  and  Emil  J.  Baumann 

Introduction — Chemistry  of  the  Carbohydrates — Classification  and  Xomen- 
clature — Constitution — Isomerism  and  Asymmetry — ^futarotation — Isom- 
erism of  the  Aldohexoses — Chemical  Reactions  of  the  Carbohydrates 
— Synthesis  and  Degradation  of  Carbohydrates — Glucosides — Special 
Properties  of  Monosaccharides — ITexoses — Methyl  Glucosides — Pentoses 
— Disaccharides — Polysaccharides — Digestion  of  Carbohydrates — Salivary 
Digestion — Action  of  Ptyalin — Gastric  Digestion  of  Carbohydrates — In- 
testinal Digestion  of  Carbohydrates — Absorption  of  Carbohydrates — ^The 
Sugar  of  the  Blood — Carbohydrate  Tolerance — Carbohydrate  Tolerance 
Standard — -Glycogenesis  and  Carbohydrate  Tolerance — Glucolysis  and 
Carbohydrate  Tolerance — Endocrine  and  Nerve  Control  of  Glycogenesis, 
Glycogenolysis  and  Glucolysis — Influence  of'  the  Thyroid  Glands — Influ- 
ence of  the  Pituitary  Gland — The  Intermediary  ^letabolism  of  Carbo- 
hydrates— The  Formation  from  Carbohydrate — The  Function  of  Carbo- 
hydrate in  the  Diet — Influence  of  Carbohydrate  on  Intermediary  Metab- 
olism of  Fat — Antiketogenesis. 


The  Carbohydrates  and  Their 
Metabolism 


A.  I.  EIXGER 

AND 

EMIL  J.  BAUMAXX 

HmW   YORK 

1.     Introduction 

The  carbohydrates,  or  sugars  as  they  are  called,  are  found  in  all  cells. 
The  name  sugar  is  commonly  applied  to  anything  having  a  sweet  taste,  as 
sugar  of  lead  for  lead  acetate.  It  is  now  used  non-technically  for  some 
of  the  simpler  members  of  this  group — -milk  sugar  (lactose),  cane  sugar 
(sucrose),  etc.  The  generic  name  carbohydrate  is  derived  from  the  fact 
that  these  substances  are  composed  of  the  elements  carbon,  hydrogen  and 
oxygen,  the  latter  two  being  in  the  proportion  in  which-  they  exist  in 
water — two  atoms  of  hydrogen  to  one  of  oxygen — in  most,  though  not  all 
cases ;  in  other  words,  they  are  hydrates  of  carbon  or  carbohydrates. 

In  the  plant  world  the  carbohydrates  are  found  sers'ing  two  main 
functions :  lirst,  they  act  as  the  main  constituent  of  supporting  tissues  or 
framework  of  the  cell — cellulose;  second,  reserve  food  is  stored  up  in  this 
form  as  starches.  In  the  animal  world,  carbohydrates  no  longer  act  as 
supporting  structures  of  cells.  !N'itrogenous  substances,  belonging  mainly 
to  the  class  called  proteins,  take  the  place  of  them,  but  they  are  found 
as  a  form  of  reserve  food — glycogen  or  animal  starch.  It  is  interesting 
to  note  that  in  some  of  the  lower  animal  fonns  (in  some  molluscs),  the 
supporting  tissue,  chitin,  is  a  substance  that  may  be  considered  as  an 
inteiTaediate  of  the  proteins  and  carbohydrates.  It  is  a  nitr6genous  carbo- 
hydrate from  w^hich  glucosamine  can  readily  be  obtained.  Carlx>hydrates 
are  also  found  in  the  nuclei  of  all  cells,  in  nucleic  acids,  and  one  of 
the  simplest  sugars,  glucose,  is  almost  always  present  in  tissue  fluids. 
They  are  the  simplest  organic  substances  found  in  living  matter  and  the 
most  abundant.  All  the  more  complex  constituents  of  cells  are  derived 
from  them  ultimately. 


213 


2U  A.  T.  RIXGEll  AND  EMIL  J.  BAUMAXN 

2.     Chemistry  of  the  Carbohydrates 

Classification  and  Nomenclature. — The  carbohydrates,  as  has  already 
bcfii  indicated,  are  composed  of  carbon,  hydrogen  and  oxygen,  usually 
having  the  fonnula  (/xliai.Oti.  There  are  many  substances  having  this 
lieiieric  fonnula  that  are  not  carbohydrates,  e.  g.,  CHa-CirOII-COOII 
(lactic  acid),  but  a  more  comprehensive  definition,  will  develop  as  the 
subject  is  presented. 

Carbohydrates  may  be  divided  into  three  great  groups,  according 
to  the  number  of  saccharide  groups  (simple  sugars)  they  contain: 
monosaccharides,  disaccharides,  polysaccharides.  Important  monosac- 
charides are  d-glucose  or  grape  sugar,  d-fnictose  or  levulose,  d-mannose, 
d-arabinose  and  d-ribose.  Common  disaccharides  are  sucrose  or  cane 
sugar  (also  known  as  saccharose),  lactose  or  milk  sugar,  and  maltose  or 
malt  sugar.  These  comparatively  simple  carbohydrates  are  often  called 
sugars.  Common  polysaccharides  are  cellulose,  starches,  dextrins,  glyco- 
gen and  glims. 

The  monosaccharides  are  further  divided  according  to  the  number 
of  carbon  atoms  they  contiiin— trioses,  pentoses,  hexoses,  octoses,  nonoses, 
etc.  Those  found  occurring  in  nature  are  chiefly  the  tetroses,  pentoses, 
hexoses  and  a  few  heptoses.  Some  of  the  carbohydrates  have  the  proper- 
ties of  an  alcohol  and  aldehyde,  others  of  an  alcohol  and  a  ketone,  and 
these  are  known  respectively  as  aldoses  and  ketoses.  So  an  aldehyde  sugar 
having  six  carbon  atoms  would  be  called  an  aldo-hexose,  and  a  ketone 
sugar  having  six  carbon  atoms  would  be  called  a  keto-hcxose. 

Constitution. — In  the  discussion  of  the  stnicture  of  the  carbohydrates, 
d-glucose  will  be  used  as  a  typical  example  of  the  aldoses.  The  manner 
in  which  the  elements  carbon,  hydrogen  and  oxygen  are  combined  in 
these  compounds  has  been  a  problem  which  has  gradually  been  elucidated 
during  the  last  century,  although  the  last  w^ord  on  the  subject  has  not  yet 
been  written.  The  first  step  in  the  solution  of  the  problem  may  bo  said 
to  have  been  devised  by  Liebig,  when  he  gave  forth,  his  method  for  deter- 
mining the  percentages  of  carbon  and  hydrogen  in  organic  matter.  With 
the  development  of  definite  concepts  of  valency  by  Kekule  and  others, 
and  of  the  asymmetric  carbon  atom  by  Le  Bel  and  Van't  Hofl:'  in  1875,  a 
fairly  definite  idea  of  the  stnicture  of  these  substances  became  known. 

As  shown  by  elementary  analysis,  glucose  has  the  empirical  formula 
CIToO,  and  the  molecular  formula,  CoHjoOo,  as  shown  by  molecular 
weight  detenninations,  by  the  cryoscopic  and  ebullioscopic  methods.  \Mieu 
treated  with  acids,  acid  anhydrids  and  acid  chlorides,  glucose  forms  ethe- 
real salts  or  esters,^  e.g.,  acetyl  chloride  will  form  a  glucose  pentacetate, 
CeH-OCO.CO.CILOs- 

*  Alcohols  are  compounds  of  carbon  containing  one  or  more  hydroxy!  groups,  as 
CHaOII,  methyl  alcohol.    An  organic  acid  is  a  compound  containing  a  carboxyl  group 


THE  CAEBOHYDIIATES  AND  THEIR  METABOLISM  215 

O 

// 
C  — H 

I 
HCO.OC  — CH3 

I 
HCO.OC  — CH3 

I 
HCO.OC  — CH3 

I 
HCO.OC  — CII3 

I 
HCO.OC  — CII3 

II 

That  is,  glucose  behaves  like  a  compound  having  five  alcohol  (OH)  groups 
here,  and  Bertlielot,  who  first  prepared  the  acetates  of  glucose,  called  the 
sugar  a  pentatomic  aldehyde  alcohol.  When  acted  upon  by  metallic 
hydroxides,  glucose  fonns  compounds  resembling  alcoholates,  further  dem- 
onstrating the  presence  of  alcohol  groupings. 

Glucose  is  reduced  by  sodium  amalgam  to  form  a  hexahydric  alcohol, 
which  in  turn  may  be  reduced  by  hydr iodic  acid  to  iodohexane,  a  derivative 
of  normal  hexane,  which  indicates  that  glucose  is  a  noniial  chain  com- 

(COOH).  Acids  and  alcohols  react  forming  ethereal  salts  or  esters,  much  as  acids 
and  bases  react  to  form  salts,  thus: 

CH3OH  +  CH3COOH  ^  CH3COOCH, 

methyl  alcohol  acetic  acid  methyl  acetate  (ester) 

O 

Substances  having  the  group  — C  are  called  aldehydes,  and  those  that  contain 

i  ^" 

the  carbonyl  group  CO  are  known  as  ketones.  A  fundamental  distinction  between  alde- 
hydes and  ketones,  is  that  when  they  are  oxydized,  aldehydes  yield  acids  containing  the 
same  number  of  carbon  atoms  as  the  original  substance  while  ketones  break  up  on  oxi- 
dation, yielding  products  which  do  not  contain  as  many  carbon  atoms  as  the  original 
substances.    Thus: 

O 

CH,CH,C         -f  O-^CHaCH.COOH 

H 
propyl  aldehyde  propionic  acid 

CH, 

CO  -f  3  O  _>  CH3CO6H  +  HCOOH 

CH3 

methyl  ketone  acetic  and  formic  acids 

(acetone) 


210 


A.  I.  lUAGEll  AKD  EMIL  J.  BAU:MANN 


Table  I. — Classification  of  Carbohydrates 


xates 


1.  Monosaccharides 


\2,  Dimccliarides 


3.  Pohj saccharides 


1. 


B loses 
Trioses 


3.  Tetroses 


4.  Pentoses 


5.  Hexoses    - 


6. 


aldose  (p:lvcolicalcle]iy(le) 

Jaldose  (glycerose) 

1  ketone  (ditjxyacctone) 
aldose  (erytiirose)  ; 

ketose  (erythrulose) 
aldoses  (arabinose,  xylose,  ri- 
ketose  (arabimilose)  bose) 

aldoses  (glucose,  galactose,  man- 
nose) 
ketoses  (fructose,  sorbose) 
-p.  /aldoses  (mannoheptose,  gluco- 

XXt  1/10003       I         1  .  V 

^  {     beptose) 

Type  1.    Aldehyde  r/roup  functional 

Maltose  (glucose  and  glucose) 
Isomaltose  (glucose  and  glucose) 
Lactose  (glucose  and  galactose) 
Turanose  (glucose  and  fructose) 

Type  2.    Aldehyde  not  functional 

Sucrose  (glucose  and  fructose) 
Trehalose  (glucose  and  glucose) 
Type  1.     ^lannotriose  (glucose  and  galac- 
tose and  galactose) 

1.  Trisaccbar-J  fKaffinose  (galactose  and  glu- 
ides                Im        2    i  cose  and  fructose) 

^^     '   jMelicitose  (glucose  and  glu- 
[  cose  and  fructose) 

2.  Tetrasac-      fStacbyose  (fructose  and  glucose  and 
cbarides  \  galactose  and  galactose) 

Dextrins 


3.  Colloidal 

Polysaccbarides 


Glycogen 
Starches 
Celluloses 
Gums 


THE  CARBOHYDKATES  AXD  THEIR  METABOLISM  217 

|K)nii(l.  By  oxidizin^t!:  jilucosc  \vith  bromine,  liliiconic  acid  is  obtained. 
This  has  the  same  number  of  carbon  atoms  as  glucose,  and  in  this  way  the 
presence  of  an  ahh'hyrlc  is  indicated,  a  fact  wliich  is  confirmed  by  oxidizing 
ghicosc  with  nitric  acid  to  saccharic  acid,  a  dicarboxylic  acid,  also  con- 
taining six  carbon  atoms. 

C,II,,0, +  0 ^C«H,„Oj 

Ghicose  Gluconic  Acid 

CJIioO, +  0 — ^c,.nioO,, 

Gluconic  Acid  Saccharic  Acid 

Owing  to  the  stability  of  glucose  it  may  be  assumed  that  each  hydroxyl 
group  is  attached  to  a  ditl'erent  carbon  atom,  and  as  glucose  is  a  derivative 
of  nomial  hexane,  as  shown  above,  its  formula  may  be  written 

CHO 

I 
CH— OH 

I 
CH— OH 

I 
CH— OH 

-  I 
CH— OH 

I 
CHo  —  OH 

This  formula  was  originally  proposed  by  Baeyer  (1)  and  Fittig  (2)^ 
But  glucose  is  far  less  active  than  might  be  expected  of  a  compound  that 
is  an  hydroxy  aldehyde.  Thus  it  does  not  react  easily  with  sodium  sulphite, 
pyrotartaric  acid,  nor  with  phenylhydrazineparasulphonic  acid  as  might 
be  expected  of  a  substance  having  the  fonnula  shown.  It  does  not 
undergo  Perkins'  reaction  for  aldehydes  with  acetic  anhydride  and  so- 
dium acetate.  Aldehydes  are  generally  more  volatile  than  the  corre- 
sponding alcohols.  This  is  not  true  of  glucose.  Moreover,  glucose  and 
many  of  its  derivatives,  as  shall  be  seen  presently,  occur  in  two  isomeric 
forms  which  exliibit  no  aldehyde  properties  at  all.  This  difficulty  was 
overcome  by  Tollens'  (1883)  suggestion  of  a  ring  (the  y-oxide  or  y-lactone) 
fonnula  for  glucose.     This  formula  has  now  been  generally  adopted.     On 

-The  presence  of  a  ketone  group  (CO)  in  carbohydrates  waa  first  demonstrated 
by  Kiliani  in  1885  when  ho  showed  that,  unlike  gluco:>ie,  wliich  owing  to  its  aldehydic 
nature  yields  compounds  with  the  same  number  of  carbon  atoms  when  oxidized,  fructose, 
under  simihir  conditions,  yeilds  a  number  of  products  having  less  than  the  same 
number  of  carbon  atoms  than  tlie  original  substance,  as,  for  instance,  trihydroxy- 
butvric  acid. 


218 


A.  1.   RIXGEH  AXI)  EMIL  J.  I^AFMAXX 


tlio  basis  of  this  con fipi ration  it  is  assuniod  that  glucose  may  readily 
behave  like  an  aldehyde  by  breaking  the  yoxido  ring,  thus: 


a  carbon 
(5  carbon 
7  carbon 
6  carbon 


H 

HO— C— OH 

I 
HCOH 
-f  water        I  —  water 


■^  HOCll 


CH.OH 


Closed  ring  or 
Y-oxide  form 


water         |  +  water 

HCOH 

I 
HCOH 

I 
CH2OH 

Aldehydrol 


C 

|\H 
HCOH 

I 
HOCH 

I 
HCOH 

I 
HCOH 

I 
CH2OH 

Aldehyde 


An  intermediate  aldehyde-hydrate  or  aldehydrol  form  is  believed  to 
result  by  hydrolysis,  and  from  this  in  turn  the  aldehyde  fonn  originates. 
The  action  is  a  reversible  one,  and  it  is  assumed  that  when  an  agent  that 
will  act  upon  the  aldehyde  group  is  added  to  an  aqueous  solution  of  glucose, 
the  small  amount  of  aldehyde-hydrate  present  is  acted  upon,  thereby  dis- 
turbing the  equilibrium.  A  fresh  quantity  of  the  hydrate  is  formed  and 
so  the  process  is  kept  up. 

Isomerism  and  Asymmetry. — Bodies  having  the  same  elementary  com- 
position, but  possessing  different  properties,  are  called  isomers  or  isome- 

Cll,\ 
rides.     Thus  ethyl  alcohol  Cn.>  and  methyl  ether  O  are  isomers. 

I  CH,/ 

CH2OH 
Both  have  the  empirical  formula  of  CoHoO.  When,  however,  in  addition 
to  having  the  same  number  of  atoms  of  the  same  kind,  these  atoms  are  ar- 
ranged ill  the  same  general  way,  so  that  each  compound  has  the  same  chemi- 
cal groups,  and  consequently  similar  chemical  properties,  but  the  ''space 
relationships"  of  these  groups  within  the  molecule  are  different,  such  sul>- 
stances  are  said  to  be  stereoisomeric. 

Sugars  illustrate  this  fonn  of  isomerism  especially  well.  For  example, 
glucose  and  galactose  are  both  aldohexoses.  They  have  the  same  empirical 
formula)  and  the  same  chemical  groups,  but  the  space  relationships  or 
configuration  of  these  groups  differ. 

These  differences  are  illustrated  in  the  followins:  structural  foimulas : 


THE  (JARBOIIYDKATES  AND  THEIR  METABOLISM  219 
O  O 

%  ^\ 

!     H  I     II 

IICOH  HCOH 

I  I 

IIOCH  HOCII 

I  .  I 

HCOH  HOCII 

I  I 

HCOII  HCOH 

I  I 

CHoOH  CILOH 

d-Glucose  d-Galactose 

Pasteur  was  the  first  to  clearly  demonstrate  the  importance  of  the 
relationship  of  the  atoms  to  one  another  in  the  molecule,  and  added  one 
of  the  most  fundamental  facts  concerning  the  structure  of  the  molecule  to 
the  chapter  of  chemistry.  To  biochemistry,  or  for  that  matter  to  all  medi- 
cal sciences,  Pasteur's  contribution  on  this  fascinating  subject  is  of  supreme 
importance,  and  to-day  we  are  really  only  beginning  to  appreciate  how 
important  molecular  structure  is  in  metabolism. 

While  Pasteur  was  studying  crystalline  structure  (in  1848)  he  investi- 
gated the  tartaric  acids.  Two  forms  of  tartaric  acid  were  known  then — ■ 
that  obtained  from  wine,  which  rotated  the  plane  of  polarized  light  to  the 
right,  and  that,  called  racemic  acid,  having  the  same  composition,  and  no 
action  on  polarized  light.  Ho  expected  that  these  two  forms  of  tartaric 
acid  would  have  different  crystalline  fonns.  He  worked  with  the  sodium 
ammonium  salts  of  these  acids  and  found  that  the  ordinary  tartaric  acid 
from  grapes  had  pretty  much  the  same  form  as  racemic  acid.  However, 
closer  examination  of  the  crystals  of  racemic  acid  showed  that  there  were 
really  two  types  present,  one  having  a  pair  of  diagonally  opposite  facets 
so  arranged  that  if  superimposed  upon  the  other,  these  facets  would  not 
correspond.  In  the  one  type,  one  of  these  facets  was  on  the  right  side, 
and  in  the  other  type  of  crystal,  the  corresponding  facet  was  on  the  left 
side.  And  one  of  the  fonns  of  racemic  acid  proved  to  be  the  same  as  the 
optically  active  tartaric  acid  obtained  from  wine. 

Pasteur  then  separate«l  the  two  types  of  crystals  found  in  racemic 
acid,  studied  their  behavior  toward  polarized  light,  and  discovered  that 
in  one  case  the  plane  of  polarized  light  was  rotated  to  the  right,  and  in 
the  other  the  plane  of  polarized  light  was  rotated  to  the  left.  The  ditTer- 
ence  between  the  two  forms  of  tartaric  acid  thus  became  apparent.  The 
natural  tartaric  acid  rotates  the  plane  of  polarized  light  to  the  right; 


220 


A.  I.  KIXGEK  AXD  E.MIL  J.  EAU^LANN 


the  form  isolated  by  Pasteur  from  raccmic  acid  rotates  tlie  piano  of 
polarized  li^lit  to  the  left ;  racemic  acid,  oj)tically  inactive,  is  in  reality  a 
mixture  of  both — the  dextrorotatory  and  the  levorotatory. 

Here  are  two  substances  having  the  same  empirical  formula  and  the 
same  chemical  groups  similarly  arranged,  but  their  physical  properties-^ 
their  crystalline  form  and  behavior  toward  polarized  light — are  markedly 
different.  It  will  likewise  be  found  that  their  chemical  properties  are 
different.  These  are  not  due  to  differences  in  chemical  composition,  but 
to  difl'erences  in  molecular  form.  ]More  than  a  quarter  of  a  century 
later,  Le  Bel  and  Van't  Iloff  independently  fonnulated  the  hypothesis  of 
the  asymmetric  carbon  atom,  on  the  basis  of  Pasteur's  fundamental  dis- 
covery.    Only  such  compounds  of  carbon  as  have  so-called  asvmmetric 


Fig.  1.  Illustrating  two  carbon  atoms  with  their  four  valences  taken  up  by 
four  different  radicles  arranged  in  such  a  way  that  the  space  relationship  of  the 
two  is   like  that  of  a  mirror  ima;r.e. 


carbon  atoms  can  exist  in  stereoisomeric  forms.  An  asymmetric  carbon 
atom  is  one  that  has  four  different  atoms  or  atomic  groups  attached 
to  it. 

If  the  carbon  atom  is  pictured  as  lying  at  the  center  of  a  tetrahedron 
with  the  four  atoms  attached  to  it  at  the  apices,  it  is  possible  to  arrange' 
these  in  two  ways,  one  of  which  is  the  mirror  image  or  antipode  of  the 
other  (Fig.  1). 

]\Iolecular  asymmetry  of  this  type  is  most  readily  recognized  by  means 
of  the  action  of  such  substances  on  polarized  light.  Compounds  having  one 
or  more  asymmetric  carbon  atoms  usually  have  the  power  of  rotating  the 
plane  of  polarized  light  except  when  one  asymmetric  carbon  atom  is 
neutralized  by  one  or  more  other  asymmetric  atoms.  However,  one  does 
not  meet  such  substances  very  often.  One  of  the  first  cases  know^n  in 
which  one  asymmetric  carbon  atom  neutralizes  another  is  mesotartaric 
acid,  discovered  by  Pasteur.  The  various  tartaric  acids  may  be  repre- 
sented thus: 


THE  CARBOHYDRATES  AND  THEIR  METABOLIS^^L  221 


COOH 

COOH 
j 

COOH 
1 

II  —  G  —  Oil 

HO      C      H 

1 

H— C  — OH 

1 

HO  —  C  —  II 

H  —  C  —  OH 

j 

1 
H       C       OH 

1 

COOH 

COOH 

COOH 

d-Tartaric  acid 

1-Tai*taric  acid 

^fesotartaric  acid 

It  is  found  that  optical  antipodes  rotate  the  plane  of  polarized  light  in 
equal  amounts  but  in  opposite  directions,  so  that,  if  one  has  a  mixture  of, 
equal  parts  of  the  dextro-  and  levorotatorv  forms  of  a  compound,  the  result- 
ing mixture  would  of  course  exert  no  influence  upon  the  plane  of  polarized 
light. 

The  degree  of  rotation  varies  directly  as  the  concentration  of  the  suh- 
stance  and  inversely  as  the  length  of  the  column  of  solution  through  which 
the  observation  is  made.  It  depends  also  upon  the  temperature  (there 
being  less  rotation  in  general  as  the  temperature  increases)  and  on  the 
wave  length  of  the  light  used  in  making  observations.  The  degree  of 
rotation  for'  many  substances  is  gTcater  with  light  of  short  than  of  long 
wave  lengths.  Hence  the  necessity  of  using  a  standard  temperature  and  a 
monochromatic  source  of  light  for  making  observations.  The  unit  of 
measurement  of  rotation  of  the  plane  of  polarized  light  is  called  the  specific 
rotatory  power  and  is  defined  as  the  rotation  of  one  gram  of  substance 
dissolved  in  one  cubic  centimeter  of  solute  and  for  a  tube  one  decimeter 
in  length,  usually  at  20  degrees  centigrade  and  for  sodium  light.  It  is 
calculated  from  the  observed  angle  of  rotation,  produced  by  a  solution  of 
known  concentration,  in  a  tube  of  known  length,  by  the  following  formula : 


f"^D=^p:i 


20 


in  which  [a]        is  the  symbol  for  specific  rotation  at  20°  for  sodium  light 

(the  D  Tine  of  the  spectrum),  a  the  obser\'ed  angle  of  rotation,  P  the 
concentration  of  the  substance,  and  1  the  length  of  .the  tube  in  decimeters. 
The  solvent  is  usually  given,  as  the  angle  of  rotation  varies  somewhat 
with  different  solvents. 

Mutarotation. — Isomerism  of  Glucose. --V^^hen  pure  d-glucose,  derived 
from  natural  sources,  is  dissolved  in  water,  and  its  specific  rotation  de- 
termined at  once,  it  will  be  found  to  be  +109^.  On  standing,  the  specific 
rotatory  power  changes  slowly,  until  after  24:  lioui*s  or  more,  at  20^,  it 
becomes  +52.5°.     If  a  small  quantity  of  alkali  is  added  to  the  newly 


222 


A.  I.  RIXGER  AND  EAIIL  J.  BAOIANN 


prepared  solution,  this  eliange  will  take  place  in  a  few  minutes.  This 
phcu<;menon  was  first  observed  bj  I)ul)rnnfaut  in  184G.  By  crystallizing 
ordinarj  commercial  glucose  from  different  solvents  and  by  other  methods, 
two  different  glucoses  have  been  obtained,  having  specific  rotatory  powers 
of  +  100  and  -•-  ID  resi>ectively.  If  either  of  these  is  <lissolved  in  water, 
it  will  slowly  change  its  specific  i-otation  to  -|-  i>2.5.  This  phenomenon 
is  termed  mutan-tation  or  birotation. 

Tanret,  in  1S95  and  1806,  was  the  first  to  demonstrate  that  we  were 
here  dealing  with  more  than  one  form  of  glucose.  lie  called  the  glucose 
with  the  high  initial  specific  rotation  a  glucose,  and  the  glucose  of  the 
specific  rotatory  power  52.5  he  designated  ^-glucose.  However  it  has 
been  found  that  Tanret*s  P-glucose  was  really  a  mixture  obtained  by 
allowing  the  glucose  of  high  or  low  rotatory  power  to  reach  equilibrium. 
This  happens  when  there  are  present  37  per  cent  of  a-glucose  and  63  per 
cent  of  the  glucose  having  the  initial  specific  rotatory  power  of  +19, 
which  is  now  called  P-glucose.  The  equilibrated  mixture  of  a-and  P-glu- 
cose  is  known  as  Y-gl^^cose. 

The  difference  in  structure  of  a  and  P-glucose  is  due  to  the  difference 
in  the  positions  of  the  hydrogen  atom  and  hydroxyl  group  of  the  carbon 
atom  that  is  potentially  aldehydic.    It  may  be  represented  as  follows : 


CH^OH 
a-Glucose 


H-C-OII 

I 
HCOII 


IICOII 

I 
CH2OH 

p-Glucose 


The  conversion  of  pne  form  to  the  other  is  assumed  to  take  place  by 
the  formation  of  an  intermediary  compound,  the  exact  nature  of  which  is 
still  a  matter  of  dispute. 

Isomerism  of  the  Aldohexoses. — The  number  of  possible  stereoiso- 
meric  fonns  of  a  substance  can  be  calculated  by  the  foraiula  of  Le  Bel 
and  Vari't  Hoff.  Xumber  =  2%  where  n  is  the  number  of  asymmetric 
carbon  atoms  in  the  molecule.  If  the  open  chain  fonnula  of  glucose  is 
examined  it  will  be  found  that  it  has  four  asymmetric  cai*bon  atoms: 


THE  CArwiiOlIYJJllATES  AXD  THEIR  METABOLISM  223 

O 

< 

H 
*I1C0II 

I 
*IICOII 

I 

*IICOII 

I 

*HCOII 

I 
CIIoOlI 


Accordinoly  there  may  be  2  ^  or  IG  possible  aldohexoses.  Largely  through 
tho  researches  of  Emil  Fischer,  14  of  these  are  now  known,  although  only 
three — glucose,  mannose,  galactose — occur  naturally.  These  isomers  are 
represented  in  Table  II. 


. 

Table  II — 

-Aldohexoses 

1,     Mannitol  Series 

COH 

COH 

COH 

COH 
1 

H-C-OH 

HO-C-H 

HO-C-H 

1 

1 
H-C-OH 

H-C-OH 

HO-C-H 

-  H-C-OH 

1 

1 

Hac-ii 
1 

HO-C-H 

1 

H-C-OH 

HO-C-H 

1 

1 

H-C-OH 
1 

HO-C-II 

1 

H-C-OH 

1 

1 
HO-C-H 

1 

1 
H-C-OII 
1 

CH2OH 

CH2OH 

CH2OH 

CH2OH 

1-Mannose 

d-Mannose 

1-Glucose 

d-Glucose  ^ 

■  All  sui,'ars  known  as  d-su^^ars  are  not  necessarily  dextronitatory,  nor  ar€  all 
l-s«;^ar8  neeeasarily  levorotatory.  All  compounds  derived  from  d-glueose  by  reactions 
that  leave  the  stereochemical  structure  imchanwed  are  designated  d-compoimds,  re- 
gardless of  their  rotation,  and  similarly  for  I-forms. 


224: 


A.  I.  RIXGER  AXD  EMIL  J.  BAUMAXX 


con 

1 

con 

1 
IIO-OH 

ii-c-on 

H-C-OII 

1 

HO-C-II 

1 

1 

HO-c-ir 

j 

1 

II-C-OII 

H-C-OII 

IIO-C-II 

cii.oir 

enroll 

l-ldose 

d-Idose 

con 

I 

II-C-OII 

I 

II-C-OII 

I 

IIO-C-II 

I 

II-C-OII 

I 

CII20II 

1-Gliicose 


coil 

i 

HO-C-II 

I 
IIO-C-H 

I 
H-C-OII 

I 
HO-C-II 

I 
CII2OH 

d-GIucose 


2.     Dulcitol  Series 


COH 

1 

COH 

COH 

COH 
1 

HG-C-II 

H-C-OH 

1 

H-C-OII 

1 

1 

HO-C-H 

1 

HX'-OH 

1 

HO-C-H 

1 
H-C-OII 

1 

HO-C-H 

II-C-OII 

HO-C-H 

H-C-OII 

HO-C-H 

HO-C-H 

H-C-OII 

j 

Hac-H 

1 

H-C-OH 
j 

CH2OH 

CH2OH 

1 
CH20H 

CH.OH 

1-Galactose 

d-Galactose 

1-Talose 

d-Talose 

COH 

1 

COH 

1 

COH 

1 

COH 

1 

HO-C-H 

H-C-OII 

H-C-OH 

HO-C-H 

HO-C-H 

H-C-OH 

HO-C-H 

H-C-OH 

HO-C-H 

1 

H-C-OII 

HO-C-H 

1 

H-C-OH 

HO-C-H 

H-C-OH 

1 
HO-C-H 

1 

H-C-OH 

CII2OII 

CILOH 

1 
CII2OH 

CILOH 

1-Allose 

d-AlIose 

1-Altrose 

d-Altrose 

unknown 

unknown 

THE  CARBOHYDRATES  AxVD  THEIR  METABOLISIM:.  225 

Since  there  are  two  closed  ring  foniis  for  each  aldohexose,  the  a  and 
P  fomis,  there  should  l)e  'i2  closed  chain  aldehexwses,"*  with  which  the  16 
already  discussed  make  a  total  of  48  isomeric  aldohexoses  theoretically 
possible.  ^Jost  of  the  carhohydrates  exist  in  mare  than  one  form  and 
possess  the  power  of  mutarotatiou. 

TABLE  III 
Specific  Rotations  of  Sucajr 


Sugars 

o-form 

/3-lorm 

Equilibrated 
Mixture 

d-Glucose    

+  110° 
+    7ti^ 
+  140^ 
+    17' 
+    76° 
+  100° 
—      7° 
+  100° 
+    86° 
+  171° 

+   2tV° 

—  14° 
+  53° 
— 140° 
+  184° 

—  8° 
+   52° 
+  119° 
+  35- 
+  124" 

+    52.5° 

+    14° 

d-Galiictose    

+    81° 

d-Fruetose    

—    93°     • 

l-Arabinose    

+  104° 

d-X vlose   

+    19° 

1-Rhamnose    

+      9° 

d-Maltose  

+  137° 

d-Lactose  hydrate 

+    55° 

d-^Ielibiose    

+  143° 

d-Kibose    

+    18.8° 
+    60.5° 

Sucrose    

o  Methyl  glucoside  +157°.    /3  Methyl  glucoside  — 3Sl*^ 


Chemical  Reactions  of  the  CarlK)hydrates 

In  most  cases  glucose  will  be  used  as  a  typical  carbohydrate  in  dis- 
cussing the  reactions  which  the  carbohydrates  undergo.  (Only  those  that 
have  a  direct  interest  to  the  biochemist  will  be  presented.) 

Synthesis  and  Degradation  of  Carbohydrates. — ^lost  of  the  methods 
of  synthesizing  the  carbohydrates  we  owe  to  tlic  masterly  researches  of 
Emil  Fischer,  who  devised  most  of  the  methods  and  synthesized  a  vast 
number  of  them. 

1.  Polymerization  {aldol  condensation)  of  mmple  sugars  by  action 
of  dilute  alkali,  e.g., 


Glycerose 


Fructose 


This  reaction  is  somewhat  similar  to  one  by  which  it  is  believed  carbo- 
hydrates may  be  formed  in  plants  from  formaldehyde.  Baeyer,  in  1870, 
first  advanced  the  theory  that  the  plant  tissues  foniied  formaldehyde  from 
CO.  and  11^0.  Loew,  in  1880,  discovere<l  that  formaldehyde  (IICOII) 
and  lime  water  at  room  temperature  produced  a  sweet  substance  whicli  was 
unfeiinentable.    Fischer  later  showed  that  what  isfonned  here  is  a  acrose, 

*In  the  closed  chain  formula  there  ia  an  additional  asymmetric  carbon  atom,  so 
that  the  number  of  isomers  is  2^^  or  32. 


22G 


A.  T.  HINGE K  AND  EMIL  J.  i^AU.MANN 


which  is  the  inactive  form  of  fructose,  so  that  chemically  at  least  this  is  a 
possible  mechanism  by  which  plants  synthesi/x*  carbohydrates. 

l\  i'^ynlhesis  of  hujher  forms  fr^jw  a  loircr  niono.sarc/iarose. — Here,  a 
method  of  wi<le  application  in  chemistry  has  been  successfully  used  to 
synthesize  a  large  number  of  carbohydrates.  It  consists  in  fonning  a 
cvanhvdrin  of  a  lower  aldose  with  hvdrocvanic  acid,  hvdrolvzinir  the 
nitrile  to  form  the  corresponding  acid  and  reducing  this  substance  to  the 
next  liigher  sugar,  e.  g.,  glucose  may  be  converted  to  glucobeptose  in  this 
wav.  ^ 

CN 


110— C—H 

i\ 
IICOII 

I 

Hocir 


CN" 

^o  +  I   - 

H 


no— C—H 

I 

IICOH 

I 

HOCII 


Hydrolysis 
> 

+  2  H2O 


no 

I 

HCOH 


CHgOH 


a-Glucose    +     Hydrocyanic 
acid 


HCOH 

I 
HCOH 

I 
CH2OH 

a-Glucose 
nitrile 


COOH 

I 
HOCH 


G 

HOCH 


HCOH 

HOCH 

I 
HCOH 

I   • 
HCOH 


Reduction 
with 

sodium 
amalgam 


HCOH 

I 
HOCH 

I 
HCOH 

t 
HCOH 


CH^OH 

a^Glucoheptonic 
Acid 


CH2OH 

a-Glucoheptose 
Aldehyde  Formula 


The  ability  of  hydrocyanic  acid  to  unite  with  aldoses  is  of  considerable 
interest  physiologically.    This  acid  is  found  in  small  amounts  in  a  number 


THE  CARBOHYDEATES  AND  THEIR  METABOLISM  227 


of  plant  tissues.  It  greatly  accelerates  the  action  of  a  proteolytic  enzyme 
(papain)  which  it  may  do  by  means  of  a  reaction  somewhat  similar  to  the 
first  stage  indicated  above. 

3.  Conversion  of  a  higher  to  a  lower  monosaccharose. — By  the  action 
of  hvdroxylamine  upon  glucose,  glucose-oxime  is  produced.  This  product 
is  converted  to  gluconic  nitrile  by  the  action  of  acetic  anhydrid  and  sodium 
acetate,  removing  one  molecule  of  water  and  acetylating  the  hydi'oxyl 
groups,  forming  pcnta-acetyl  gluconic  acid.  Ammoniacal  silver  solution  re- 
moves hydrocyanic  acid  from  this  substance,  leaving  the  acetyl  derivative 
of  the  pentose  arabinose.  Ammonia  will  form  an  acetamid  arabinose, 
which  in  turn  yields  arabinose  by  the  action  of  dilute  sulphuric  acid. 


/O 

c 

|\H 
HCOII 

I 
HOCH 

I 
HCOH 

I 
HCOH 

I 
CH2OH 

Glucose 


+     OHNH2 

: ; > 

Hydroxyl- 
amin 


CH:XOH 

I 
HCOH 

I 
HOCH 

I 
HCOH 

I 
HCOH 

I 
CH2OH 

Glucose 
Oxime 


plus 


Acetic 
Anhydrid 


ir.co 


I 
HCO.OC 

I 
OCH 

I 
HCO.OC 


CH. 


CH. 


plus 


ammoniacal 

silver         CH^ 
solution 


H  — CO.OC  — CH3 

I 
CO.  OCH 

I 
HCO.OC  — CH3 


HCO.OC  — CH, 


HCO.OC  — CH, 


CII2O.OC  — CHj 


CIL,O.OC  — CH3 

arabinose  pentacetate 


By  this  reaction  glucose  has  been  converted  successively  into  arabinose, 
erythrose,  glycerose  and  glycollic  aldehyde. 

Oxidation.  Action  of  alkalies. — Most  of  the  simpler  carbohydrates 
are  unstable  in  alkaline  solution  and  undergo  a  great  variety  of  changes, 


228 


A.  I.  lUNGEK  AND  EMIL  J.  BAUMAXN 


the  exact  nature  of  them  all  not  being  known  yet.  If  the  sugars  are  treated 
with  a  weak  alkali  at  room  temperature^  a  molecular  rearrangement  takes 
place  slowly  which  is  known  as  a  tautomeric  rearrangement.  The  mechan- 
ism of  these  interesting  changes  will  be  presented  later.  If  an  aldose  or 
ketose  is  treated  with  strong  alkali,  it  becomes  yellow  or  brownish  and 
acquires  the  odor  of  caramel.  This  is  the  basis  of  ^loore^s  test  for  the 
detection  of  carbohydrates.  The  character  of  the  products  formed  varies 
with  the  strength  of  alkali  used  and  the  amount  of  oxygen  available,  for 
the  products  are  largely  oxidation  products,  the  sugar  being  a  reducing 
agent.  Over  one  hundred  degradation  substances  have  been  identified 
as  the  products  of  the  interaction  of  sodium  hydroxid  and  glucose. 

Among  others,  a  large  series  of  acids  may  be  formed,  varying  in  com- 
plexity from  carl'onic  acid,  formic  acid,  oxalic  and  lactic  acids,  to  saccharic 
and  gluconic  acids.  In  the  absence  of  much  oxygen,  products  like  glycolic- 
aldehyde  CII2OH,  glycericaldehvde   CHoOH,  glyoxal    CIIO,       oxyace- 

I  I  '  I 

CHO  CHOH  CHO 


1 


CHO 


tone  CII2OH,  etc.,  are  formed. 
I 

I 

CII, 


The  first  stages  in  the  oxidation  of  glucose  results  in  the  foraiation  of 
gluconic  and  glucuronic  acids — both  monocarboxylic  acids,  and  then  sac- 
charic acid — a  dicarboxvlic  acid. 


CIIO 


CHO 


COOH 


COOH 


CHOH 

I 
CHOH 

i 

CHOH 

I 
CHOH 

I 
CILOH 

Glucose 


CHOH 

I 
CHOH 

I 
CHOH 

I 
CHOH 

I 
COOH 

Glucuronic 
Acid 


CHOH 

I 
CHOH 

1 
CHOH 

I 
CHOH 

I 
CHoOH 

Gluconic 
Acid 


CHOH 

I 
CHOH 

I 
CHOH 

I 
CHOH 

I 
COOH 

Saccharic 
Acid 


(Glucuronic  acid  is  the  most  interesting  of  these  derivatives  physiologically. 
Many  substances  that  are  not  readily  oxidized  in  the  body,  such  as  camphor, 


THE  CARBOIIYDEATES  AND  TIIEIK  METABOLIS]^!  229 

chloral,  thymol  or  phenol,  are  excreted  in  the  urine  of  the  camivora  and 
herbivora  as  conjugated  glucuronates.  These  glucoside  *"'  compounds  ser^o 
as  a  means  of  removing  injurious  substances  from  the  body.  In  the 
plant  kingdom,  glucuronates  have  also  been  found  frequently,  e.g.,  in 
the  sugar  beet.) 

As  one  would  expect  of  ketones,  the  ketohexoses  do  not  yield  acids 
containing  the  same  number  of  carbon  atoms  on  oxidation.  The  molecule 
divides  at  the  ketone  group. 

^Monosaccharides,  and  many  disaccharides  and  trisaccharides,  are  oxi- 
dized in  acid  solution,  forming  products  similar  to  those  formed  by  the 
action  of  alkali,  but  the  oxidation  occurs  much  less  readily. 

These  reducing  powers  of  the  simpler  carbohydrates  are  utilized  in 
detecting  and  estimating  them  quantitatively.  In  alkaline  solution  they 
will  reduce  many  metallic  hydroxides,  such  as  those  of  copper,  mercury, 
bismuth,  silver,  gold,  etc.  Methylene  blue,  permanganates,  bromin, 
chlorin,  etc.,  are  also  reduced  by  sugars,  the  last  three  in  acid  solution  as 
well  as  in  alkaline  solution. 

The  carbohydrates  are  usually  estimated  quantitatively  or  detected 
qualitatively  by  an  alkaline  cupric  tartrate  solution,  known  as  Fehling 
solution  or  some  modification  of  it.  If  glucose  be  heated  with  cupric  hy- 
droxid  [Cu(0H)2]  and  sodium  hydroxid,  it  will  reduce  some  cupric  hy- 
droxid  to  cuprous  oxid  [CugO].  When  much  cupric  hydroxid  is  present 
it  will  remain  partly  dissolved  and  some  of  it  may  be  dehydrated  to  fonii 
black  cupric  oxid  [CuO]. 

Many  substances,  usually  those  having  several  hydroxyl  groups,  such 
as  tartrates,  citrates,  glycerol  and  sugars,  possess  the  property  of  dissolving 
metallic  hydroxids,  as  in  the  case  of  sodium  tartrate  and  CuCOH)^  foi-ra- 
ing  cupric  tartrate.  If  enough  sodium  tartrate  be  added  to  cupric  hy- 
droxid and  sodium  hydroxid,  all  the  cupric  hydroxid  will  dissolve.  When 
glucose  is  heated  with  such  a  solution  reduction  of  the  cupric  hydroxid 
will  occur  with  no  danger  of  formation  of  cupric  oxid,  which  might  obscure 
the  result.  Fehling's  solution  is  an  alkaline  cupric  tartrate  solution  made 
from  copper  sulphate,  sodium  potassium  tartrate  (Rochelle  salt)  and  sodi- 
um or  potassium  hydroxid.  When  kept  for  any  length  of  time,  the  tartrate 
will  reduce  the  cupric  salt.  To  avoid  this  the  copper  sulphate  is  kept  sepa- 
rate and  is  known  as  Fehling's  solution  "A^'  and  the  alkaline  tartrate  solu- 
tion as  Fehling's  solution  "B". 

The  stages  in  the  reduction  of  copper  by  reducing  sugars  are  roughly 
as  follows:  the  alkali  decomposes  the  sugar  into  a  number  of  fragments 
which  reduce  the  cupric  salt  to  insoluble  yellow  cuprous  hydroxid,  first. 
If  heating  is  continued,  the  cuprous  hydroxid  loses  a  molecule  of  water 
and  is  converted  into  red  cuprous  oxid,  which  is  also  insoluble.^ 

•A  glucoside  is  an  ether  of  glucose  (or  other  sugars)  and  an  alcohol.  On  hydrol- 
ysis with  acid,  the  sugar  is  liberated. 


230 


A.  I.  RIXGEK  Ai\D  E.MIL  J.  BAUMAXN 


2  Cu 


/OH 
\OII 


minus 
> 


CiiOII 


CuOII 


minus 


water 


Cu\ 

Cu/ 


water  and  oxygen 
blue  yellow  red 

It  should  be  noted  that  in  Fehling's  solution  both  cupric  hydroxid 
and  cupric  tartrate  exist  in  equilibrium.  As  reduction  occurs,  more  cupric 
hydroxid  is  foi*med  from  the  tartrate. 

This  reaction  is  not  completed  in  a  definite  time,  since  many  of  the 
degradation  products,  as  gluconic  acid,  are  slowly  oxidized.  So  that  when 
quantitative  estimations  are  made,  very  definite  conditions  of  concentration 
and  time  of  heating  must  l)e  ol)ser\^ed.  The  cuprous  oxid  formed  may  be 
weighed  directly  or  oxidized  to  cupric  oxid  and  this  weighed.  Or  it  may 
bo  dissolved  in  acid  and  estimated  electrolytically  or  by  a  number  of 
volumetric  methods. 

To  avoid  the  inconvenience  of  keeping  two  solutions,  Benedict  has 
substituted  sodium  citrate  for  Eochelle  salts  in  Fehling's  solution  and 
sodium  carbonate  for  sodium  hydroxid.  This  solution  keeps  indefinitely 
and  serves  very  well  for  the  qualitative  detection  of  reducing  substances. 

Reduction  of  Carbohydrates. — While  most  of  the  reactions  which  carbo- 
hydrates undergo  in  living  matter  are  oxidation  reactions,  not  an  incon- 
siderable number  are  reductions,  such  as  the  processes  whereby  micro- 
organisms, of  the  group  known  as  anaerobes^  metabolize  sugars  and  give 
off  carbon  dioxid  in  the  absence  of  air. 

Sugars  are  reduced  by  sodium  amalgam,  forming,  in  the  ease  of  hexoses, 
hexahydric  alcohols. 

//O 
C  CHoOII 

|\H  I    ' 

HCOH  HCOH 


HOCH 

I 

HCOH 
I 

HCOH 

I 
CH2OH 

Glucose 


-f  2  H 


HOCH 

I 
HCOH 

I 
HCOH 

I 
CH.OH 

Sorbitol 


A  number  of  these  alcohols  are  found  in  plants,  such  as  sorbitol,  which 
is  derived  from  glucose ;  mannitol  from  mannose ;  dulcitol  from  galactose. 
IMannitol  is  especially  widely  distributed.  In  some  fungi  there  is  more 
mannitol  present  than  glucose.     Like  the  sugars,  they  are  sweet. 


THE  CARBOHYDRATES  AXl)  TIIEIR  METABOLISM  231 

Conversion  of  Glucose  into  Fructose  and  Mannose. — Tn  the  presence 
of  alkalis^  aqueous  solutions  of  glucose,  mannose  and  fnictose  are  con- 
verted into  one  another;  slowly  at  room  temi>erature,  more  quickly  and 
with  some  decomposition  at  higher  temperatures.  These  most  interesting 
and  important  reactions  were  first  observed  by  Lohry  de  Bruyn  and  A. 
Van  Ekenstein,  1 902-1  OOo.  They  noticed  that  if  glucose  were  treated 
with  weak  alkali  at  room  temperature,  the  spe(*ific  rotation  changed  from 
+  52.5^  to  about  0°.  After  standing  several  days  or  weeks,  mannose  and 
fnictose,  as  well  as  glucose,  could  be  isolated  from  the  solution.  The 
mechanism  of  the  process  was  explained  by  Wohl.  It  will  be  remembered 
that  except  for  the  teiininal  and  a-carbon  atoms,  the  space  configuration 
of  glucose,  fructose  and  mannose  is  the  same.  The  hydrogen  atom  at- 
tached to  the  ot-carbon  in  glucose  and  mannose  "swings"  from  its  position 
to  give  rise  to  the  common  enol  form.  In  the  case  of  fructose  the  swing- 
ing H  atom  is  attached  to  the  terminal  C  atom.  The  enol  form  is  then 
converted  into  all  three  of  the  possible  hexoses. 


Clio 

HCOH 

I 
HOCH 

I         : 

HCOH 

I 
HCOII 

I 
CH^OH 

Glucose 


CHOII 

II 
COH 

I 
HOCH 

I 
HCOH 

I 
HCOH 

I 
CH2OH 

Enol  Form 


CH2OH 


CHO 

I 
HOCH 

I 
HOCH 

I 
HCOH 

I 
HCOH 

I 

CH2OH 

Mannose 


CO 


HOCH 


HCOH 

I 
HCOH 

I 
CII2OH 

Fructose 


232 


A.  L  RIXGER  AXD  E:\fIL  J.  BAUMAlsm 


Lohry  de  Enijn  isolated  anotlier  hexosc,  gliitose,  as  a  product  of  the 
action  of  alkali  on  glucose.  Glutose  is  formed  through  the  intennediate 
stage  of  a  second  enolic  forai  derived  from  fructose,  thus : 

CH2OII  CII2OH  CHgOH 

I  I  I 

CO  con  ciioH 

I  II  I 

IIOCH  COH  CO 


HCOH 

I 
HCOH 

I 
CH2OH 

Fructose 


HCOH 

I 
HCOH 


CH2OH 
Enol  Form 


HCOH 

I 
HCOH 

I 
CH2OH 

Glutose 


d-Galactose  behaves  similarly  to  d-glucose  when  treated  with  dihite  alkalis. 
An  equilibrium  ensues  between  it  and  d-talose,  d-tagatose  and  1-sorbosa 

Reactions  of  sugars  vnth  Substituted  Hydrazines. — One  of  the  most 
important  reactions  in  sugar  chemistry  for  identification  of  sugars  is 
that  which  takes  place  when  aldoses  or  ketoses  are  heated  with  an  excess 
of  phenylhydrazine  in  dilute  acetic  acid.  Quite  insoluble  definite  crystal- 
line compounds  are  formed,  called  hydrazones  and  osazones,  which  are 
readily  identified  by  their  crystalline  structure,  melting  point,  etc.  These 
osazones  (and  hydrazones)  were  the  compounds  that  enabled  E.  Fischer  to 
elucidate  the  chemistry  of  the  sugars. 

The  reaction  takes  place  in  two  stages.  In  the  first,  which  goes  on  at 
20°  C,  a  hydrazone  is  formed. 


//O 

c 

|\H 
HCOH 


CHiN.XH  — CcHe 

I 
HCOH 


HOGH     +  Cjr,XH.KH2     HOCH 


+  H,0 


HCOH 

I 
HCOH 


HCOH 

I 
HCOH 


CHoOH 
Pheny  Ihy  d  razone 


CH2OH 

Aldose       Phenylhydrazine 
(Glucose) 

An  excess  of  phenylhydrazine  (which  should  be  present)  then  acts  as  an 
oxidizing  agent,  foiToing  a  carbonyl  group  (CO)  from  a  CHOH  group. 


THE  CARBOHYDRATES  AXD  THEIR  METAB0LIS:M  233 


while  the  phenylhvdrazine  is  converted  to  anilin  and  ammonia.  The  car- 
bonyl  group  tlien  reacts  with  another  molecule  of  phenylhydrazine  to 
f oi*m  the  osazone,  thus : 

CHiX.yn  — cjig 

I 

CO 


+  CoH5XH2+2v^H, 


CH:N.:N^n— C.Hs 

I 
HCOH 

I  I 

HOCH  nocH 

I       +C6n,OTI.NH2  I 

HCOH         >         HCOH 

I  I 

HCOH  HCOH 

I  I 

CH2OH  CH2OH 

Phenylhydrazone  +  phenylhydra-   intennediary  •+-  anilin  +  ammonia 

zine  oxidation 

product 

CH  :K .  :^H  —  CfiHg  CH  iX  .XH  —  C^Hg 


CO 

I 
HOCH 

I  +CeH5NH.NH2 

HCOH  > 


C:X.XH 

I 
HOCH 

i 
HCOH 


CgHj 


+    H^O 


HCOH 


HCOH 


CHoOH  CHoOH 

Intermediary  oxida-  +  phenylhydra-  phenylosazone     +     water 

tion  product  zine 

Because  the  second  stage  of  the  reaction  is  a  process  of  oxidation,  it 
follows  that  those  sugars  that  are  most  easily  oxidized  (as  d-fructose)  most 
readily  form  osazones. 

Aldcses  and  ketoses  may  be  differentiated  by  means  of  their  reaction 
with  methyl  phenylhydrazine.  According  to  Xewberg,  ketoses  foim  osa- 
zones, while  aldoses  reach  only  the  hydrazone  stage.  The  asymmetrically 
substituted  hydrazines  do  not  act  as  oxidizing  agents.  Since  the  conversion 
of  hydrazone  to  osazone  involves  oxidation,  the  reason  for  this  behavior 
is  evident. 

Most  of  the  hydrazones  are  very  soluble  in  water  and  therefore  not 
adapted  for  identification.  Mannose,  however,  is  a  notable  exception. 
It  fonns  a  crystalline  precipitate  easily  identifiable.  The  osazones  are, 
as  a  rule,  quite  insoluble  in  water.     In  order  to  fonn  more  specific  com- 


234  A.  I.  KINGEll  AXJ)  E.MIL  J.  EAUMANN 

pounds  for  identification,  disubstituted  hydrazines  have  been  used  with 
excellent  results  in  many  cases.  Thus,  galactose  forrns  a  very  characteristic 
methyl  phenylhydriizoue  with  methylphenylhydrazine.  Other  characteris- 
tic sugar  compounds  with  the  hydrazines  are  the  diphenylhydrazone  of 
arahinose,  benzoylphenylhydrazones,  etc. 

Glucose,  fructose  and  mannose  form  the  same  phenylosazone — glucos- 
azone — as  would  of  course  be  expected  from  their  configuration,  as  previ- 
ously noted  (see  page  231 ). 

As  stated  above,  the  asymmetrically  substituted  hydrazines  do  not 
form  osazones  with  glucose  because  they  cannot  act  as  oxidizing  agents. 
Fructose,  however,  already  having  a  CO  group  present,  is  readily  attacked 
by  them. 

The  osazones  and  hydrazones,  then,  form  an  admirable  means  of  isolat- 
ing carbohydrates  from  a  solution  containing  inorganic  and  organic  sub- 
stances, i.  e.,  biological  fluids,  like  blood,  urine,  etc.  To  recover  the  free 
sugar  from  the  hydrazonc,  Fischer  .decomposed  them  with  hydrochloric 
acid  into  phenylhydrazine  and  sugar.  It  was  later  discovered  that  boiling 
them  with  benzaldehyde  and  water,  in  the  case  of  the  monosubstitiited 
hydrazones,  or  with  foiinaldehyde,  in  the  case  of  the  disubstituted  hydra- 
zones,  was  advantageous  (Heizfeld,  Ruff  and  Ollendorf),  for  then,  in- 
soluble benzaldehyde  phenylhydiazone  or  fonnylphenylhydrazone  were 
formed,  and  the  phenylhydrazones  could  be  removed  by  filtering  off  these 
insoluble  derivatives. 

CeHi205:]Sr.NH— CeH5+C6H5CHO-^CeHi,06+CeH5CH:N.XH— G^Hs 
Phenylhydrazone  +    benzaldehyde    -^    sugar    +    benzaldehyde 

phenylhydrazone 

Sugars  cannot,  however,  be  so  readily  recovered  from  their  osazones. 
When  the  latter  are  treated  with  concentrated  hydrochloric  acid  it  will 
remove  both  hydrazine  groups,  forming  an  osone: 

/o 

CH:N.NH— CcHs  C 

I  |\H 

C:N.H  — CoHs  C==0 

I  I 

HOCH       +  2  HCl  +  2  H^O-^HOCH     +  2  CeHsNH .  XHj .  HCl 

I  *  I 

HCOH  HCOH 

I  I 

HCOH  HCOH 

!  I 

CHjOH  .  CH2OH 

Phenylosazone  -j-  liydrocbloric  acid  -^  osoue  +  phenj-lhydraziue  hydro- 
and  water  chlorid 


THE  CARBOHYDRATES  AND  THEFR  METABOLISM  235 

The  osones  are  colorless  liquids  which  act  as  strong  reducing  agents. 
By  reducing  them  the  sugars  may  he  ohtairied.  Glucose,  fructose  and 
mannose  fonn  the  same  osazone,  and  so,  of  coiir-se,  the  same  osone.  When 
glucosone  is  reduced,  d-fructose  is  obtained.  These  reactions  may  there- 
fore be  used  for  converting  an  aldose  into  a  ketose. 

TABLE  IV 
Melting  Points 


OF 

HYDRAZOXES 

Arabi- 
nose 

Glucose 

Mannos« 

rjalactose 

Maltose 

Lactose 

Phenvlb vdrazone   

151-3'' 

144-6** 

186-8* 

158* 

p-bromopheny Ihydrazone    . . . 
a -niethvlphenvlh vdrazone    .. 

150<> 

164-6** 

208-10* 

168* 

IGl** 

130** 

178* 

180* 

a-etlivlphenvlhvdrazone   .... 

ir>.j° 

.... 

159* 

160* 

a-amvlphenylhvdrazone    

120* 

128* 

1.34* 

116* 

1*23* 

a  -allvlphenylhydrazone    

14.>° 

15.5* 

142* 

157* 

132* 

o-benzovlphenvlhydrazone    . 

170** 

165* 

165* 

1.54* 

128* 

di-pbenvlhvdrazone    

218** 

161* 

155* 

157* 



^-naphthylhydrazone 

141° 



157* 

167* 

176* 

203* 

OF   OSAZONES 


Phenylosazone    

p-bromophenylosazone 
p-nitrophenylosazone  . 


Arabi- 
noae 

Glucose 

Mann€>5e 

Galactose 

Maltose 

160* 
196-200* 

208* 
222* 
257* 

208* 

193* 

206* 
198* 
261* 

Lactose 
200* 
258* 


Glucosides 

A  glucosido  is  a  compound  which,  upon  hydrolysis  with  acids,  yields 
glucose  (or  another  sugar)  and  oue  or  more  other  substances.  A  great  va- 
riety of  substances  occur  in  plants,  and  to  a  lesser  extent  in  animals,  com- 
bined with  a  sugar  (usually  d-glucose).    The  general  formula  is 

/H 


HCOH 

I 
HOCH 


CHoOH 

in  which  R  may  represent  an  alcohol,  acid,  aldehyde,  phenol  or  a  large  num- 
ber of  other  substances. 


236 


A.  I.  RINGER  AND  EMIL  J.  BAUMAXN 


They  are  usually  prepared  by  extraction  with  water  or  alcohol,  and 
are  mostly  colorless,  levorotatory,  crystaliine  substances,  with  a  bitter 
.  taste. 

:^rost  glucosidcs  may  Ix?  hydrolyzcd  by  enzymes  contained  in  the  same 
tissue,  but  in  other  cells  of  the  same  plant  from  which  the  glucoside  is 
obtained.  Those  enzymes  have  the  generic  name  of  glucosidases.  The 
best  known  glucosidase  is  emulsin  of  almonds.  It  hydrolyzes  only  P-glu- 
cosides,  i.  e.,  derivatives  of  p-glucose.  Maltase  hydrolyzes  a-glucosides. 
These  specific  reactions  have  proven  very  useful  in  the  elucidation  of  the 
structure  of  many  glucosides  and  polysaccharides.  Myrosin,  obtained 
from  black  mustard  seeds,  is  another  enzyme  of  wide  application.  It 
acts  upon  many  glucosides,  all  of  which  contain  sulphur,  such  as  glucotro- 
paolin, sinalbin  and  sinigrin. 

While  d-glucose  is  found  as  a  constituent  of  glucosides  more  often 
than  all  other  sugars,  many  other  sugars  may  be  found  in  glucoside  com- 
bination. Galactose  is  a  constituent  of  a  number  of  plant  glucosides  (solan- 
in,  digitonin,  etc.)  and  of  a  group  of  substances  found  in  nerve  tissue, 
called  galactosides  or  cerebrosides.  d-Ribose  also  forms  important  gluco- 
sides, among  which  are  the  four  nucleotides,  which  make  up  plant  nucleic 
acids.  Glucosides  of  d-arabinose  and  1-arabinose,  1-xylose  and  a  number 
of  methyl  pentoses  are  also  known. 


TABLE  V 
Some  of  the  Natural  Glucostoes 


Glucoside 

M.P. 

Products  of  Hydrolysis 

Arhutin  

170** 

Phenols 
Glucose  +  hydroquinone 
Glucose  +  phloretin 

riilorhizin 

Amygdalin    

C:.H„0„N 

200** 

A  Idehydes 
2  Glucose  +  d-mandelonitrile 

•Jalapin    

G„H«,0„ 

131* 

138° 
126*^ 

Acids 
Glucose  +  jalapinolic  acid 
Rhamnose  +  mannose  -j-  strophantidin 

Strophantin    

Glucotropaolin  . . . 
Sinalbin    

Sinigrin    

C„n,ANS,K 
C,,HioO«XSJC 

Mustard  Oils 
Glucose  -f  benzyl  isothiocyanate  -\-  KIISO4 
Glucose  -f  sinapin  acid  sulphate  +  acrinyl- 

isothiocyanate 
Glucose  +  allyl  isothiocyanate  +  KIISO* 

Dioritalin 

Dioritonin    

Digitoxin   

In<lican    

C3JI«0„ 
C.JI.AN 

2ir 

225'* 
145* 

lOQ* 

Vatnous 
Glucose  +  digitalose  +  digitaligenin 
Glucose  +  galactose  -f  digitogenin 
2  Digitoxose  +  digitoxigenin 
Gluco'^e  +  indoxyl 

Saponarin 

Saponins  

Vernin 

Glucose  +  saponaretin 

Glucose  4-  galactose  4-  sapogenins 

d-Rihose  +  guanine 

C.„H„O.N, 

•Arranged  after  R.   F.   Armstrong,   The   Simple  Carbohydrates   and   Glucosides, 
Longmans,  Green  &  Co.,  N.  Y.,  1912. 


THE  CARBOHYDRATES  AND  THEIR  METABOLISM  237 


Special  Properties  of  Monosaccharides. — The  general  properties  and 
reactions  of  the  monosaccharides  have  just  been  presented  and  it  remains 
to  point  out  properties  of  the  individual  carbcdiydrates  that  are  of  special 
interest  ])ioloiiically. 

Hexoses. — Only  two  hexoses  are  found  naturally  as  such,  d-glucose  and 
d-fruetose;  d-glucose,  the  most  common  monosaccharide  occurring  in  na- 
ture, is  found  in  most  plant  and  animal  tissues.  Connnercially  it  is  ol>- 
tained  by  hydrolyzing  starch  with  dilute  acid.  This  glucose  is  a  mixture  of 
a-  and  Pglucose  and  is  called  Y-gl"cose.  It  is  readily  purified  by  one 
crystallization  from  glacial  acetic  acid  and  washing  with  alcohol.  From 
aqueous  solution  it  crystallizes  with  one  molecule  of  water.  This  form 
melts  at  80°  C.  The  anhydrous  form,  obtained  by  crystallization  from 
aqueous  solution  at  high  temperature,  melts  at  14G°  C.  One  hundred 
parts  of  water  dissolve  81.7  parts  of  anhydrous  glucose  at  15°  C,  while  in 
alcohol  it  is  rather  insoluble.  It  is  insoluble  in  ether  and  almost  insoluble 
in  acetone.     Its  aqueous  solutions  are  neutral  and  are  not  electrolytes. 

When  heated  to  170°  it  darkens  and  gives  off  much  water,  leaving 
in  the  residue  a  deliquescent  substance,  glucosan,  which  can  be  converted 
to  glucose  by  boiling  with  water  or  acids.  It  is  not  sweet  nor  does  it 
undergo  fennentation.     It  is  dextrorotatory. 

Methyl  Glucosides. — a-Methyl  glucoside  was  first  obtained  by  E. 
Fischer,  by  dissolving  glucose  in  acetone-free  anhydrous  methyl  alcohol, 
containing  0.25  per  cent  hydrogen  chlorid,  heating  it  under  pressure,  dis- 
tilling off  the  alcohol  and  obtaining  the  crystals  from  the  residual  solution. 
Both  the  «-  and  P-methyl  glucosides  are  found  in  this  reaction,  the  equilib- 
rated mixture  containing  77  per  cent  of  the  c^form. 

.  a-Methyl  glucoside  forms  rhombic  crystals  melting  at  165°  C,  easily 
soluble  in  water,  difficultly  soluble  in  cold  alcohol,  practically  insoluble  in 
ether.  Its  specific  rotation  is  +157°  and  does  not  show  mutarotation. 
It  does  not  reduce,  does  not  form  hydrazones,  nor  exhibit  any-  aldehydic 
properties  and  is  therefore  believed  to  exist  in  the  y-lactone  form  only. 


CH,  — O  — CH 


O  — CH, 


HOCH 


CILOH 
a-^Iethyl  Glucoside 


CILOII 
P-'Methyl  Glucoside 


238  A.  I.  lUNGEK  AND  EAIIL  J.  BAUMANN 

If  the  inotlier  liquid  from  tlio  methyl  gliicoside  be  concentrated  to  a 
sjrup  and  allowed  to  stand  for  several  weeks,  p-niethyl  glucoside  w^ill  crys- 
tallize out.  It  can  be  more  readily  obtained  from  this  mother  liquid  by 
treating  it  with  yeast,  which  hydrolyzes  the  a,  but  not  the  P-form,  to 
ghicose,  and  this  in  turn  is  converted  to  ethyl  alcohol  and  carbon  dioxid. 
(^-methyl  glucoside  crystallizes  with  one  half  molecule  of  water  of  crystal- 
lization, and  melts  at  108°  C.     Its  specific  mtation  is  —  32°. 

By  boiling  with  acids  both  methyl  glucosides  are  converted  into  glucose 
and  methyl  alcohol.  a-Methyl  glucoside  is  also  hydrolyzed  by  maltase,  an 
enzyme  of  yeast,  but  P-methyl  glucoside  is  not.  Emulsin,  an  enzyme  found 
in  bitter  almonds,  decomposes  the  P-methyl  glucoside,  but  not  the  a-fonn. 
This  is  a  splendid  illustration  of  the  specificity  of  biochemical  reactions. 

il/ann^se.— d-Mannose  occurs  free  in  some  plants,  but  usually  it  is 
found  as  an  anhydride  condensation  product  called  Mannan.**  It  is 
most  readily  prepared  from  the  vegetable  ivory  nut  by  hydrolysis  with 
dilute  hydrochloric  acid,  neutralizing  the  acid  and  converting  the  man- 
nose  to  the  very  insoluble,  characteristic  mannose  hydrazone,  from  which 
mannose  is  obtained  in  the  usual  way.  A  not  uncommon  form  in  which 
mannose  also  occurs  in  nature  is  as  the  alcohol  mannitol.  Mannose  can 
be  obtained  from  mannitol  by  oxidation.  This  was  the  method  by  which 
it  was  first  prepared  (Fischer  and  Hirschberger)  and  only  later  was  it 
identified  with  the  natural  product.  On  the  other  hand,  d-mannitol  may 
be  prepared  by  reduction  of  d-mannose  with  sodium  amalgam. 

In  general  behavior,  mannose  is  quite  similar  to  d-glucose.  It  forms 
the  same  phenyl  osazone,  exhibits  mutarotation  and  has  similar  solubilities. 
It  foi-ms  rhombic  crystals,  melting  at  132*^  C. 

Galactose. — d-Galactose  is  rarely  found  free  in  nature.  When  found, 
it  is  often  the  result  of  special  conditions.  For  example,  Lippmann  dis- 
covered galactose  as  a  crystalline  efflorescense  in  ivy  berries  after  a  sharp 
frost — the  first  of  the  autumn.  Usually  galactose  occurs  combined  with 
sugars  and  with  other  substances  as  galactosides.  It  is  most  commonly 
found  combined  with  glucose,  as  lactose  in  milk,  and  with  sucrose  in  the 
trisaccharide  raffinose,  in  beets. 

C12H22O11  +  H2O     >     C«H,oO«+CeH,o06 

lactose  d-glucose    d-galactose 

CisHs^Oio  +  2H2O     >     C«Hi20c  +  C,H,,0,  +  CeHi^Oc 

Eaffinose  d-Fnictose    d-Galactose    d-Glucose 

It  is  interesting  to  observe  that  the  amount  of  raffinose  found  in  the  beet 
is  increased  when  the  plant  is  subjected  to  a  sudden  frost. 

From  algti',  lichens  and  mosses,  mucilages  can  be  obtained  that  yield 

*  Polymers  ofj  the  sugars  are  given  the  name  of  the  sugar  v/ith  the  ending — an. 
Thus  common  starch  is  a  glucosan. 


THE  CAR?>OTrYDRATES  AXD  TITETR  METABOLISM  239 

galactose  on  hydrolysis.  Galactose  is  present  here  in  a  jx^lymcric  form 
called  galactans.  Galactans  are  also  found  in  certain  ginns  and  pectins. 
The  pectins  are  found  in  api>les,  pears,  beets,  carrots,  flax,  etc.,  and  these, 
on  mild  hydrolysis,  are  converted  to  pectic  acids,  the  calcium  salts  of  which 
cause  fruit  juices  to  jell.  On  hydrolysis  with  acids  they  yield  d-gakctose 
and  1-arabinose. 

It  is  usually  prepared  from  lactose  by  heating  with  two  per  cent 
sulphuric  acid,  precipitating  the  sulphuric  acid  with  barium  carbonate 
and  concentrating  the  filtrate  to  a  syrup  from  which  d-galactose  slowly 
crystallizes  in  large  prisms  with  one  molecule  of  water  of  ciystallization. 
The  hydrated  form  melts  at  118-120°  C.  From  alcoholic  solution  it 
crystallizes  in  leaflets  which  melt  at  about  165°  C.  It  is  sweet,  easily 
soluble  in  water,  but  practically  insoluble  in  absolute  alcohol  aiid  in  ether. 
It  behaves  somewhat  like  d-glucose;  it  exhibits  mutarotation,  both  ct-  and 
P-forms  having  been  prepared  and  when  treated  with  sodium  amalgam, 
it  is  reduced  to  the  alcohol  dulcitol,  whicji  occurs  naturally  in  Madagascar 
manna. 

On  oxidation  with  nitric  acid  mucic  acid  is  formed.  Mucic  acid  is 
a  very  characteristic  oxidation  product  of  galactose  (and  lactose),  with  a 
melting  point  of  212-215°  C,  quite  insoluble  in  water  (about  0..3  per 
cent  at  15°  C),  and  therefore  is  used  frequently  as  a  means  of  identify- 
ing galactose.    It  is  optically  inactive. 

Fructose. — d-Fructose  (levulose)  was  discovered  by  Dubrunfaut  in 
1847  in  the  hydrolysis  products  of  cane  sugar.  It  occurs  in  the  juices  of 
many  plants  and  fruits  with,  glucose,  especially  in  tomatoes,  certain  man- 
na and  mangoes.  In  young  sugar  cane  it  occurs  in  equal  amount  with 
glucose  and  sucrose.  As  the  cane  grows  older,  the  proportion  of  fructose 
to  the  two  other  sugars  decreases  to  about  15  per  cent  and  in  the  mature 
plant  to  about  1.5  per  cent  of  the  total  amount  of  the  three  sugars  present. 
In  honey,  glucose  and  fructose  are  found  in  nearly  equal  proportions,  to- 
gether with  a  little  sucrose  and  dextrine. 

d'Fructose  also  occurs  combined  with  other  sugars,  as  in  sucrose  (glu- 
cose and  fructose)  ;  raffinose  (glucose,  galactose  and  fructose)  ;  etc.  It 
is  a  constituent  of  certain  glucosides  and  saponins.  The  polysaccharide 
inulin,  which  is  obtained  in  quantity  from  the  tubers  of  the  dahlia,  sun- 
flower and  other  members  of  the  same  family,  is  a  fructosan^  and  hence 
yields  only  fructose  on  hydrolysis.  This  is,  *in  fact,  the  simplest  way  to 
obtain  fructose,  as  from  7  to  17  per  cent  of  inulin  is  found  in  the  roots 
of  the  dahlia.    It  is  purified  by  recrystallization  from  water  at  00-70°  C. 

Fructose  forms  anhydrous  rhombic  crystals,  tastes  almost  as  sweet  as 
cane  sugar  and  melts  between  95  to  105°  C.  It  is  very  soluble  in  water 
and  hot  alcohol,  but  only  slightly  soluble  in  cold  alcohol.  Its  aqueous  solu- 
tions exhibit  the  property  of  mutarotation  and  exist  in  solution,  presum- 
ably as  an  equilibrated  mixture  of  stercoisomeric  fonns,  but  the  two  fonns 


240 


A.  L  PtIXGER  AX  I)  EMIL  J,  P>ArMAXX 


have  not  yet  been  separated,  as  have  the  two  forms  of  ghicose  and  other 
sugars. 

Fructose  is  reduced  by  sodium  amalgam  to  two  alcohols,  d-maunitol 
and  d-sorbitol  being  formed  in  equal  quantities. 


CILOH 

1 

CH.OH 

1 

CHoOH 
1 

1 
IICOII 

1 

1 
CO 

1 

HOCH 

1 

1 

HOCII 

1          ^ 

1 

HOCH 

1 

HOCH 

HCOH 
1 

HCOH 

HCOH 
1 

HCOH 

1 

HCOH 
1 

HCOH 
1  . 

1 
CH^OH 

1 
CH.OH 

1 
CHoOH 

d-Sorbitol 

d-Fructose 

d-Mannitol 

By  oxidation  with  mercuric  oxid,  for  example,  fructose  is  converted 
to  acids  having  less  than  six  carbon  atoms,  such  as  carbonic,  foniiic,  glycol- 
lic,  oxalic,  tai'taric  and  d-erythronic  acids.  When  boiled  with  dilute  mineral 
acids,  it  forms  levulinic  acid  (CH,  — CO-^  CHg  —  CH.  —  COOH), 
formic  acid  and  other  substances.  Levulinic  acid  is  a  characteristic  degra- 
dation product  of  hexoses  and  hexosans,  and  is  used  as  a  means  of  diifer- 
entiating  between  hexoses  and  pentoses. 

Levulinic  acid  is  a  colorless  oil  that  boils  at  146°  C.  at  IS  mm.  pres- 
sure. It  crystallizes  in  rhombic  leaflets  when  placed  over  sulphuric  acid  in 
a  cool  place.  The  crystals  are  deliquescent,  easily  soluble  in  water,  al- 
cohol and  ether,  and  melt  at  33°  C. 

Pentoses. — Eight  aldopentoses  are  theoretically  possible,  and  of  these 
seven  are  known.  Pentoses  exhibit  mutarotation,  and  therefore,  like  the 
hexoses,  indicating  that  they  exist  in  an  a  and  P  and  Y  lactone  form.  Two 
of  them,  arablnose  and  xylose,  are  widely  distributed  in  the  vegetable 
world  as  polysaccharides,  called  pentosans.  They  are  very  resistant  to 
the  action  of  alkali  and  are  hydrolyzed  by  dilute  acids  to  form  the  simple 


(CjHsOJ^  +  (H,0)n 
Pentosan 


(C,H,o05)„ 
Pentose 


Pentoses  are  distinonished  from  hexoses  bv  their  behavior  when  boiled 
for  a  long  time  with  hydrochloric  acid.  Hexoses  are  converted  to  levulinic 
acid  by  this  treatment,  while  pentoses  form  furfuraldehyde.  Pentoses  may 
be  estimated  by  the  use  of  this  reaction.  The  furfuraldehyde  is  distilled 
off  and  then  coupled  with  phloroglucinol  and  the  condensation  product 
is  weighed. 


THE  CARBOHYDRATES  AND  THEIR  METABOLIS:^!  241 


con 

I 
HOCH 

I 
HOCH 

I 
HOCH 

I 
CHoOH 

1-Ribose 

COH 

I 
HCOH 

I 
HOCH 

I 

HOCH 

I 
CH2OH 

1-Arabinose 


Table  VI — Albopextoses 
COH 


COH 

I 
HCOH 

I 
HCOH 

I 
HCOH 

I 
CII.OII 

d-Ribose 

COH 

I 
HOCH 

I 
HCOH 

I 
HCOH 

I 
CH2OH 

d-Arabinose 


HCOH 

I 
HOCH 

I 
HCOH 

I 
CHoOII 

1-Xylose 

COH 

I 
HCOH 

I 
HCOH 

I 
HOCH 

I 
CH.OH 

1-Lvxose 


.  COH 

I 
HOCH 

I 
HCOH 

I 
HOCH 

I 
CHoOH 

d-Xylose 

COH 

I 
HOCH 

I 
HOCH 

1 
HCOH 

I 
CH2OH 

d-Lyxose 


The  same  reaction  is  used  for  the  qualitative  detection  of  pentoses. 
Color  reactions  are  obtained  by  heating  pentose  with  hydrochloric  acid 
in  the  presence  of  phloroglncinol  or  orcinol. 

Xylose. — ^1- Xylose  (wood  sugar)  is  formed  from  the  xylans  called 
wood  gaims,  found  in  vegetable  cell  walls,  and  next  to  cellulose  the  most 
important  carbohydrate  found  in  plants.  It  forms  monoclinie  prisms 
or  needles,  has  a  sweet  taste,  is  readily  soluble  in  water  and  hot  alcohol, 
but  not  in  ether.  It  melts  at  135°  according  to  some,  as  high  as  154°, 
according  to  others.  Its  specific  rotation  is  -f"  85.7°.  The  equilibrated 
mixture  has  a  specific  rotation  of  +  18.5°. 

It  gives  the  usual  aldose  reactions.  It  is  best  identified  by  oxidizing 
to  1-xylonic  acid  and  converting  the  latter  to  the  characteristic  double 
cadmium  bromid  salt. 

^(C5HoOg)2  .  Cd .  CdBro .  2HoO 

l-Arahinose, — This  pentose  was  first  isolated  by  Scheibler  (1873).  The 
gums  of  cherry,  plum,  gum  arabic,  etc.,  are  composed  chiefiy  of  arabans, 
and  from  them  1-arabinose  is  obtained  on  hydrolysis  wath  acids. 

It  crystallizes  in  needles,  melting  at  100°  C.  It  is  readily  soluble  in 
water,  difficultly  soluble  in  95  per  cent  alcohol  and  almost  insoluble  in 


212  A.  1.  lUXGEK  AND  EMU.  J.  BAUMANJST 

absoliito  alcoliol.  It  exliibits  strong  mutarotation  in  aqueous  solution. 
Tlio  specific  rotations  for  a-1-arabinose,  P-l-arabinf)se  and  the  equilibrated 
mixture  are  +  70^,  +184°  and  -r  104^  respectively. 

The  mo.^t  characteristic  conl|K)und^^  of  arabinose  are  parabromopbenjl 
hydrazone,  di phenyl  hydrazone  and  phenyl-osazonc.  The  di phenyl  hydra- 
zone,  meltiuL^  at  ^IS^  C,  is  a  colorless  crystalline  substance  and  is  usually 
used  for  identifying  arabinose. 

d-Ribose. — Unlike  the  other  two  pentoses  which  have  been  considered, 
d-ribose  does  not  appear  as  a  pentosan,  but  is  an  important  constituent 
of  plant  nucleic  acid,  as  proven  by  Levenc  and  Jacobs  (1J)12).  It  seems 
probable  that  the  known  plant  nucleic  acids  are  quite  similar,  and  it  has 
been  established  that*  there  are  four  molecules  of  d-ribosc  in  those  plant 
nucleic  acids  that  are  known. 

Methyl  Pentoses. — Several  of  these  have  recently  been  isolated  from 
plants.  They  differ  from  pentoses  in  having  a  methyl  radical  replace  one 
of  the  hydrogens  of  the  primary  alcohol,  —  CHgOH,  forming  the  group 
CH0H.CIl3,asin 

COH 

I 
HCOII 

i 
HCOH 

I 
HOCH 

I 
HOCH 

I 
CH3 

Rhamnose. — 1-Ehamnose  is  a  constituent  of  many  glucosides  and  is 
perhaps  the  most  common  of  the  methyl  pentoses.  It  crystallizes  with  one 
molecule  of  water  and  exists  in  a  and  P  forms. 

Bigitoxose  is  probably  a  reduced  methyl  pentose  obtained  from  digi- 
talis : 

CH3 .  CHOII .  CHOII .  CHOH .  CH. .  COH 

The  methyl  pentoses  behave  like  the  pentoses  on  the  whole,  but  yield 
metbylfurfuraldehyde  on  distillation  with  acids. 

Biases,  Triases,  Tetroses,  etc. — The  simplest  sugar  is  the  diose,  glycol- 
ic-aldehyde,  COH     but  it  has  not  been  found  in  nature.     It  is  of  inter- 

I 

CILOH 
est,  however,  as  a  possible  product  of  the  intermediary  metabolism  of  carbo- 
hydrates.   There  are  three  trioses  of  interest,  two  aldoses,  d-and  1-glyceroses 
or  glycericaldehydes,  and  one  ketose,  dihydroxyacetone. 


THE  CARBOHYDRATES  AND  THEIR  METABOLISM  243 

con  con     .  CII2OH 

I  I  I 

HCOII  HOCII  CO 

I  !  I 

CH,OII  CH,OH  CIIoOH 

d-Glycericaldehyde  1-GlyeericaUlehyde  Dihydroxy  acetone 
or                                        or 
d-Glycerose                          1-Glyccrose 

All  of  these  substances  are  intermediary  products  in  the  metabolism  of 
carbohydrates,  and  are  of  interest  on  that  account. 

There  are  four  possible  aldotetroses  of  which  three  are  known,  but  they 
have  not  been  found  to  occur  in  nature  in  the  free  states. 

COH  COH  COH     .  COH 

I  i  I  1 

HOCH  HCOH  HCOII  HOCH 

I  i  II 

HOCH  HCOH  HOCH  HCOH 

I  1  I  I 

CH2OH  CILOH  CHoOH  CHoOH 

1-Erythrose  d-Erythrose  1-Threose  d-Threose 

The  alcohol  of  erythrose,  erythritol,  has  been  obtained  from  various  algse 
and  mosses. 

Disaccharides 

These  sugars  contain  twelve  carbon  atoms  and  are  made  up  of  two 
hexoses  united  by  an  oxygen  atom.  When  acted  upon  by  hydrolytic  agents, 
they  take  up  one  molecule  of  water  and  are  converted  into  the  hexoses  of 
which  they  are  composed. 

The  hexoses  in  these  carbohydrates  are  bound  together  in  much  the 
same  way  as  they  are  in  the  glucosides;  hence  the  aldehyde  or  ketone 
radical  of  one  of  the  hexoses  is  the  point  of  union,  while  the  ketone  or 
aldehyde  radical  of  the  other  hexose  may  or  may  not  remain  free. 

Those  disaccharides  that  have  a  potentially  free  aldehyde  or  ketonic 
group  give  the  typical  reactions  of  the  hexoses,  such  as  reduction  of  alkaline 
copper  and  other  metallic  hydroxides  and  combination  with  hydrocyanic 
acid.  They  exhibit  mutarotation  and  exist  in  two  forms  which  are  in 
equilibrium  in  aqueous  solution.  The  union  of  the  two  hexoses  is  similar 
to  that  found  in  the  case  of  the  glucosides.  In  fact,  many  of  them  are 
hydrolyzed  by  certain  glucosidases. 

When  an  aldehyde  or  ketone  gi*oup  is  free,  as  in  maltose,  phenyl  osa- 
zones,  that  are  only  slightly  soluble  but  difficult  to  purify,  are  obtained. 
The  hydrazones  are  almost  all  easily  soluble  in  water.    The  disaccharides 


244 


A.  T.  RIXGER  xVXD  EMIX  J.  BAUMAl>rN 


GIIoOH 


HCOH 

I 
CH2OH 

Glucose  Radical 


HC' 


CHoOII 
Fructose  Radical 

Sucrose  or  Cane  Sugar 
CNeiiheY  aldehyde  nor  ketone  functional) 


CII2OH 
Glucose  Radical 


Glitcose  Radical 


Maltose 
(One  aldehyde  radical  free  and  functional) 


COH 


HCOH 

I 
HOCH 


CH2OH 

Galactose  Radical 


CH3 
Glucose  Radical 


Ladose 
(One  aldehyde  radical  free  and  functional) 


/ 


THP:  CARBOIIYDEATES  AXD  their  metabolism  245 

that  have  no  frco  aldehyde  or  ketone  do  not  form  osazones.  Other  than 
(he  phenyl  osazones,  the  disaccharides  form  no  compounds  that  are  char- 
acteristic. 

In  th(^  dcteniiination  of  the  confiirn ration  of  the  disaccharides,  the 
chief  points  to  ho  elucidated  wero  (1)  the  nature  of  the  component  hexoses, 
(2)  whether  the  disaccharide  was  an  a-  or  ^glucoside,  (3)  the  phicc  of 
union  of  the  two  monosaccharides. 

The  nature  of  the  component  hexoses  was  determined  hy  hydrolyzing 
the  disaccharide  with  acid  and  identifying  the  hexoses.  The  nature  of  the 
iihicosidic  union  was  established  by  the  behavior  of  the  disaccharide  toward 
maltose  and  emulsin.  If  the  disaccharide  is  hydrolyzed  by  raaltase,  it  is  an 
a-giucoside;  if  by  emulsin,  it  is  a  P-glucoside.  This  ix)int  has  also  been  de- 
termined by  studying  the  optical  behavior  of  the  hexoses  as  soon  as  foimed 
by  the  action  of  an  enzyme,  toward  a  drop  of  alkali.  If  the  rotation  is 
increased,  it  indicates  the  presence  of  a  P-glucose;  if  the  mutarotation  is 
in  the  other  direction,  an  a-glucose  has  been  foniied. 

Points  of  special  interest  of  the  individual  disaccharides  will  now 
bo  presented. 

/S^i(c rose.— Sucrose,  known  also  as  saccharose  or  cane  sugar,  is  indus- 
trially the  most  important  of  the  disaccharides.  It  is  verv'  widely  dis- 
tributed in  the  plant  world,  where  it  seiTCs  chiefly  as  a  reserve  material. 

It  crystallizes  readily,  is  very  soluble  in  water  and  very  sweet.  It 
does  not  exhibit  mutarotation  in  aqueous  solution.  It  is  dextrarotary  and 
has  a  specific  rotation  of  +  66.5°.  When  heated,  it  melts  at  160°  C, 
and  at  200°  C.  it  darkens,  forming  caramel,  in  which  process  water  is 
given  off. 

Chemically,  sucrose  behaves  neither  as  an  aldehyde  nor  as  a  ketone; 
it  does  not  fonn  hydrazones  or  osazones,  nor  does  it  reduce  Fehling's 
solution.  Sucrose  is  readily  hydrolyzed  by  boiling  with  acids,  one  mole- 
cule of  glucose  and  one  of  fructose  being  formed.  The  same  hydrolysis 
may  be  brought  about  by  an  enzyme,  invertase  or  sucrase,  present  in  yeasts 
and  other  fungi,  as  well  as  in  many  other  plants  and  in  the  digestive  tracts 
of  many  animals. 

The  products  of  hydrolysis  of  sucrose  have  a  resultant  levorotation, 
since  fiiictose  is  more  levorotatory  than  glucose  is  dextrorotatory.  This 
process  is  therefore  called  inversion  and  the  product  invert  sugar.  Because 
sucrose  exhibits  neither  aldehyde  nor  ketone  properties,  it  is  believed  that 
the  glucose  and  fructose  molecules,  that  compose  the  sucrose  molecule,  are 
united  in  such  a  way  that  both  aldehyde  and  ketone  groups  are  destroyed. 
The  formula  usually  ascribed  to  sucrose,  is  Fischei'^s  modification  of  the 
Tollens  formula,  in  which  it  is  both  a  glucoside  and  a  fructoside. 

Lactose. — Lactose  or  milk  sugar  was  first  obtained  about  1615  by 
Fabricio  Bartoletti.  It  is  always  found  in  the  mammary  secretion,  but 
has  not  been  found  in  the  vegetable  kingdom.     It  is  often  found  in  the 


240  A.  I.  PJXOEH  AND  E:^IIL  J,  T3AUMANN 

urine  of  pregnant  and  lactating  women.  Human  milk  contains  5  to  7 
per  cent  lactose,  occasionally  more,  while  the  milk  of  other  animals  con- 
tains somewhat  less. 

Lactose  is  readily  prepared  from  milk  by  coagulation  of  the  casein 
with  the  enxyme  rennet,,  and  the  clear  liquid  or  whey  which  separates  from 
tin*  precipitated  protein  is  concentrated  under  diminished  pressure  to  a 
syrup,  from  which  crude  lactosc'crystallizes.  It  is  purified  by  recrystalliza- 
lion  from  water. 

Erdmann  (18.55)  obtained  lactose  in  two  crystalline  forais,  one  of 
which  had  a  specific  rotation  of  4-  90°  and  the  other  of  +  35^,  each  show- 
inir  a  motarotation  and  the  specific  rotation  of  the  ecpiilibrated  solution 
being  +  55.-3^.  This  was  the  first  of  the  disaccharides  in  which  the  ex- 
istence of  more  than  one  form  was  demonstrated. 

Sodium  amalgam  reduces  lactose,  fomiing  mannitol,  dulcitol,  lactic 
acid,  hexyl-alcohol  and  other  products.  Lactose  is  a  glucose-galactoside 
and  not  a  i»alaotose-glucoside,  as  shown  by  its  behavior  on  gentle  oxidation, 
so  that  only  the  free  aldehyde  group  will  be  oxidized.  Under  such  con- 
ditions lactobionic  acid  is  fonued,  which  on  hydrolysis  yields  galactose  and 
gluconic  acid,  showing  that  the  free  aldehyde  group  is  that  of  glucose, 
while,  if  the  free  aldehyde  group  were  that  of  galactose,  galactonic  acid  and 
glucose  would  result  from  the  hydrolysis  of  the  oxidation  product. 

Lactose  is  much  more  difficultly  hydrolyzed  by  acids  than  sucrose.  It 
is  also  hydrolyzed  by  the  enzyme  lactase,  found  in  the  intestinal  mucose  of 
animals,  as  well  as  by  aqueous  extracts  of  kefir  and  some  yeasts  and  al- 
monds (ciiTde  emulsin).  It  is  not  hydrolyzed  by  maltase,  invertase  or 
any  enzymes  in  brewers'  yeast.  This  serves  as  a  simple  means  of  distin- 
guishing between  lactose  and  glucose,  a  problem  often  met  with  by  the  path- 
ological chemist,  since  glucose  is  readily  fennented  by  yoast.  Lactose  also 
forms  a  fairly  characteristic  osazone,  which  may  be  readily  distingiiislied 
from  glncosazone.  A  good  way  to  prepare  the  osazones  from  biological 
material  is  to  precipitate  most  of  the  interfering  substances  by  adding 
mercuric  nitrate  in  dilute  nitric  acid  solution  and  then  solid  sodium  car- 
]>onate.  Then  filter,  cover  the  filtrate  and  prepare  the  osazone  in  the  usual 
v/ay  with  plienylhydrazine  hydro(!hlorid  and  sodium  nitrate. 

Maltose. — ^laltoso  or  raalt  sugar  is  formed  bv  the  action  of  diastase 
upon  starch.  The  sugar  was  first  isolated  by  De  Saussure  in  1819,  but  its 
identity  was  deteimined  by  Debnitifaut  in  1847  and  he  gave  it  the  name 
maltose.  It  occurs  in  plants  and  animal  tissues  to  some  extent,  and  re- 
sults from  the  action  of  diastase  of  the  pancreatic  secretion,  or  ptyalin  of 
saliva  on  starch  or  glycog'en. 

Maltose  crystallizes  in  small  needles  with  one  molecule  of  water  of 
crystallization.  It  is  easily  solul)le  in  water  and  in  alcohol  its  solubility 
is  5  per  cent.  Its  solutions  show  rnutarotation.  Its  specific  rotation  in- 
itially is  -|-  119''  and  that  of  the  equilibrated  mixture  is  +  1 37°. 


THE  CARBOHYDRATES  AXD  THEIR  METABOJ.ISM  247 

Maltaso  reduces  Eehliiig's  solution  and  forms  a  phenyl  osazone.  It 
is  hydrolyzed  by  acids  fonning  two  molecules  of  glucose,  but  is  more 
resistant  to  hydrolysis  than  sucrose.  Maltose  is  also  hydrolyzed  by  mal- 
tase  in  the  same  way,  but  is  not  hydrolyzed  by  emulsin.  Because  of  tliis 
behavior,  maltose  is  assumed  to  be  a  glucose-a-glucoside. 

Polysaccharides 

Those  considered  under  this  heading  form  colloidal  solutions  or  are 
insoluble  in  water.  The  more  important  ones  are  starch,  glycogen,  cellu- 
lose, dextrins,  inulin  and  gums.  They  are  usually  named  from  the  sugar 
they  yield  on  hydrolysis,  with  the  suffix  "an."  Thus  starch  is  a  glucosan; 
inulin  is  a  levulan. 

Starch  is  one  of  the  polysaccharides  found  in  plants  in  the  form  of 
a  granule  with  a  characteristic  structure,  so  that  it  is  possible  to  identify 
the  plant  from  which  the  starch  came  by  microscopic  examination.  It 
forms  the  reserve  food  of  the  plant  cell.  It  is  insoluble  in  the  ordinary 
solvents,  but  if  poured  into  boiling  water  the  granule  is  disrupted  and  a 
colloidal  solution  results. 

Upon  hydrolysis  with  acids  or  enzymes,  a  series  of  simple  polysaccha- 
rides are  formed,  namely,  soluble  starch,  erythrodextrin,  achroodextrin, 
and  finally,  maltose  and  glucose.  It  has  been  quite  difficult  to  obtain  any 
knowledge  of  the  number  of  hexose  groups  in  starch  and  the  dextrins. 

Inulin  is  a  levulan,  found  in  the  tubers  of  the  dahlia  and  Jerusalem 
artichokes.  It  forms  the  best  source  of  obtaining  d-levulose.  It  is  not 
unlike  starch  in  its  chemical  behavior. 

Cellulose  is  the  main  constituent  of  the  wall  of  plaxit  cells.  It  has  a 
more  complex  structure  than  starch.  It  is  insoluble  in  all  the  -usual  sol- 
vents, but  will  dissolve  in  ammoniacal  copper  salt  solutions.  On  hydrolysis 
with  acids  it  yields  glucose  and  other  monosaccharides.  Xitric  acid  with 
cellulose  foims  nitrocellulose  or  gun  cotton.  Concentrated  sulphuric  acid 
dissolves  cellulose.  Upon  diluting  w^ith  water,  it  is  again  precipitated,  but 
in  a  different  form.     The  resulting  compound  gives  a  blue  color  with 

iodin  and  is  called  amvloid. 

«/ 

A  number  of  cellulose-like  substances,  called  hemi-celhiloses,  are 
found  in  seeds  and  young  plant  tissues.  They  probably  act  both  as  sup- 
porting stnictures  and  as  a  source  of  reserve  food.  Upon  acid  hydrolysis 
they  yield  galactose,  arabinose,  mannose,  rhamnose  and  occasionally  fruc- 
tose. 

Gums  are  usually  pentosans.  They  are  white  substances  which  dis- 
solve in  water,  giving  a  thick,  viscid,  mucillaginous  solution.  Examples 
are  gum  acacia  (or  arabic)  and  gum  tragacanth.  Upon  hydrolysis  they 
yield  pentoses  or  their  derivatives,  such  as  arabinose  and  rhamnose.  Oc- 
casionally hexoses  also  result  from  hydrolysis  of  some  gimis,  such  as  man- 


2i8  A.  L  RIXGEK  AN1>  EMIL  J.  BAUMAN:^ 

nose  and  glucose.  Phosphoric  acid  is  usually  associated  with  the  gums, 
as  with  many  other  polysaccharides,  and  it  is  most  difficult  if  not  impos- 
sible to  separate  them.  This  suggests  that  sugar  phophate  may  be  pres- 
ent in  the  polysaccharide  molecule.  Phosphoric  acid  sugar  compounds 
phiy  a  great  role  in  biochemical  phenumena. 


Digestion  of  Carbohydrates 

The  carbohydrates  that  play  a  role  in  human  metabolism  are  the  poly- 
saccharides, starches,  glycogen  and  cellulose,  and  the  disaccharides,  suc- 
rose, lactose  and  maltose.  During  the  process  of  digestion,  the  higher 
carbohydrates  are  converted  into  monosaccharides,  by  processes  of  hydro- 
lysis. 

Salivary  Digestion. — The  first  enzyme  that  acts  upon  carbohydrates 
is  encoimtered  in  the  salivary  secretion  and  is  known  under  the  names  of 
amylolytic  fei-ment,  diastase  and  ptyalin.  It  is  a  ferment  that  is  suscep- 
tible to  changes  in  temperature.  At  0°  C.  its  activity  is  entirely  suspended, 
whereas  at  body  temperature  it  shows  its  optimum  activity.  If  the  tem- 
perature is  raised  above  that,  its  activity  diminishes  until  it  reaches  65°  to 
70°  C,  when  it  is  completely  destroyed. 

It  is  also  highly  sensitive  to  the  hydrogen  ion  concentration,  showing 

greatest  activity  in  an  acid  concentration  of  <     An  acid  solution  of 

N  .  •       . 

-—  inhibits  the  action  of  the  diastase  completely,  as  will  also  a  strongly 

alkaline  reaction. 

Salts,  especially  phosphates,  seem  necessary  for  ptyalin  digestion  for, 
when  saliva  is  dialyzed,  it  loses  much  of  its  amylolytic  powers.  These 
may  be  restored  by  the  addition  of  a  little  phosphate.  It  is  quite  pos- 
sible that  a  carbohydrate-phosphate  intermediary  product  of  digestion  is 
formed  similar  to  the  hexose-phosphatc  that  Harden  and  Young  found 
to  be  essential  in  fermentation.  Salts  of  the  heavy  metals — such  as 
uranium,  silver  and  mercury — will  severely  inhibit  the  action  of  ptyalin. 

During  the  process  of  mastication  the  food  is  brought  into  intimate 
contact  with  the  saliva,  but  does  not  have  sufficient  time  to  bring  about 
considerable  digestion.  The  greatest  activity  of  ptyalin  takes  place  in 
the  fundus  of  the  stomach,  before  the  acidity  of  th«  stomach  reaches  tlie 
level  of  concentration  at  which  it  inhibits  the  action  of  ptyalin. 

Action  of  Ptyalin. — The  ptyalin  does  not  affect  cellulose.  It  acts  on 
boiled  starch  much  more  readily  than  on  native  starch.  It  acts  by  bringing 
about  a  process  of  hydrolysis  whereby  the  large  starch  molecule,  which 
belongs  to  tlie  suspension  colloidal  group,  is  broken  up  into  smaller  and 
smaller  molecules,  passing  through  various  stages  of  ^^colloidality,"  be* 


THE  CARBOHYDRATES  AND  THEIR  METABOLISM  249 

coming  a  soluble  starch,  then  going  through  various  stages  of  dextrins, 
until  it  finally  reaches  th(?  stage  of  the  perfectly  soluble  di saccharide, 
maltose. 

It  is  impossible  at  present  to  sharply  separate  the  different  inter- 
mediary products  in  starch  digestion.  The  ditferent  stages,  however,  can 
be  recognized  by  means  of  the  iodin  reaction.  The  native  starches  give 
a  blue  coloration  with  iodin,  and  as  digestion  progresses  dextrins  are 
fonned  which  give  at  first  a  violet,  red,  then  brown  red,  and  finally  no 
color  reaction  at  all  with  iodin.  These  dextrins  are  known  respectively  as- 
erythrodextrins  and  achroodextrins. 

In  the  salivary  secretion  we  find  another  enzyme  which  acts  on  maltose 
and  is  known  as  maltase.  It  acts  on  the  maltose  molecule,  making  it  un- 
dergo hydrolysis,  and  converting  it  into  two  molecules  of  glucose. 

Gastric  Digestion  of  Carbohydrates. — In  the  gastric  secretion  there 
are  no  enzymes  which  attack  carbohydrates.  As  long  as  the  acidity  of  the 
gastric  contents  is  low  the  ptyalin  and  maltase,  which  are  swallowed  with 
the  saliva,  may  continue  their  activity.  When  the  gastric  acidity  in- 
creases in  concentration  it  may  help  in  hydrolyzing  the  disaccharides,  but 
this  takes  place  only  to  an  insignificant  extent. 

Intestinal  Digestion  of  Carbohydrates. — In  the  pancreatic  secretions 
we  find  an  amylolytic  enzyme  which  has  all  the  properties  of  ptyalin,  but 
which  has  the  power  of  acting  at  a  much  greater  velocity.  The  intestinal 
juices  also  contain  three  enzymes:  sucrase,  which  has  the  power  of  split- 
ting sucrose  into  glucose  and  levulose;  maltase,  which  splits  maltose  into 
two  molecules  of  glucose,  and  lactase,  which  splits  lactose  into  glucose 
and  galactose.  All  the  carbohydrates,  therefore,  are  brought  down  in  the 
intestinal  canal  to  the  stago  of  monosaccharides.  Separate  enzymes  are 
present  there  for  all  types  of  carbohydrates  that  the  human  individual 
ingests,  except  cellulose,  which  is  left  entirely  untouched,  and  is  eliminated 
as  such. 

Absorption  of  Carbohydrates 

The  products  of  carbohydrate  digestion  are  very  soluble  and  easily  dif- 
fusible. The  amount  that  is  absorbed  by  the  stomach  is  very  small  and 
of  no  practical  consequence.  Practically  all  of  the  digested  carbohydrates 
are  absorbed  in  the  small  intestines  and  very  little  is  left  in  the  material 
that  reaches  the  ileocecal  valve. 

All  the  absorbed  carbohydrates  are  carried  away  by  the  blood  stream 
into  the  portal  vein,  thence  to  the  liver.  It  is  remarkable  that  in  spite 
nf  the  easy  solubility  of  sucrose  and  lactose,  none  of  it  is  absorbed  under 
ordinary  circumstances.  The  intestinal  wall  is  almost  impermeable  to 
them,  whereas  maltose  may  be  absorbed  to  a  slight  extent.  The  body 
cells  have  the  power  of  utilizing  maltose,  probably  because  of  the  pres- 
ence of  a  maltase  in  the  blood  stream,  but  cannot  utilize  sucrose  or  lactose; 


250  A.  T.  KINOER  AND  EMJL  ,f.   lUrMAXISr 

and  if  these  enter  the  blood  stream  pareuterally,  they  are  quantitatively 
excreted  in  the  urine. 

The  earbohydrates  that  are  absorbable,  therefore,  are  the  three  mono- 
.-;if(l«aridf'.> — lihu'ose,  levulose,  tia lactose — and  the  one  disaceharide — mal- 

The  Sugar  of  the  Blood.— That  ijlucose  is  the  most  important  sugar 
of  the  blood  we  know  definitely.  Whether  levulose  and  galactose  exist 
in  the  blood  as  such  is  at  present  not  known.  From  the  ease  with  which 
these  two  sugars  are  converted  into  glucose  when  fed  to  a  diabetic  indi- 
vidual, we  have  every  reason  to  Ixdieve  that  they  are  converted  into  glucose 
either  in  the  process  of  absorption  or  soon  thereafter. 

Glucose  exists  in  the  blood  in  a  state  of  free  solution  and  not  in  any 
chemical  union.  (^Michaelis  and  Rona  (1908).) 

When  one  examines  the  blood  of  an  individual  for  its  glucose  concen- 
tration at  frequent  intei'\*als  of  time,  one  finds  that  under  normal  conditions 
it  fluctuates  within  surprisingly  narrow  limits.  In  the  morning  before 
breakfast,  it  usually  is  at  its  lowest  level,  between  0.07  to  0.10  per  cent. 
Between  one  and  one  and  a  half  hours  after  a  meal  rich  in  carbohydrates, 
it  rises  to  a  level  of  0.10  to  0.15  per  cent.  After  that  it  gxadually  comes 
down,  to  reach  the  fasting  level  about  two  to  three  hours  after  the  meal. 
This  cycle  of  events  repeats  itself  with  each  meal. 

If  a  normal  individual  is  allowed  to  fast  for  some  time,  the  blood 
sugar  remains  about  0.07  per  cent  and  very  seldom  sinks  below  that  fig- 
ure. In  such  cases  there  is  hardly  any  fluctuation  in  the  blood  sugar  con- 
centration from  hour  to  hour. 

There  are  a  number  of  forces  which  are  operative  in  keeping  the  blood 
5:ugar  concentration  at  such  a  constant  level,  and  these  are:  I.  Those 
that  prevent  it  from  rising  above  nonnal  levels;  IL  Those  that  prevent 
it  from  falling  below  normal  levels. 

I'he  factors  that  prevent  the  blood  sugar  from  rising  above  normal  levels 
are:  1.  Polymerization  of  glucose  into  glycogen  by  the  cells  of  the  liver 
and  muscles;  2.  Utilization  of  glucose  (oxidation)  by  the  cells  of  the  body 
for  dynamogenetic  purposes ;  3.  Conversion  of  glucose  into  fat. 

The  factors  that  prevent  the  blood  sugar  concentration  from  falling 
below  nonnal  levels  are:  1.  Mobilization  of  glyct^gen  from  its  storehouses 
— liver  and  muscle — and  its  hydrolysis,  which  results  in  glucose  fomiation ; 
2.  Increase  in  protein  metabolism  with  the  result  that  a  large  number  of 
amino  acids  are  converted  into  glucose. 

The  moment  sugar  enters  the  intestinal  canal  its  absorption  begins. 
This  causes  an  increase  in  the  glucose  concentration  of  the  blood  in  the  por- 
tal vein.  Synchronous  with  the  increase  in  the  portal  concentration,  there 
takes  place  a  withdrawal  of  glucose  frcmi  the  blood  by  the  liver  cells  and 
their  pohnnerization  of  the  glucose  into  glycogen.  On  the  other  hand,  when 
absorption  of  carbohydrates  from  the  intestinal  canal  has  stopped,  the 


THE  CAlll^>OIiYDRATES  AKD  TIIEIE  ]\[ETABOLISM  251 

venous  blood  becomes  poorer  in  glucose.  The  process  then  reverses.  The 
glycogen  in  the  liver  cells  becomes  hydrolyzed  and  a  stream  of  glucose  starts 
into  the  blood.  Apparently  there  must  exist  a  very  delicately  adjusted 
physicocheniical  rcLationship  between  the  glucose  concentration  of  the 
portal  blood,  the  glycogen  content  of  the  liver,  and  the  glucose  concentra- 
tion of  the  hepatic  vessels. 

The  capacity  of  the  liver  to  store  glycogen  is  enormous.  Schoendorf 
(lOOo  (h))  showed  that  tho  liver  of  dogs  may  contain  as  nnich  as  18.7  per 
cent  of  glycogen,  and  Otto  (1891)  showed  that  rabbit's  liver  may  contain 
as  much  as  10.8  per  cent  of  glycogen  after  ingestion  of  large  amounts  of 
carbohydrates.  The  liver  of  a  man  weighing  about  TO  kilos  weighs  ap- 
proximately 2000  grams.  On  the  basis  of  the  above  figures,  we  can  readily 
see  that  it  can  hold  as  much  as  300  grams  of  glycogen,  which  is  considerably 
more  carbohydrate  than  the  average  man  consumes  in  any  one  meal. 

The  liver,  therefore,  through  its  glycogenetic  function  acts  as  a  won- 
derful regulator  of  the  sugar  in  the  blood.  It  prevents  any  marked  fluctua- 
tions in  the  concentration,  and  above  all,  any  sudden  increases  in  the  sugar 
content,  which  would  be  followed  by  loss  of  sugar  through  glucosuria. 

The  utilization  of  glucose  by  the  muscle  cells  occurs  as  soon  as  its 
absorption  from  the  intestinal  canal  begins  (Lusk,  1912-1915).  Ap- 
parently the  body  cells  burn  glucose  with  greater  ease  than  any  other  food- 
stuff, for,  when  glucose  is  present  in  abundance,  the  combustion  of  fat  is 
stopped  almost  completely,  and  that  of  protein  is  reduced  to  an  absolute 
minimum.  Glucose  in  the  body  burns  to  CO2  and  HgO,  according  to  the 
following  reaction: 

CelliaOc  +  6  Oo     >     G  COg  -f  6  IT2O 

From  this  we  see  that  when  glucose  is  oxidized  a  certain  volume  of  oxy- 
gen is  required,  and  for  every  volume  of  oxygen  used,  a  corresponding  vol- 
ume of  carbon  dioxid  is  given  off.     The  ratio  between  the  volumes  of 

CO 

CO2  and  O2  is  known  as  the  Respiratory  Quotient.     The  value  of  -~ 

O2 

in  this  case  equals  1.     In  the  combustion  of  no  other  foodstuff  does  the 

CO. 

Respiratory  Quotient  equal  1.    When  fat  burns  the  -pr-^  quotient  is  0.707, 

O2 
and  w^hen  protein  bums,  the  quotient  is  0.801. 

In  Lusk's  experiments  on  dogs,  forty-five  minutes  after  glucose  in- 
gestion, the  respiratory  quotient  was  0.99,  showing  that  glucose  burnt 
almost  exclusively. 

If  the  absorption  of  glucose  from  the  intestinal  canal  still  continues, 
we  have  a  third  factor  brought  into  play,  namely  its  conversion  into  fat. 

In  nonnal  individuals,  during  the  process  of  glucose  absorption  from 
the  intestinal  canal,  we  have  a  series  of  three  outlets  which  are  operating 
to  prevent  its  accumulation  in  the  blood.     Schematically  we  may  repre- 


252 


A.  I.  KINGER  AND  E^^flL  J.  BAUMANN 


sent  the  aiTangoment  by  an  inclined  tiihc  that  has  a  series  of  outlets  at 
different  levels,  with  openings  at  the  bottom  through  whicli  sugar  may  bo 
pumped  in.  The  level  of  sugar  in  this  inclined  tube  will  depend  upon 
the  spc^d  with  which  it  i.s  pumped  in  and  with  which  it  pours  out  at  the 
various  outlets.  If  the  inflow  is  so  rapid  that  the  first  outlet  cannot  take 
care  of  it  all,  it  will  mount  until  it  reaches  the  second.  If  that  is  not 
sufficient,  it  will  reach  tho  third,  and  if  that  is  not  sufficient,  it  will  mount 
still  higher. 


Blood  augar  ^^^^ ^  ^^^^  CotAvA  or  Pancreatk Hormone. 

Level .  \^       ^  -y 

®  RcgaUled     by  Renal  TKtbsKoIA. 


Fi>.  2.     Scliematic  illustration  of  the  factors  which  regulate  the  sugar  concentra- 
tion of  the  blood. 


The  level  of  sugar  in  this  tube  at  any  given  time  wnll  depend  upon  the 
relationship  between  the  velocity  and  volume  of  the  sugar  inflow  at  the 
bottom,  and  the  volume  and  velocity  of  its  outflow  through  tlio  three 
noiTual  channels. 

In  the  body,  the  glucose  concentration  of  the  blood  at  any  given  time 
also  depends  upon  the  speed  and  amount  of  its  absoi'ption  from  the  in- 
testinal canal,  and  upon  the  speed  of  its  removal  by  utilization,  glycogen 
and  fat  formations.  ^N'onnally  it  seldom  goes  above  0^12  or  0.13  per 
coiit,  because  the  glycogen  formation  proceeds  at  such  a  rapid  pace  that 
it  does  not  pennit  its  accumulation  in  the  blood.  When  we  ingest  carbo- 
hydrates in  the  form  of  starch,  w^e  can  take  absolutely  unlimited  quantities. 
Because  the  digestion  of  it  is  rather  slow,  the  absorption  follows  suit,  and 


THE  CAEBOIIYDRATES  AXD  THEIR  METABOLISM  253 

at  no  time  do  \vc  find  an  accumulation  above  those  levels.  If,  however, 
we  ingest  a  large  amount  of  carbohydrates  in  the  form  of  glucose  which 
requires  no  digestion  at  all,  and  which  is  absorbed  with  great  rapidity, 
we  find  that  glucose  enters  the  blot)d  stream  at  such  a  rapid  pace  that 
tlio  three  outlets — utilization,  glycogen  formation,  fat  formation — are  not 
sufficient  to  remove  it  all.  Its  concentration  in  the  blood  stream  rises 
and  we  develop  what  is  known  as  a  condition  of  hyperglueemia. 

Another  process  may  be  brought  into  play  at  this  stage,  namely  that 
of  glucosuria. 

It  is  a  well-known  fact  that  the  kidneys  exercise  a  selective  action  on  the 
substances  that  circulate  through  it  in  the  bhx)d  stream.  At  the  present 
state  of  our  physicochemical  knowledge  it  is  difficult  to  say  what  the 
mechanism  of  kidney  secretion  is.  But  we  do  know  that  for  a  numbel* 
of  crystalloids  the  rate  and  amount  of  their  excretion  bears  a  definite  re- 
lationship to  their  concentration  in  the  blood.  (Amhard  and  Weil,  1914; 
McClean,  F.  C,  1915.) 

The  behavior  of  glucose  in  the  blood  is  like  that  of  a  pure  crystalloid 
(Michaelis  and  Rona,  1908),  and  one  would  expect  the  kidneys  to  per- 
mit its  free  secretion  in  the  urine.  This,  however,  is  not  the  case.  With 
the  ordinary  reduction  tests  (Fehling's  solution,  Benedict's  solution,  etc) 
we  cannot  detect  the  presence  of  glucose  in  the  urine  of  normal  indi- 
viduals "^  if  the  blood  sugar  concentration  fluctuates  within  the  normal 
limits.  When,  however,  the  concentration  of  glucose  in  the  blood  rises, 
there  comes  a  point  at  which  the  kidneys  begin  to  excrete  it  in  easily  de- 
tectible  quantities. 

The  height  of  blood  sugar  concentration  at  which  the  kidneys  begin 
to  secrete  sugar  differs  with  different  individuals  and  is  known  as  the 
kidneu  threshold  for  sugar.  With  a  very  few  it  lies  as  low  as  0.08  per 
cent,  which  means  that  those  people  excrete  glucose  in  detectible  quanti- 
ties all  the  time,  and  they  suffer  from  a  condition  that  is  recognized  as 
renal  glucosuria.  Others  will  not  excrete  it  even  when  the  concentration  is 
as  high  as  0.26  per  cent,  as  in  cases  of  chronic  nephritis.  These  two  ex- 
tremes are  comparatively  rare.  The  great  majority  of  noimal  individuals, 
however,  excrete  glucose  in  the  urine  in  detectible  quantities  when  the 
glucose  concentration  of  the  blood  rises  above  0.15  to  0.16  per  cent.  There 
is  at  present  no  explanation  for  this  individual  variation,  except  for  the 
statement  that  there  must  exist  a  difference  in  sensitiveness  for  glucose  in 

^Stanley  R.  Benedict  has  recently  reported  (1918)  that  the  urine  of  a  normal  dog 
and  of  two.  normal,  men  can  be  shown  to  contain  substances  which  are  fermentible  by 
yeast  and  which  reduce  picric  acid.  He  assumes  that  it  is  glucose.  The  dog  weighing 
18  kilos  excreted  in  the  nei;:,'hborhood  of  390  mgs.  per  24  hours  when  kept  on  an  ordi- 
nary carbohydrate  diet;  281  mgs.  when  kept  on  a  low  carbohydrate  diet;  194  mga.  when 
fasting.  His  human  subject,  E.  O.,  weighing  86  kilos,  excreted  996  mgs.  per  24  hours 
when  on  an  ordinary  carbohydrate  diet;  777  mgs.  when  on  a  low  carbohydrate  diet; 
1470  mgs.  when  on  *a  carbohydrate-rich  diet.  The  second  subject,  weighing  57  kilos, 
excreted  640  mgs.  when  on  an  ordinary  diet;  .543  mgs.  when  on  a  low  carbohydrate  diet; 
847, '1156  and  1528  mgs.  on  each  of  three  davs  of  carbohydrate  diet. 


254  A.  I.  EIXGER  AXI)  EMIL  J.  BAUMA2s^X 

the  kidney  cells  of  different  individuals.  Because  tins  glucosuria  is  caused 
by  too  rapid  absorption  of  glucose  from  the  alimentary  canal,  it  is  known  as 
alimenfarif  glucmuria. 

Carbohydrate  Tolerance.  — In  the  preceding  chapters  it  was  shown  that 
the  !)ody  is  capable  of  taking  care  of  large  quantities  of  carbohydrates 
(glucose)  1,  by  storing  it  in  the  cell^  of  the  liver  and  muscles  in  the  form 
of  a  colloidal  &tate — glycogen;  2,  by  utilizing,  i.  e.,  oxidizing  it  in  prefer- 
ence to  other  foodstuffs;  3,  by  converting  it  into  fat.  It  was  further  shown 
that  these  three  factors  tended  to  prevent  the  glucose  from  accumulating 
in  the  blood  above  certain  concentrations,  at  which  it  surpasses  the  kid- 
ney threshold  aad  forces  the  kidney  cells  to  excrete  the  glucose  in  the 
urine. 

The  appearance  of  glucose  in  the  urine  in  detectible  quantities  by 
means  of  the  ordinary  reagents  (Benedict's  or  Fehling's  solutions)  has 
always  been  considered  a  sign  that  the  individual  has  overtaxed  the  "car- 
bohydrate tolerating"  mechanism,  and  the  amount  of  carbohydrate  that 
it  takes  to  bring  about  this  condition  has  been  known  as  the  limit  of  his 
tolerance.  I 

We  shall  see  later  that  there  are  a  number  of  pathological  conditions 
which  affect  the  carbohydrate  tolerance  of  individuals  and  that  the  carbo- 
hydrate tolerance  is  tlierefore  utilized  as  a  means  of  detecting  these  patho- 
logical conditions.  It  is  therefore  of  the  utmost  importance  to  have  a  clear 
concept  of  all  the  factors  that  determine  and  that  may  influence  the  carbo- 
hydrate tolerance  of  perfectly  normal  people. 

In  the  light  of  our  present  knowledge  that  glucosuria  is  the  result  of 
hyperglucemia  and  that  there  exists  a  difference  in  the  sensitiveness  of  the 
kidneys  of  different  individuals  to  glucose  concentration  in  the  blood,  it 
is  advisable  to  eliminate  this  variable  factor,  and  to  determine  the  toler- 
ance for  carbohydrate  on  the  basis  of  the  blood  sugar  concentration.  We 
would  therefore  define  the  carhohijdrate  tolerance  of  an  individual  as 
thai  amount  of  carhohydrates  {cjlucoseY  which  the  individual  can  ingest 
without  developing  hyperglucemia,  and  is  in  reality  a  test  for  the  prompt- 
ness with  which  the  individual  can  convert  glucose  into  glycogen  and  fat 
and  also  oxidize  it. 

Of  course,  one  should  not  imply  from  the  above  that  urinaiT  examina- 
tion for  sugar  is  not  necessary.  It  frequently  does  give  valuable  informa- 
tion. 

Soon  after  the  introduction  of  reliable  methods  for  blood  sugar  de- 
tennination  (Lewis-Benedict,  Bang)  a  whole  series  of  studies  were  pub- 
lished on  the  blo<3d  sugar  curves  after  the  ingestion  of  variable  amounts 
of  glucose  (Hamman  and  Ilirschman,  1017.  Hopkins^  1015.  Jacobson, 
1913.     Bailey,  1919).     The  most  satisfactory-  results  are  obtained  after 

•Glucose  is  used  because  this  requires  no  time  for  digestion  and  thus  another 
possibly  variable  factor  is  eliminated. 


THE  CARBOIIYDEATES  AXD  THEIK  METABOLISM  255 

administering  100  grams  of  glucose  dissolved  in  400  c.c.  of  water  to 
which  has  been  added  the  extract  1  or  IY2  lemons.  This  is  to  be  taken 
in  the  morning  before  breakfast.  The  blood  is  examined  for  sugar  ira- 
mcdiatt'ly  Itefore  the  test  meal,  and  at  intei-^als  of  half  hours  after  the 
meal,  until  the  blood  sugar  comes  back  to  normal. 

With  this  procedure  it  is  found  that  most  subjects  have  an  initial  fast- 
ing blood  sugar  of  0.07  to  0.10  p<:'r  cent;  that  about  one  hour  after  the 
ingestion  of  the  glucose  the  blood  sugar  reaches  the  highest  point,  which 
is  usually  about  0.15  per  cent  or  below;  by  the  end  of  the  second  hour,  it 
is  well  on  the  way  to  normal  again. 

If  the  individuaUs  blood  sugar  rises  above  the  level  of  0.15  at  any  time 
after  the  ingestion  of  100  grams  of  glucose,  we  are  justified  in  concluding 
that  he  has  interference  with  his  carbohydrate  tolerance.  A  number  of 
records  have  been  published  on  individuals  classed  as  normal  who  show  a 
much  higher  blood  sugar  concentration  one  hour  after  glucose  ingestion. 
Future  obscnations  on  the  same  individuals  will  reveal  whether  or  not 
they  were  normal. 

Carbohydrate  Tolerance  Standard. — It  is  of  no  practical  value  to  know 
the  maximum  glucose  tolerance  of  a  person.  But  it  is  of  great  practical 
importance  to  know  that  by  far  the  great  majority  of  hundreds  of  cases 
of  normal  individuals  who  have  received  100  grams  of  glucose  have  been 
able  to  tolerate  it,  i.  e.,  have  shown  no  hyperglucemia  and  no  glucosuria 
when  tested  with  the  ordinary  reagents. 

The  setting  of  any  physiological  standard  is  difficult.  We  have,  for 
example,  standard  tables  of  weights.  Are  they  in  reality  tables  of  what 
we  do  weigh  or  of  w^hat  we  should  weigh  ?  How  many  perfectly  normal 
human  individuals  actually  bear  the  exact  height  to  weight  ratio?  Still 
we  have  accepted  them  as  definite  standards,  realizing,  of  course,  that 
we  may  have  plus  or  minus  variations  from  the  theoretical  without  being 
classed  as  abnomial. 

The  study  of  the  carbohydrate  tolerance  of  human  individuals  is  of 
comparatively  recent  development.  And  it  will  advance  our  science  ma- 
terially if  those  workers  who  reported  hyperglucemias  in  what  appeared 
to  be  normal  individuals  will  repeat  their  tests  on  the  same  individuals 
at  intervals  of  several  years  to  see  whether  those  people  do  not  ultimately 
develop  glucosuria  and  diabetes. 

For  persons  weighing  GO  kilos  or  more  100  gTams  of  glucose  should 
be  given.  For  those  weighing  less,  the  amount  should  be  reduced  pro- 
portionately. But  under  no  circumstances  should  more  than  100  grams 
be  given  to  people  weighing  mare  than  GO  kilos,  because  the  increase  in 
weight  is  not  so  much  due  to  muscle  and  liver  (the  glycogenetic  organs) 
as  to  fat  and  skeleton  Avhich  play  no  rule  in  carbohydrate  tolerance. 

Glycogenesis  and  Carbohydrate  Tolerance. — Wliile  we  have  three  out- 
lets for  the  stabilization  of  the  blood  sugar  concentrations,  the  most  im- 


256 


A.  1.  KIXGEK  AND  EMIL  J.  BAUMAXX 


portant  one,  because  of  its  enormous  elasticity,  is  the  glycogenctic  function. 
It  may  truly  be  classed  as  a  sort  of  ''shock  absorber''  in  the  carbohydrate 
metabolism.  The  capacity  of  the  liver  for  glycogen  may  reach  300  grams, 
while  the  muscles  may  hold  as  much  as  four  per  cent  of  their  weight. 

Glucolysis  and  Carbohydrate  Tolerance. — The  amount  of  glucose  oxi- 
dation that  can  go  on  during  a  period  of  glucose  plethora  (as  after  in- 
gestion of  large  amounts  of  glucose)  is  comparatively  fixed  and  limited 
by  the  body's  requirement  for  energy.  Under  those  conditions  no  fat  is 
burned  and  the  utilization  of  protein  is  reduced  to  the  "wear  and  tear'' 
quota,  which,  from  the  dynamogenetic  point  of  view,  is  insignificant. 
A  man  weighing  70  kilos  will,  when  at  rest,  require  approximately  35 
calories  per  kilo  per  24  hours.  That  means  70  X  35  =  2450  calories 
per  24  hours  or  102  calories  per  hour.  If  all  that  were  to  come  from 
glucose  the  maximum  amount  of  glucose  that  he  could  utilize,  i.  e.,  oxidize, 

102 
would  be  -—:  =  27  grams  per  hour  (each  gram  of  glucose  yields  3.7  cal- 
0.7 

ories),  or  for  the  two  hours  in  which  the  carbohydrate  tolerance  test  is 
made  a  maximum  of  54  grams  of  glucose  can  be  burnt.  Fully  half  of 
the  quantity  given  with  a  100  gram  test  can  be  taken  care  of  by  oxidation. 
The  amount  that  can  be  taken  care  of  by  fat  formation  we  do  not 
know.  It  can  bo  determined  by  studying  the  respiratory  quotient  (Lusk, 
1912),  but  has  not  been  worked  out  for  man  after  a  100  gram  glucose  in- 
gestion. 

TABLE  VII 
Typical  Blood  Sugar  Curats.of  Normal  Individuals* 


M.     McX.     Healthy  medical  student,  aged  24.     Original  Lewis-Benedict  method 

Hour 

Blood  Sugar  Per  Cent 

Urine   Volume 

Urine  Sugar 

8.25  A.M. 

0.096 

8.30 

100  grams  of  glucose  in  300  c.c.  of  water 

8.42  ' 

0.095 

44 

0 

9.07 

0.095 

374 

0 

9.23 

0.104 

572 

0 

9.40 

0.114 

60 

0 

10.15 

0.124 

157 

0 

10.45 

0.108 

364 

0 

12.00 

0.0S6 

251 

0 

H.  G.     Weight  53  kg.     Folin  method  for  sugar  determination  f 


Hour 

Blood  Sugar  Per  Cent 

Urine  Sugar 

9.35 
9.40 
10.40 
11.40 
12.30 

0.006 
93  grams  of  glucose  ingested 
0.130 
0.142 
0.101 

0 

a 

0 
0 

*  Hamman  and  Hirschman. 
t  Montefiore  Hospital  Records. 


THE  CAKP>OIiyDRATES  AXD  THEIR  METABOLISM  257 

Endocrine  and  Nerve  Control  of  Glycogenesis,  Glycogenolysis  and 

Glucolysis 

Influence  of  the  sympathetic  vervous  sy.<tem  and  of  the  adrenal-^. 

We.  now  come  to  one  of  the  most  fascinating  chapters  in  modem  fliVM- 
ology.  Claude  Bernard,  in  the  middle  of  last  century,  found  that  by 
puncturing  tlie  medulla,  between  the  levels  of  origin  of  the  vagus  and 
auditory  nerves  of  animals,  he  was  able  to  bring  about  glucosuria,  which 
was  proven  later  to  be  the  result  of  hyperglucemia.  The  intensity  of 
the  reaction  was  found  to  bo  directly  related  to  the  nutritional  condition 
of  the  animal.  Those  that  were  w^ell  fed  and  contained  a  large  amount 
of  glycogen  in  the  liver  reacted  very  strongly,  showing  hyperglucemia  and 
marked  glucosuria ;  those  that  w^ere  starved  and  contained  little  glycogen 
in  the  liver  reacted  only  feebly. 

In  1901  Blum  made  the  very  important  discovery  that  the  injection 
of  adrenalin  was  also  followed  by  glucosuria.  which  w^as  later  proven  to 
be  the  result  of  hyperglucemia.  The  adrenalin  glucosuria  resembled  the 
puncture  or  piqure  glucosuria,  as  it  is  called,  in  many  respects.  Its  in- 
tensity is  also  dependent  upon  the  amount  of  glycogen  in  the  liver,  and 
it  also  fails  to  produce  hyperglucemia  and  glucosuria  if  the  liver  and 
muscles  are  free  from  glycogen. 

It  was  further  shown  that  repeated  injections  of  adrenalin  into  animals 
with  large  amounts  of  glycogen  will  ultimately  result  in  a  complete  dis- 
charge of  all  the  glycogen  from  the  liver. 

A  more  intimate  view  of  the  relationship  of  the  above  two  funda- 
mental discoveries,  one  may  gather  from  an  analysis  of  the  work  carried 
out  in  Macleod's  laboratory.  First  it  was  shown  that  by  giving  a  sufScient 
amount  of  nicotine  to  cause  a  complete  blocking  of  the  sympathetic  ganglia, 
the  subsequent  performance  of  the  piqure  experiment  is  followed  by  no 
glucosuria,  indicating  that  the  sympathetic  ner\^e  fibers  may  be  the  car- 
riers of  the  impulses  to  the  liver. 

Secondly  it  was  shown  that  by  electrical  stimulation  of  the  great 
splanchnic  nerve  on  the  left  side  a  ver^^  marked  hyperglucemia  may  be  pro- 
duced. 

It  w^as  further  shown  by  G.  1^.  Stewart  that  stimulation  of  the  great 
splanchnic  ner\-e  is  followed  by  the  appearance  of  marked  and  easily 
detectable  quantities  of  adrenalin  in  the  blood  of  the  supra i*enal 
veins. 

Lastly,  it  was  shown  by  Mayer  that  after  adrenalectomy  in  rabbits, 
piqure  produced  no  hyperglucemia  nor  glucosuria. 

From  all  the  above,  a  chain  of  evidence  seems  to  be  established  that 
piqure  and  adrenalin  glucosuria  are  in  reality  one  and  the  same  kind  of 
stimulation  to  the  liver,  and  as  we  shall  see  later,  every  gland  of  internal 
secretion  that  possesses  the  power  of  sj^mpathetic  stimulation  possesses 


258 


A.  L  PtTXGER  AXD  E:\1TL  J.  BAOrAXX 


TABLE  VJIT 

IXFLUEXCK   OF  AliKEXALIN    O.N    1*1.001)   SfGAH 


Rabbit  I 


iJaLbit  II 


Before  Injection 

Blood  .Su|>ar 
Per  Cent 

Trinarv  Sunrar 
Per'  Cent 

Jilood  Suj/ar 
Per  Cent 

Urinarv  Sugar 
Per  Cent 

0.11 

0 

0.12 

0 

After  injection  of  1.0  mg.  of  adrenalin  subcutaneou.-lv 


15  minutes 

0.18 

0.16 

30 

0.2.5 

0.19 

0.09 

60 

0..3.5 

0.28 

0.21 

1%  hours 

0.37 

0.38 

1.21 

2 

0.33 

0.43 

0.39 

2^4       " 

0.35 

0.34 

1.69 

3 

4 

0.24 

1.55 

4Vj       " 

0.27 

3.55 

5 

51/,       « 

0.16 

6 

GVj       ** 

0.13 

3.9 

7 

7V2      " 

0.12 

3.11 

*  Bang's  experiment. 

the  power,  through  its  hyperactivity,  to  cause  a  discharge  of  the  glycogen 
iu  the  liver  which  is  followed  hy  hyperglucemia  and  glucosuria. 

There  is  no  interference  with  the  animal's  power  to  iitilize  carbo- 
hydrates, i.  e.,  to  oxidize  it,  after  adrenalin  administration. 

Influence  of  the  Pancreas, — In  1889  von  Mering  and  ^linkowski  made 
the  path  finding  discovery  that  the  complete  removal  of  the  pancreas  of  an 
animal  is  followed  by  the  appearance  of  marked  glucosuria,  with  all  the 
other  symptoms  of  human  diabetes.  It  was  later  found  that  with  this 
glucosuria  there  runs  parallel  a  very  marked  hyperglucemia.  The  glu- 
cosuria  persists  e^en  if  no  carbohydrate  is  given  in  the  food,  and  it  was 
found  that  the  sugar  in  the  urine  bears  a  definite  relationship  to  the  nitro- 
gen that  is  excreted.  For  every  gram  of  nitrogen  that  was  found  in  the 
urine  2.8  gi-ams  of  glucose  were  present.  Since  one  gram  of  nitrogen  is 
contained  in  G.25  gi-ams  of  protein,  it  is  evident  that  the  depancreatized 
dog  has  the  power  of  converting  G.25  grams  of  protein  into  2.8  grams 
of  glucose. 

The  glycogen  completely  disappeared  from  the  liver  in  spite  of  the 
high  blood  sugar  concentration,  and  if  carbohydrate  was  administered  to 
the  animal,  it  was  quantitatively  eliminated  in  the  urine. 

Experiments  in  which  only  portions  of  the  pancreas  were  removed  re- 
vealed that  animals  have  a  large  "factor  of  safety'^  in  their  pancreas  and 


THE  CA11P>0JIYDEATES  xVXD  THEIR  METABOLISM  259 

that  by  far  the  greatest  portion  can  be  removed  with  impunity.  Of  course 
there  is  a  certain  degree  of  variation  in  different  animals,  but  in  the  great 
majority  as  much  as  four-fifths  of  the  organ  may  be  removed  without  pn> 
duciug-  any  dia]3etes.  When  only  very  small  i>ortions  of  the  pancreas  are 
left  intact,  the  aninuils  develop  a  tendency  towards  alimentary  glucosuria, 
but  no  true  diabetes.  The  transition  from  this  stage  to  that  of  tnie  dia- 
betes is  entirely  d<'pcndent  upon  the  amount  of  pancreatic  tissue  left  intact. 

The  most  convincing  proof  that  the  absence  of  the  pancreas  was  re- 
sponsible for  the  glucosuria  was  presented  by  Minkowski  in  experiments 
in  which  nc  showed  that  animals  that  had  their  pancreas  entirely  removed 
did  not  develop  diabetes  if  a  portion  of  the  pancreas  was  transplanted  sul> 
cutaneously. 

Since  this  was  established  attempts  have  been  repeatedly  made  to  ex- 
tract a  hormone  from  the  pancreas  and  supply  that  to  the  depaucreatized 
animals  with  the  hope  that  the  pancreatic  function  would  be  replaced. 
All  attempts  have  failed,  and  the  reason  for  it  may  be  found  in  the  fact 
that  the  digestive  ferments  of  the  pancreas  destroy  that  honnone. 

Two  very  interesting  series  of  experiments  were  performed  by  Forsch- 
bach  (1008  and  1913)  and  by  A.  J.  Carlson  and  F.  M.  Drennan  (1911). 

Forschbach  performed  an  operation  on  two  dogs  in  such  a  way  that 
the  blood  of  dog  A  was  made  to  circulate  in  dog  B.  He  then  completely 
removed  the  pancreas  of  dog  B.  As  long  as  dog  B  received  the  blood 
from  dog  A,  dog  B  did  not  develop  any  glucosuria,  proving  conclusively 
that  the  blood  of  dog  A  carries  a  substance  (horaione)  which  takes  the 
place  of  the  pancreatic  function.  This  was  later  corroborated  by  Hedon 
(1900),  who  found  that  the  glucosuria  of  depancreatized  dogs  disap- 
peared soon  after  he  transfused  it  with  the  blood  of  a  normal  dog. 

Carlson's  experiments  were  based  upon  principles  similar  to  the  above, 
namely,  that  the  blood  carries  a  substance  that  is  supplied  to  it  by  the 
pancreas.  He  therefore  performed  complete  pancreatectomy  in  animals 
that  were  in  the  latter  stages  of  pregnancy.  Either  very  slight  or  no  glu- 
cosuria set  in.  After  the  birth  of  the  puppies,  however,  the  mother  be- 
came diabetic,  proving  that  the  fetus  was  able  to  supply  the  mother  with 
its  pancreatic  honnone ;  true  diabetes  setting  in  after  the  fetal  supply  was 
removed. 

There  is  therefore  no  more  question  to-day  but  that  the  pancreas  is 
directly  concerned  with  carbohydrate  metabolism.  It  enables  the  body 
to  oxidize  glucose  and  it  enables  the  body  to  convert  glucose  into  glyco- 
gen. In  its  absence,  or  in  case  of  its  failure  to  functionate  properly,  the 
two  functions  disappear  and  the  body  loses  the  power  to  oxidize  glucose 
and  it  also  loses  the  power  to  convert  glucose  into  glycogen,  both  of  which 
result  in  hyperglucemia  and  glucosuria. 

We  are  now  confronted  by  the  problem  of  how  the  pancreas  exerts  its 
influence  on  the  carbohydrate  metabolism.     It  will  be  a  conservative  esti- 


260  A.  I.  KIXGER  AXD  EMIL  J.  BAUMAXN 

mate  to  state  that  at  least  200  publications  Lave  appeared  on  this  sub- 
ject." Every  conceivable  theoretical  possibility  finds  its  defense  and  ex- 
perimental sup^wrt  in  one  place  and  is  met  by  just  as  convincing  objection 
in  another  place. 

That  we  are  dealing  with  an  intei-nal  secretion  there  is  absolutely  no 
question.  That  it  is  the  pancreas  that  is  supplying  that  internal  secre- 
tion seems  proved  beyond  doubt  but  its  modus  operandi  and  locus  nascendi 
is  as  problematical  to-day  as  heretofore.  To  the  Islands  of  Langerhans 
we  are  now  inclined  to  attribute  the  production  of  the  "antidiabetic" 
hormones,  but  there  is  still  room  for  direct  and  crucial  experiments  to 
prove  this  hypothesis. 

Influence  of  the  Thyroid  Gands. — The  thyroid  influences  the  carbo- 
hydrate metabolism  to  a  very  considerable  extent.  Because  it  seems  to 
have  a  stimulating  effect  on  the  entire  plane  of  metabolism  it  undoubtedly 
affects  the  velocity  of  carbohydrate  oxidation  at  the  same  time.  Speci- 
ficallv  it  affects  the  carbohvdrate  metabolism  in  such  a  way  that  whenever 
tJiero  is  a  hypei'f unction  there  is  a  tendency  to  lowered  carbohydrate  toler- 
ance, i.  e.,  hyperglucemia  and  glucosuria  after  the  ingestion  of  100  grams 
of  glucose,  and  when  there  is  a  hypof unction,  as  in  the  ease  of  cretinism  and 
myxedema,  we  usually  find  a  normal  or  increased  tolerance  for  carbo- 
hydrates.    (Janney  and  Isaacson,  1918.) 

A  great  deal  of  confusion  exists  in  the  literature  on  the  subject,  prob- 
ably because  of  tJie  studies  published  on  clinical  cases  that  are  not  clearly 
defined.  Because  of  the^present  tendency  to  attribute  a  great  many  cases 
of  nen'ous  disturbances  to  hyperthyroidism,  one  will  naturally  get  a  good 
many  negative  results.  But  w^hen  one  examines  the  records  of  authentic 
eases  of  hyperthyroidism,  one  seldom  fails  to  find  evidences  of  a  verj^ 
marked  lowering  of  the  carbohvdrate  tolerance.  Of  interest  in  this  con- 
nection is  the  obsen'ation  of  Jones  (1S93)  and  of  Fr.  Miiller  (190G(c)), 
both  of  whom  reported  the  development  of  glucosuria  in  patients  w^ho  were 
taking  thyroid  gland  in  excessive  amounts.  Von  Xotthaft  (1898)  also 
reports  a  case  of  true  exophthalmic  goiter  complicated  by  glucosuria  de- 
veloping in  an  obese  individual  who  had  taken  1000  thyroid  tablets  in  the 
course  of  five  weeks. 

There  is  no  interference  with  carbohydrate  oxidation  in  case  of  hyper- 
thyroidism. The  respiratory  quotient  after  the  ingestion  of  100  gi*ams  of 
glucose,  in  the  obseiTations  of  DuBois  (191G(&) ),  was  0.94  and  0.98,  in  the 
latter  case  showing  that  89  per  cent  of  the  calories  was  derived  from  the 
glucose  oxidation.  On  the  other  hand,  the  basal  metabolism  of  the  pa- 
tient 17  hours  after  the  last  meal  shows  a  respiratory  quotient  of  0.77, 

'Excellent  reviews  of  the  literature  up  to  190S  are  given  by  S.  Piosenborg:  "Innere 
Sekretion,  Pankreas  unci  Glykolyse,"  in  Oppenlieimer's  Handbuch  dcr  IJiochemie  des 
Menschen  und  der  Tiere.  Vol.  Til,  part  I.  pp.  245-270.  And  up  to  10] 3  by  F.  M.  Allen 
in  Studies  concerning  Glycosuria  and  Diabetes,  chapter  XXI,  pp.  898-985. 


THE  CARBOHYDRATES  AND  THEIR  METABOLISM  261 

which  indicates  a  low  carbohydrate  combustion  which  can  only  be  ex- 
plained on  the  basis  of  low  glycogen  resci-voir.  This  is  in  conformity  with 
the  findings  of  Cramer  and  Kraus  (li>l.*5j  who  found  that  after  thyroid 
ingestion  the  liver  does  not  retain  glycogen  as  well  as  before. 

The  etlect  of  the  tliyroid  on  carbohydrate  metabolism,  therefore,  is 
purely  through  its  interference  with  glycogen  formation  and  mobilization. 
Its  effect  is  similar  to  that  of  adrenalin  and  sympathetic  stimulation,  and 
the  probabilities  are,  that  they  all  act  through  the  same  channel. 

Influence  of  the  Pituitary  Gland. — The  pituitary  gland,  similar  to 
the  thyroid,  has  a  tendency  to  aflect  the  carbohydrate  metabolism  when 
in  a  state  of  hyperactivity.  Cushing  (1013)  found  that  the  administra- 
tion of  extract  of  the  posterior  lobe  of  pituitary  was  followed  by  a  reduc- 
tion in  the  carbohydrate  tolerance  and  by  a  mobilization  of  glycogen.  On 
the  other  hand,  patients  with  acromegaly,  who  are  sup[K>sed  to  suffer  from 
an  hyperfunctioning  of  the  anterior  lobe  of  the  pituitary,  very  frequently 
show  evidences  of  lowered  carbohydrate  tolerance  and  of  glucosuria. 

Borchhardt  (1008)  found  glucosuria  in  40  per  cent  of  his  cases  of 
acromegaly,  but  in  no  case  of  tumor  of  the  pituitary  that  was  not  acro- 

ialic. 

There  is  at  present  no  reason  to  believe  that  the  pituitary  extracts 
affect  the  carbohydrate  metabolism  in  any  other  way  than  do  the  extracts 
of  the  adrenals  and  thyroid.  All  three  seem  to  have  the  power  of  stimulat- 
ing the  sympathetic  nervous  system,  and  the  reaction  they  produce  differs 
only  in  degree.  The  effect  of  adrenalin  is  most  powerful;  those  of  the 
thyroid  and  pituitary  will  only  bo  determined  after  their  respective  ef- 
fects have  been  studied  with  their  active  principles. 

Just  as  the  patellar  reflex  may  he  used  clinically  for  roughly  de- 
tenmning  the  state  of  nervous  tension  of  an  individual,  so  the  carbo- 
hydrate tolerance  test  may  he  used  clinically  for  determining  roughly 
the  state  of  an  individual's  tonus  of  the  sym pathetic  nervous  system.  But 
we  cannot  employ  that  at  present  to  differentiate  between  affections  of  the 
thyroid,  pituitary  or  adrenal. 


The  Intermediary  Metabolism  of  Carbohydrates 

All  the  processes  of  metabolism  aim  at  two  objects,  first  to  build  up 
and  maintain  the  body  structure,  second  to  produce  the  material  that  can 
be  used  for  d^namogenetic  purposes.  It  is  most  surprising  that  in  spite 
of  the  large  number  of  chemical  compounds  that  play  a  role  in  metabolism, 
only  ver)^  few  are  "fit  to  burn."  In  the  chapter  on  protein  metabolism  it 
was  brought  out  that  fully  fifty-eight  per  cent  of  the  protein  molecule 
passes  through  a  glucose  stage.  Over  ten  per  cent  of  the  fat  molecule 
(the  glycerol  fraction)   passes  through  a  glucose  stage,  and  all  of  the 


202  A.  I.  lUXGEK  AND  E.M1J.  J.  BAIJMANJS^ 

carLolijdratcs  aro  converted  into  glucose..  We  can  therefore  see  that  glu- 
cose is  the  main  channel  of  chemical  action  in  the  animal  body,  for  from 
all  sides  the  reaction  swings  in  its  direction. 

Ihit  the  cells  of  the  hxiy  cannot  oxidize  glucose  directly.  The  glucose 
molecnde  must  first  undergo  a  series  of  reactions  during  which  it  is  broken 
up  into  much  smaller  and  simpler  compounds,  and  only  those  can  be  oxi- 
dized by  the  cells  to  yield  energy.  We  may  liken  the  process  to  the  grind- 
ing down  of  grain  to  a  flour  in  a  mill,  which  is  at  the  same  time  forcing 
the  product  through  a  series  of  sieves,  each  consecutive  sieve  having  smaller 
and  smaller  meshes.  Only  those  particles  that  can  go  through  the  finest 
mesh  will  be  fit  for  consumption.  All  tlie  others  must  be  reground.  One 
difference  between  the  mill  and  the  animal  body  is  that  in  the  mill  tho 
process  is  irreversible,  that  is  to  say,  a  particle  that  is  once  ground  down 
remains  so,  whereas  in  the  animal  body  tho  process  is  a  reversible  one, 
the  particles  possessing  the  jwwer  of  again  polymerizing  and  flying  back 
into  an  upper  sieve.  The  result  is  a  continuous  and  endless  grinding  pres- 
sure from  above  and  a  continuous  flying  back  to  the  upper  sieves. 

The  grinding  down  pi'ocess  may  be  illustrated  thus  (the  double  arrow 
showing  where  the  process  is  reversible). 

GLUCOSE 

I 

Glyceric  Aldehyde  7:"^  Glycerol  ;     ^  To  fat  formation. 
Pyruvic  Aldehyde 

Jfw    : 

Lactic  Acid^HlAlanin^ZlTo  protein  formation. 
Pyruvic  Acid 

J 

Acetaldehyde ^  Aldol  Condensation  ->  Fatty  acid  formation 

Acetic  Acid  Alcohol 

U       /\ 

GO2    H2O        COo     HoO 

The  study  of  the  intermediary  metabolism  of  carbohydrates  is  fraught 
with  great  difficulty.     In  the  first  place  we  deal  with  substances  that  arc 


THE  CAKBOIIYDRATES  AND  THEIR  METABOLISM  263 

exceedingly  soluble  and  therefore  offer  great  technical  difficulties  in  their 
isolation,  purification  and  identification.  Secoudly,  most  of  the  sub- 
stances are  oxidized  with  great  ease  so  that  at  no  time  can  one  find  more 
than  traces  of  them,  even  though  throughout  the  twenty-four  hours  hirgo 
quantities  may  have  been  [)roduced.  Our  infonnation  therefore  must  be 
}>ieced  together  from  various  and  indirect  sources. 

It  has  long  been  known  that  in  the  presence  of  alkali,  glucose  undergoes 
decomposition,  giving  rise  to  lactic  acid.  In  the  animal  body  lactic  acid  ap- 
pears in  the  blood  and  urino  in  cases  of  asphyxiation,  severe  anemias,  and 
after  great  muscular  exertion.  The  following  experimental  proof  shows 
that  this  lactic  acid  can  have  its  origin  in  glucose.  !Mandel  and  Lusk 
(1006)  found  that  after  giving  phosphonis  to  a  dog  lactic  acid  appeared 
in  the  urine  in  large  quantities.  When  they  administered  phlorhizin  to 
the  same  dog  the  animal  of  course  became  diabetic,  and  the  lactic  acid 
disappeared  from  the  urine,  indicating  that  the  lactic  acid  could  have  been 
derived  only  from  the  catabolized  glucose.  This  work  is  corroborated  by 
von  Fiirth  (1914,  b)  who  found  that  the  amount  of  lactic  acid  excreted  in 
phosphorus  poisoning  is  increased  after  administering  glucose  to  the  ani- 
mal. Final  and  most  convincing  evidence  was  brought  forward  by  Levene 
and  IMeyer  (1913,  b)  when  they  showed  that  leucocytes  and  kidney  tissues 
possess  the  power  of  converting  glucose  into  lactic  acid,  and  by  Embden 
and  Krausa  (1912)  who  found  that  the  addition  of  glucose  to  blood  that  is 
perfused  through  a  surviving  liver  causes  the  appearance  of  considerable 
amounts  of  lactic  acid. 

Embden,  Baldes  and  Schmitz  (1912)  also  demonstrated  that  washed 
blood  corpuscles  have  the  power  of  converting  glyceric  aldehyde  into  lactic 
acid  to  the  same  extent  that  they  do  glucose,  indicating  the  possibility  of 
glyceric  aldehyde  being  an  intermediaiy  stage.  They  also  showed  that 
glyceric  aldehyde  when  perfused  through  the  liver  is  reduced  to  glycerol, 
and  S.  Oppenheimer  (1912)  added  the  infonnation  that  glycerol  when 
perfused  through  the  liver  gives  rise  to  lactic  acid. 

Then  follow  experiments  by  Mayer  (1912)  in  which  he  showed  that 
after  administering  pymvic  acid  to  animals  lactic  acid  appeared  in  the 
urine,  and  by  Embden  and  Oppenheimer  who  obtained  large  amounts  of 
lactic  acid  after  perfusing  the  liver  with  pyruvic  acid. 

Finally,  there  is  a  whole  array  of  experimental  proof,  showing  with 
what  ease  various  substances  which  are  believed  to  bo  products  of  inter- 
mediary metabolism  are  converted  back  into  glucose  when  fed  to  dial)etic 
j-nimals;  for  glyceric  aldehyde,  Woodyatt  (1915)  ;  for  dioxyacetone,  Ringer 
and  Frankel  (1914(c))  ;  for  pyruvic  aldehyde,  Dakin  and  Dudley  (1913)  ; 
for  pynivic  acid.  Ringer  (1913),  Dakin  and  Janney  (1913),  Cremer 
( 1913)  ;  for  lactic  acid,  ^landel  and  Lusk  (1906). 

In  the  following  chart  the  various  reactions  that  may  take  place  in 
the  intermediaiy  metabolism  of  glucose  are  indicated. 


264 


A.  I.  RIXGER  AND  EMIL  J.  BAUMANN 


O  >  ^ 


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g  o 


woo 
o— o— O 


o^  w    o'5^ 

C-      O      K  J^TJ 

o  — -o  — o  :l?2 


q.  t:  a  ^  ^-  o 
K  o  o  tii.  o  a 
o  — o  — -o  — o  — u  — o 

K      Jh      O      ^ 


THE  CAIiBOlIYDRATES  AND  THEIR  METABOLISM  265 


d   O 


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s"  a      d'   8 

>. 

U— O      —O— Q 

^ 

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a 

o 

V» 

u 

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P^ 

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s   w      w   8 

o— o    — o— o 

k 

a 

o 

n 

/-T 

T» 

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o 

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o  — O     =0  — o  — o 


I    -  I 

-      O      O  § 


2GG  A.  I.  EIiVGER  AXD  EMIL  J.  BAUMANIS^     : 

We  must  picture  these  changes  more  from  the  dynamic  point  of  view 
than  from  the  static.  We  must  realize  that  in  every  cell  of  the  body  the 
protoplasm  is  in  constant  motion.  It  is  a  system  where  hundreds  of  chem- 
ical reactions  are  going  on  continuously  and  almost  simultaneously,  where 
molecules  are  flying  hither  and  thither,  some  imdergoing  oxidation,  others 
undergoing  reduction,  and  the  whole  struggling  to  reach  an  equilibrium. 
This  struggle  for  chemical  equilibrium  constitutes  the  life  of  the  cell. 
It  is  important  also  to  bear  in  mind  that  the  substances  formulated  in 
the  chart  do  not  normally  represent  products  of  intermediary  metabolism, 
but  rather  stages  or  stations  along  a  certain  route  of  decomposition.  *  The 
reaction  does  not  stop  at  any  of  these  points  for  any  length  of  time  to  allow 
an  accumulation  of  the  products,  except  under  abnonnal  conditions.  For 
example,  when  the  supply  of  oxygen  is  insufficient  the  process  may  halt  at 
the  lactic  acid  stage,  then  lactic  acid  can  be  detected  in  quantity.  Just 
as  an  express  train  operating  between  New  York  and  Chicago  cannot 
arrive  at  its  destination  suddenly,  but  must  go  through  certain  stations 
along  the  route,  so  glucose  must  pass  certain  intermediary  stages  before 
reaching  carbon  dioxid  and  water.  If  the  power  does  not  hold  out,  natur- 
ally there  will  be  a  forced  stop  at  one  of  the  stations. 

When  we  view  the  reactions  on  the  chart  we  must  also  realize  that  there 
are  two  forces  operative,  one  which  drives  the  reaction  downward  and  an- 
other wdiich  drives  it  backward  to  glucose.  We  are  inclined  to  attribute 
them  to  the  action  of  fei-ments.  But  ferments  are  blind  forces  that  do  not 
determine  the  direction  of  the  reaction.  Whether  it  goes  to  one  side  or 
another  is  controlled  by  physical  chemical  factors  such  as  the  mass  action 
or  relative  concentration  of  the  components.  When  the  glucose  concentra- 
tion is  high,  the  reaction  swings  in  two  directions  with  relatively  gi'eat 
force  and  speed.  Glucose  is  rapidly  converted  to  glycogen  on  the  one 
hand  and  to  glyceric  aldehyde  on  the  other. 

Glycogen:^GLUCOSE';z:lGlyceric  aldehyde 

But  the  reactions  from  glycogen  to  glucose  and  from  glyceric  aldehyde  to 
glucose  cannot  be  considered  stopped.  They  probably  go  on  at  the  same 
time,  but  the  former  reactions  overshadow  the  latter.  Similarly  if  gly- 
ceric aldehyde  is  fed  to  an  animal  we  may  picture  the  reaction  in  both  di- 
rections, but  going  primarily  in  the  line  of  least  resistance. 

^,^-;^Dioxyacetone 
Glucoselz::;GLYCERIC  ALDEHYDE  ::;;;^ 

"*^^  Pyruvic  aldehyde 
And  so  on  with  the  other  reactions. 

On  the  basis  of  these  last  considerations  one  may  find  an  explanation 
for  the  formation  of  glucose  from  practically  all  the  intennediary  metabo- 
lites of  glucose  when  administered  to  diabetic  animals.  When  one  gives 
any  of  these  substances  to  a  normal  animal  the  reaction  of  that  substance 


THE  CARBOHYDEATES  AXD  THEIR  lUETABOLISM  267 

swings  to  left  and  right,  that  is,  to  glucose  and  downward.  The  particles 
that  go  over  to  glucose  are  ultimately  broken  down  again,  so  that  in  the 
course  of  time  the  whole  amount  given  is  completely  oxidized  to  carbon 
dioxid  and  water.  Because  of  the  relatively  high  concentration  in  the 
blood  of  the  substance  under  discussion,  the  kidney  may  excrete  some  of  it 
and  also  those  products  which  stand  nearest  to  it  (excretion  of  lactic  acid 
in  the  urine  after  pyruvic  acid  administration).  But  if  the  same  metabo- 
lite is  fed  to  a  diabetic  animal,  the  moment  a  particle  is  converted  to 
glucose  it  beconies  trapped,  because  these  animals  have  lost  the  power  of 
splitting  the  glucose  molecule.  The  reaction  becomes  one-sided  and  ir- 
reversible, and  if  the  oxidative  processes  are  not  ver)-  great  the  substance 
may  be  completely  converted  to  glucose. 

Glucose  < METABOLITE  :^  Lower  product 

It  will  now  be  readily  seen  that  a  number  of  three  carbon  compounds, 
namely  glyceric  aldehyde,  dioxyacetone,  pyruvic  aldehyde,  lactic  acid  and 
pyruvic  acid,  may  be  safely  considered  stages  of  glucose  catabolism,  and 
that  these  substances  in  the  animal  body  may  undergo  reactions  whereby 
one  is  converted  into  the  others  either  by  processes  of  oxidation,  reduction, 
hydration,  dehydration  or  by  rearrangement  of  the  position  of  hydrogen  in 
the  molecule.    All  of  these  steps  are  reversible. 

One  of  the  later  stages  in  the  reaction  is  a  process  of  decarboxilation 
during  which  a  three  carbon  compound  is  convei-ted  into  a  two  carbon  com- 
pound with  the  loss  of  carbon  dioxid.  This  is  the  first  irreversible  reaction 
in  the  entire  chain. 

CH:,  CH3 

I  — >        i 


CO  OHO  +  CO 


COOH 
Pyruvic  Acid >     Acetaldehyde 

That  pyruvic  acid  can  be  converted  into  acetaldehyde  was  demonstrated 
in  a  series  of  experiments  by  Xeuberg  and  Karczaz  (1911,  1912).  They 
found  that  all  yeast  cells  possess  that  power  and  that  the  decarboxilation 
is  brought  about  by  an  enzyme,  ^'carboxylase." 

Acetaldehyde  is  a  very  important  intermediary  stage  of  carbohydrate 
catabolism.  Just  as  lactic  and  pyruvic  acids  link  the  carbohydrate  metab- 
olism with  that  of  protein,  so  acetaldehyde  links  carb'->hydrate  with  fat  me- 
tabolism. As  will  be  shown  later  acetaldehyde  is  in  all  probability  the  start- 
ing point  from  which  fat  is  built  up  in  the  body.  Acetaldehyde  in  the 
organism  may  undergo  oxidation  to  acetic  acid  which  on  further  oxidation 
is  converted  to  carbon  dioxid  and  water.  It  may  also  be  reduced  to  ethyl 
alcohol,  which  is  ultimately  oxidized  to  carbon  dioxid  and  water. 


268  A.  I.  RIXGER  AND  EMIL  J.  BAU:\[ANX 

It  is  only  from  these  final  oxidations  that  the  cells  of  the  body  derive 
their  energy.  All  the  changes  that  the  foodstuffs  undergo,  be  it  in  the 
process  of  digestion  or  later  in  metabolism,  are  all  aimed  to  prepare  them 
for  the  stage  in  which  the  cells  can  utilize  them  for  energy'  formation. 
Whether  we  start  with  the  complex  protein  molecule,  the  high  carbohydrate 
molecule  or  the  comparatively  simple  fat  molecule, — they  must  all  be 
ground  down  in  the  mill  of  metabolism  to  fit  the  finest  meshes  of  the  sieve. 
They  all  have  to  come  down  to  the  two  carbon  stage  which  is  burned  with 
the  liberation  of  heat  and  energy. 

Fat  Formation  from  Carbohydrate 

That  animals  can  be  fattened  by  feeding  them  large  amounts  of  carbo- 
hydrates has  been  known  to  stockmen  for  centuries.  Scientific  proof  for 
it  has  been  presented  during  the  course  of  the  last  century  by  a  number 
of  authors.  ^^ 

The  question  that  confronts  us  to-day  is,  how  can  we  picture  the  trans- 
fer of  the  highly  oxidized  glucose  molecule  to  the  oxygen  poor  fatty  acid  ? 
It  is  chemically  inconceivable  that  there  is  a  direct  abstraction  of  oxygen 
and  that  three  glucose  molecules-  become  converted  into  an  eighteen  carbon 
fatty  acid.  We  must  therefore  assume  that  the  fatty  acids  are  built  up 
from  more  elementary  compounds. 

When  one  makes  a  survey  of  all  the  fats  known  in  the  animal  and 
plant  kingdoms,  one  is  struck  by  the  fact  that  in  no  place  is  there  a  natural 
fatty  acid  to  be  found  that  has  an  odd  number  of  carbons.  In  milk,  for 
example,  there  is  present  a  variety  of  fatty  acids.     There  we  find, 

Butyric  Acid,  CHsCHoCHaCOOH  (4  Carbons) 

Caproic  Acid,  CHsCHoCHgCHgCHsCOOH  (6  Carbons) 

Caprylic  Acid,  CH3CH0CH2CH2CH2CH2CH2COOH  (8  Carbons) 

Capric  Acid,  CH3CH2CH2CH2CH2CH2CH2CH2Cn2C00H 

(10  Carbons) 

Laurie  Acid,  Cn3CH2CHoCIl2CH2CH2CH2CH2CH2CH2CH2COOK 

(12  Carbons) 

Myristic  Acid,  CH3CH2CHoCnoCH2CH,CH2CHoCH2CHo 

Cn2CIl2CH2C00H   (14  Carbons) 

Palmitic  Acid,  CH3CH2CH2CH0CH2CH2CII0CII0CH2CH2 

CH2CH2CH2CH0CH2COOH   (16  Carbons) 

Stearic  Acid,  CHaCH.CHoCH.CHoCHoCHoCHsCHsCHo 

CH2CH2CH2CH2ClLCH2Cn2COOH  (18  Carbons) 

'•A  review  of  the  literature  may  be  found  in  "Die  Fette  im  Stoffwechsel,"  bv  h. 
Magnus  Levy  and  L.  F.  Mever,  in  Oppenheiraer's  Handbuch  der  Biochemie  dea  Menschen 
und  der  Tiere,  vol.  4,  part'l,  p.  449,  1908. 


THE  CxVRBOHYDKATES  AND  THEIR  METABOLISM  269 


We  have  every  reason  to  assume  that  all  the  lower  fatty  acids  found  in 
milk  are  intermediary  in  the  building  up  of  the  higher  fatty  acids.  If 
fatty  acids  were  built  up  by  the  addition  of  one  carbon  we  should  find 
just  as  many  odd  carbon  fatty  acids  as  even.  This  consideration  led 
Xencki  as  far  back  as  1878  to  suggest  that  fatty  acids  are  built  up  by  con- 
secutive additions  of  two  carbons,  and  that  the  two  carbon  compound  is 
probably i^cetaldehyde  which  displays  exceptional  chemical  reactivity. 

Support  for  this  assumption  may  be  found  in  the  fact  that  in  their 
catabolism  fatty  acids  undergo  a  series  of  p-oxidation,  whereby  they  lose 
two  carbons  in  successive  stages  (Knoop  (1910,  h),  Ringer  (1913,  a).  In 
vitro,  acetaldehyde  will  under  certain  conditions  undergo  what  is  known  as 
aldol  condensation,  whereby  one  acetaldehyde  molecule  combines  with 
another,  forming  aldol,  which  is  a  four  carbon  aldehyde.  Raper  (1907) 
has  succeeded  in  building  up  an  eight  carbon  aldehyde  in  this  way,  which 
he  also  easily  oxidized  to  caprylic  acid. 


OH, 


CHs 


CHO 


+ 


CH3 

I 
CHO 

Acetaldehyde 


CHOH 

I 
CH2 

I 
CHO 

Aldol 


Smedley  and  Lubrynzka  (1913)  bring  forth  evidence  that  fat  formation 
in  the  body  proceeds  through  the  condensation  of  an  acetaldehyde  molecule 
with  that  of  pyruvic  acid,  forming  first  a  four  carbon  aldehyde  which 
later  combines  with  another  pyruvic  acid  molecule,  giving  rise  to  a  six 
carbon  aldehyde.  The  process  thus  repeats  itself  until  the  sixteen  and 
eighteen  carbon  fatty  acids  are  reached. 


CH, 


OH. 


CH. 


CHO     + 


CH 

II 


CH 

II       +CO, 


Acetaldehyde     CH3     Splitting  off     CH    Decarboxilation  CH 

I  ofH,0  I  I 

CO  CO  CHO 

I  I 

COOH  COOH 

Pyruvic  Acid  cc-Keto-angelic  Crotonic 


Acid 


Aldehyde 


270 


A.  I.  EIXGEK  AND  EMIL  J.  BAUMAXN 


CH3                                   CH3 

1                 +^. 

CII    >    CH2 

II     Keduction    | 

CH                     CH2 
1 

Clio                 CHO 

Crotonic     Butyl  Aldehyde 
Aldehyde 

CH, 

j 

CH3 

1 

CH3 
1 

CH, 

1 
CH, 

1 

1 
CH2 

1 
CH2 

— *         1               — > 

CH2        • 

1 

cn2 

1         +CO, 

CHO        +  Splitting  off  CH     Decarboxilation     CH 

CH3  oflLO  II  II 

Butyl  aldehyde  I  CH  CH 

CO  I  I 

I  CO  CHO 

COOH  I 

Pyruvic  Acid  COOH 

CH3  CH3 


CH, 


CHo  -^  +  H2  - 

I       Eeduction 

CH 

!l 

CH 


CH2 

I 
CH, 


Unites  with  another  molecule  of  pyruvic 
->     acid,  and  so  on  until  the  higher  com- 
pounds are  reached. 


CHO 


CH2 

I 
CH2 

I 
CHO 

Oaproic 
Aldehyde 

From  the  above  we  may  see  that  fat  formation  can  only  take  place  in  nor- 
mal animals  that  have  the  power  of  splitting  glucose,  for  the  building  stones, 
acetaldehyde  and  pyruvic  acid,  are  mainly  products  of  glucose  catabolism 
In  conditions  of  diabetes  in  which  there  is  a  loss  in  the  individuaPs  ability 
to  break  down  the  glucose  molecule,  fat  formation  from  carbohydrate  must 
be  coiTespondingly  reduced.  This  helps  to  account  for  the  extreme  and 
rapid  emaciation  in  severe  diabetes. 


THE  CARBOHYDRATES  AND  THEIR  METABOLISM  271 

The  Functions  of  Carbohydrate  in  the  Diet. — ^The  pa la mount  func- 
tion of  carbohydrate  in  the  diet  is  to  yield  enerjiv  to  the  cells  in  the  process 
of  its  oxidation.  It  burns  in  the  body  apparently  with  greafer  ease  than 
does  protein  or  fat,  hence  it  may  be  considered  as  having  a  sparing  influ- 
ence on  both.  With  r(\t»ard  to  protein  its  influence  is  more  s[>€cific,  for 
the  intermediary  products  of  carbohydrate  metabolism,  lactic  acid  and 
pyruvic  acid  have  been  shown  to  have  the  power  of  uniting  with  ammonia 
in  the  liver  and  giving  rise  to  alanin.  This  consen-es  nitrogen  for  the 
body,  which  would  ordinarily  have  been  excreted,  Knoop  (1910),  Eml> 
den  (1010),  and  Schmitz  (1010).  E(ir  further  discussion  of  the  influ- 
ence of  carbohydrate  on  pi*otein  metabolism  sec  the  chapter  on  Protein 
!Metabolisni,  page  118. 

Influence  of  Carbohydrate  on  Intermediary  Metabolism  of  Fat.  An- 
tiketogenesis.- — Or<linarily  when  fat  burns  in  the  body  it  is  completely 
oxidized  to  carbon  dioxid  and  water.  Under  certain  conditions,  however, 
the  oxidation  is  not  complete.  In  eases  of  absolute  starvation  "acetone 
bodies"  (P-hydroxybutyric  acid,  aceto-acetic  acid,  and  acetone)  appear  in 
the  iirine,  the  last  because  of  its  extreme  volatility  is  also  excreted 
through  the  breath.  If  an  individual  is  kept  on  a  diet  of  protein  and  fat 
without  any  carbohydrate,  these  bodies  will  also  appear  in  the  urine.  In 
severe  diabetes  where  the  combustion  of  carbohydrates  is  completely  lost, 
the  amount  of  acetone  bodies  form^ed  may  be  enormous,  over  one  hundred 
grams  a  da  v.    Because  the  aceto-acetic  acid  and  the  acetone  have  the  car- 

I 

nonyl  (CO)  radical,  they  are  known  as  ketones  and  their  formation  in 

I 

the  body  is  called  ketogenesis.  All  the  acetone  bodies  originate  from  the 
catabolism  of  fat  and  from  certain  of  the  amino  acids  of  protein  metal» 
lism. 

Because  it  was  recognized  that  whenever  carbohydrates  bum  in  the 
body  ketogenesis  stops  and  that  no  ketogenesis  occurs  as  long,  as  the  body 
is  capable  of  oxidizing  glucose,  antiketogenetic  properties  were  attributed 
to  glucose. 

In  normal  fasting  individuals  who  develop  ketonuria,  certain  sub- 
stances like  glycerol,  glycocoll,  alanin,  and  aspartic  acid  have  proven  to 
be  antiketogenetic.  In  diabetic  individuals,  however,  they  are  without 
effect,  because  they  are  completely  converted  to  glucose  and  excreted  as 
such.  Alcohol  has  proven  to  be  a  marked  antiketogenetic  substance.  (O. 
Xeubauer  (1900),  Benedict  and  Torok  (1900).) 

In  1913  Ringer  and  Frankel  performed  a  series  of  experiments  on 
diabetic  dogs  who  developcjd  considerable  ketonuria.  After  adminis- 
tering acetaldehyde  to  these  dogs  they  found  a  very  marked  antiketogenetie 
effect.  At  the  same  time  they  also  obtained  an  increase  in  the  glucose 
elimination.     They  suggested  the  idea  that  it  was  possible  that  acetalde- 


272  A.  I.  EIXGEK  AXI)  EMIL  J.  BAOIAXX 

hyde  acted  by  virtue  of  its  combining  power  with  P-hydroxy butyric  acid, 
fonning  a  new  compound  which  is  ghicogenetic.  We  know  to-day  that 
acetaklehyde  is  a  very  important  product  in  the  intemiediary  metabolism 
of  carbohydrate,  and  it  is  very  likely  that  the  antiketogenetic  effect  of 
glucose  is  brought  about  through  acetaldehyde-P-hydroxy butyric  acid  or 
acetaldehyde-aceto-acetic  acid  combination. 


Water  as  a  Dietary  Constituent Philip  B.  Hawk  ^ 

Introduction — Influence  of  an  Increased  Ingestion  upon  Metabolism — Influ-  ^ 

ence  on  Basal  Metabolism — Influence  of  a  Diminished  Water  Intake—  | 

Water  Drinking  with  Meals — Influence  on  Salivary  Digestion — Influence  | 

on  Gastric  Digestion — Passage  of  Water  from  the  Stomach — Influence  | 

of  Pancreatic  Digestion — Influence  on  Intestinal  Flora  and  Putrefaction  | 
— Influence  on  Absorption — Influence  on  Blood  Volume  and  Blood  Pres- 
sure— Distilled  Water — Ice  Water — Conclusions. 


Water  as  a  Dietary  Constituent 


PHILIP  B.  HAWK 

PHILADELPHIA 

Introduction 

The  average  man  who  lives  among  water  mainSy  hydrants,  and  street 
sprinklers  and  in  the  vicinity  of  rivers  and  lakes  gives  little  or  no  thought 
to  the  impoi-tant  part  water  plays  in  his  life  processes,  if  indeed  he 
possesses  any  definite  knowledge  on  the  subject.  If  such  a  man  were 
possessed  of  an  introspective  hydro-eye,  he  could  quickly  convince  him- 
self that  *Svater"  and  "life''  are  synonymous  terms  so  far  as  the  human 
body  is  concerned.  If  he  would  flash  the  rays  of  this  eye  upon  himself, 
he  would  find  that  the  hlood  plasma,  that  important  carrier  of  nutritive 
material  to  ex^ery  organ  and  tissue,  contains  over  90  per  cent  of  water; 
that  the  brain,  which  regulates  and  correlates  so  many  intricate  activities 
and  processes,  contains  from  85  to  90  per  cent  water;  that  the  liver  cell, 
which  is  associated  with  so  many  processes  which  are  vital  to  the  main- 
tenance of  normal  metabolism,  contains  75  per  cent  water;  that  the 
mighty  muscle,  which  is  so  importantly  related  to  feats  of  strength,  is 
three-fourths  water;  that  the  saliva,  which  quickly  reduces  the  cc«nplex 
and  insoluble  starch  of  our  foods  to  a  simple  soluble  sugar,  is  almost 
pure  water  (99.5  per  cent)  ;  that  hone,  which  has  been  shown  by  test  to 
possess  a  tensile  strength  (25,000  pounds  per  square  inch)  one  and  one- 
fourth  times  as  gi-eat  as  that  of  cast  iron  and  more  than  twice  that  of 
good  timber,  is  40  per  cent  water;  and  finally,  if  he  would  put  his 
150-ix>und  body  in  an  electric  oven  and  drive  oft'  all  the  water,  the  under- 
taker would  have  to  handle  only  50  pounds,  because  the  human  body  as  a 
whole  is  about  two-thirds  water. 

Since  water  is  found  in  such  large  quantities  in  all  organs,  tissues, 
and  secretions  of  the  body,  it  is  not  surprising  that  water  is  absolutely 
essential  to  the  proper  performance  of  so  many  bodily  functions.  For 
example,  in  respiration  we  have  chemical  and  physical  processes  which 
are  dependent  upon  the  presence  of  water.  The  surface  of  the  lungs  must 
be  moist  before  there  can  be  any  exchange  of  carbon  dioxid  and 
oxygen.  The  regulation  of  body  temperature  is  facilitated  by  the  presence 
of  circulating  water  and  the  evaTX>ration  of  water  from  the  surface  of  the 

275 


27G  PHILIP  B.  HAWK 

skin,  wlicreas  an  increased  water  ingestion  has  been  found  to  lower  body 
temperature.  The  mucous  surfaces  of  the  body  cannot  function  normally 
unless  they  are  in  a  moist  state.  Water  is  the  medium  whereby  nutritive 
material  is  carried  to  the  body  cells,  and  the  cells  of  the  blood  are  trans- 
ported in  a  fluid  medium.  The  kidney  can  more  satisfactorily  eliminate 
toxie  substances  if  such  substances  are  brought  to  that  organ  in  a  well- 
diluted  form.  The  normal  movement  of  joints  and  tendon  sheaths  is 
possible  only  when  fluid  is  present.  Water  is  also  importantly  related  to 
absorption.  The  end-products  of  digestion  in  the  intestine  are  not 
eflBciently  absorbed  unless  such  end-products  are  properly  diluted  (see 
p.  291).  Water  also  increases  peristalsis.  It  has  also  been  suggested 
(Smith  and  Mendel)  that  "The  large  amount  of  water  in  the  cell  may  aid 
considerably  in  maintaining  the  optimum  temperature  of  the  cell,  for 
water  has  a  high  specific  heat.  The  large  percentage  of  water  in  the 
tissues  in  which  oxidation  is  most  intense  may  be  correlated  with  this 
unique  property  of  acting  as  a  heat  buffer." 

Inasmuch,  therefore,  as  water  is  so  vitally  related  to  man^s  well  being, 
it  is  not  strange  that  water  has  been  the  object  of  considerable  investiga- 
tion by  both  the  abstract  scientist  and  the  practical  clinician. 

That  physicians,  as  long  ago  as  the  early  part  of  the  eighteenth  century, 
were  impressed  with  the  dietary  importance  of  water  is  indicated  by  a 
pamphlet  published  in  London  and  reprinted  in  Philadelphia  in  1723. 
This  pamphlet  is  by  John  Smith,  C.  M.,  and  is  entitled  "Curiosities  of 
Common  Water,  or  The  Advantages  thereof  in  Preventing  and  Curing 
Many  Distempei*s."  The  author  claims  that  the  contents  of  the  pamphlet 
were  "Gathered  from  the  Writings  of  several  Eminent  Physicians,  and 
also  frc»in  more  than  Forty  Years'  Experience."  Among  the  interesting 
excerpts  from  the  volume  are  the  following: 

"In  the  County  of  Cornwall,  the  poorer  Sort,  which  did  never,  or  but 
very  seldom,  drink  any  other  drink  but  Water,  were  strong  of  Body,  and 
lived  to  a  very  gi-eat  age." 

In  another  place  the  author  of  the  volume  quotes  a  Doctor  Manwaring 
as  saying: 

"In  the  Primitive  Ages  of  the  World,  Water-Drinkers  were  the  longest 
Livers  by  some  Hundreds  of  Years — nor  so  often  sick  and  complaining 
as  we  are." 

And  later  Sir  Heni-y  Blount  is  quoted  as  saying  that  while  in  the  Levant 
"where  the  Use  of  Wine  was  forbid,  and  where  the  common  drink  was 
Watery  he  then  had  a  better  stomach  for  his  Food,  and  digested  it  more 
kindly  than  he  ever  did  before  or  since."  j 

To-day  practically  all  up-to-date  medical  men  appreciate  fully  the  im- 
portance of  water  to  the  human  body.  This  fact  is  attested  by  the  great 
development  along  certain  hydrotherapeutic  aspects  of  treatment  How- 
ever, some  doctors  say  to  their  patients,  "Drink  freely  of  water,  at  all 


WATER  AS  A  DIETAEY  COXSTITUEXT 


277 


times  except  during  meals,"  and  include  almost  invariably  a  warning 
against  ice  water  and  generally  against,  distilled  neater.  Such  advice  is 
analyzed  in  the  following  pages. 


Influence  of  an  Increased  Water  Ingestion  upon 

Metabolism 

That  an  increase  in  water  intake  will  produce  a  change  in  the  metabolie 
response  of  the  human  body  has  been  repeatedly  demonstrated  (Eichhorst, 
Feder(a)(&),  1878,  1881,  Falck,  E.  P.  and  F.  A.,  Genth,  Gruzdiev,  Matz- 
kevich,  Becher,  Neumann  (a),  Panum,  Itubner(6),  Schondorff(a),  Weige- 
lin,  Hawk(a) ).  The  consensus  of  opinion  on  this  point  is  that  an  increase 
of  500-5000  c.c.  in  the  daily  water  intake  of  a  normal  man  will  cause  an 
increased  excretion  of  total  nitrogen,  urea,  phosphorus,  and  generally 
sulphur  in  the  urine.  The  increase  in  total  nitrogen  and  urea  is  believed 
to  be  due  partly  to  the  washing  out  of  the  tissues  of  the  urea  previously 
formed,  but  which  has  not  been  removed  in  the  normal  processes,  and 
partly  to  a  stimulation  of  protein  catabolism.  The  increase  in  the  excre- 
tion of  phosphorus  is  probably  due  to  increased  cellular  activity  and  the 
accompanying  catabolism  of  nucleoprot^ins,  lecithins,  and  other  phos- 
phorus-containing bodies.  A  typical  nitrogen  balance  from  one  of  the 
writer's  experiments  follows: 

TABLE  C— INCOME  AND  OUTGO  OF  NITROGEN 

EXPEKIMEXT   I 


Experi- 
mental 
Period 

Length 

Period 
Days 

Nitrogen   (grams) 

Sub- 
ject 

In 
Food 

25.68 
25.68 
51.36 

In 
Urine 

In 
Feces 

Gain  or  Loss 
(+or— ) 

Average 

Gain  or  Loss 

per  Day 

Nature  of 
the  Diet 

I 
I 
I 

I 

II 

III 

2 
2 

4 

22.13 
24.30 
44.82 

2.95 

3.067 

4.568 

+  0.60 
— 1.687 
-f  1.972 

+  0.30 
—  0.844 
+  0.493 

Normal. 
4500  c.c.  wa- 
ter   added 

daily. 
Normal. 

Total 

8 

102.72 

9L2o 

10.585 

+  0.885 

+  0.110 

In  discussing  the  influence  of  water  upon  metabolism  Bischoff,  as  early 
as  1853,  wrote  as  follows: 

"Water  exercises  before  all  other  agencies,  apart  from  the  nitrogen 
content  of  the  food,  the  gi*eatest  influence  upon  the  excretion  of  urea 
by  the  urine." 

And  Foster,  the  eminent  English  physiologist,  said  in  an  early  edition 
of  his  "Text-book  of  Physiology'" : 

"Water  has  an  eifect  on  metabolism,  as  slio^vn,  among  other  thing-s,  by 


278 


PHILIP  B.  HAWK 


the  fact  tliat  when  tlie  water  of  a  diet  is  increased  the  urea  is  increased  to 
an  extent  heyand  that  whicli  can  be  explained  by  the  increase  of  fluid 
increasing  the  facilities  of  mere  excretion/* 

The  most  direct  evidence  that  an  increased  water  ingestion  increases 
cellular  activity  was  furnished  by  an  experiment  made  in  the  writer's 
laboratory  (Howe,  ^lattill  and  Hawk  (a).  Wreath  and  Hawk). 

A  dog  was  given  700  c.c.  of  water  daily  during  a  50-day  fast,  at 
wdiich  point  the  water  ingestion  was  increased  to  2,100  c.c.  for  each  day 
of  a  four-day  interval.  The  increased  water  intake  caused  an  increased 
excretion  of  "total  purin  nitrogen,"  i.e.,  nitrogen  in  the  form  of  purin 
bases,  uric  acid,  and  allantoin.  Inasmuch  as  this  form  of  nitrogen  has  its 
origin  in  the  cell  nucleus,  we  may  consider  that  an  increased  output  indi- 
cates stimulated  cellular  activity  and  increased  tissue  disintegration. 

Certain  other  observations  also  indicate  that  water  stimulates  tissue 
changes.  For  example  in  the  case  of  the  fasting  dog  just  mentioned,  the 
increased  water  intake  caused  the  appearance  of  considerable  creatin  in 
the  urine.  There  had  been  no  creatin  in  this  dog's  urine  for  a  considerable 
interval  before  the  high  water  intake.  However,  as  j  soon  as  the  water 
ingestion  of  the  animal  was  increased,  creatin  appeared  in  considerable 
quantity  in  the  urine.  The  creatin  was  interpreted  as  having  arisen,  at 
least  in  part,  from  disintegi-ated  muscular  tissue.  The  data  on  this  point 
are  embraced  in  the  following  table: 


TABLE  II 
Percentage  Excretion*  ix  Terms  of  Total  Nitrogex 


Dav  of 
Fast 

Urea 

Ammonia 

Creatinin        Creatin 

1 

Purin 

Allantoin 

Undeter- 
mined 

FASTIXG 700   c.c.    water  PER   DAY 

54-57 
58-50 

85.57 
85.28 

9.31 

8.55 

5.76 
5.75 

0.50 
0.57 

0..37 
0.42 

.... 

-     FASTiXG— 2100  C.C.  watp:i:  per  day 

60 
61 
62 
63 

79..54 

80.76 

78.40 
78.88 

9.20 

0.81 

12.63 

10.17 

4.38 
4.71 
4..30 
4.04 

0.67 
1.02 
1.03 
1.61 

0.10 
0.11 
0.06 
0.07 

0.71 
0.65 
1.16 
1.00 

5.41 
2.03 
2.04 
3.3.'? 

Other  observations  made  on  men  have  been  interpreted  as  indicating 
that  a  high  water  ingestion  causes  a  partial  muscular  disintegration  result- 
ing in  the  release  of  creatin,  but  not  profound  enough  to  yield  the  total 
nitrogen  content  of  the  muscle.  The  output  of  creatin  is,  therefore,  out 
of  all  proportion  to  the  increase  in  the  excretion  of  total  nitrogen  (Fowler 
and  Hawk). 

That  the  chloride  content  of  the  urine  is  increased  as  a  result  of  an 


WATER  AS  A  DIETARY  CONSTITUENT  279 

aiigiiicnted  water  intake  has  also  been  demonstrated  (Heilner(a.),  Kast, 
Rulon  and  Hawk,  Foster  and  Davis,  Benedict  (a)  ). 

Influence  on  Basal  Metabolism. — Apparently  Speck  is  the  only  ob- 
server who  has  studied  this  question  after  the  ingestion  of  volumes  of 
water  as  gi-eat  as  those  used  in  the  writer's  experiments,  i.e.,  3,000-4,500 
c.c.  per  day.  According  to  this  observer,  when  1,250  c.c.  of  water  was 
taken,  there  was  a  noticeable  rise  in  metabolism.  Benedict  and  Carpenter 
(6)  conclude  that  with  more  than  500  grams  of  cold  water,  an  increase 
as  great  as  10  per  cent  above  the  basal  value  may  be  obtained. 

Influence  of  a  Diminished  Water  Intake.  — If  no  water,  or  an  in- 
sufficient (Quantity  of  water,  enters  our  body,  we  quickly  become  abnormal. 
This  point  was  emphasized  in  connection  with  a  metal)olism  test  in  the 
writer's  hiboratory.  We  were  to  study  the  influence  of  an  increased  water 
ingestion.  Therefore,  in  order  to  have  a  pronounced  difference  between 
the  water  intake  of  the  preliminary  and  experimental  periods,  the  water 
quota  of  the  diet  of  the  preliminary  period  was  reduced  to  a  minimum. 
The  subjects  (men)  of  the  experiment  soon  gave  evidence  of  abnormal 
function  as  shown  by  headaches,  nervousness,  loss  of  appetite,  digestive 
disturbances,  and  inability  to  concentrate  on  the  performance  of  accurate 
chemical  work.  As  soon  as  the  above  symptoms  appeared,  the  water  con- 
tent of  the  diet  was  increased,  and  with  this  single  change  the  experiment 
proceeded  satisfactorily.  Dennig  and  Niles  have  also  shown  the  undesir- 
able effect  of  a  diminished  water  intake. 

That  man  or  a  lower  animal  ivlll  live  longer  loithoid  food  than  iviihoul 
ivater  is  well  recog-nized.  If  we  give  a  dog  all  the  food  he  wishes  but 
no  water,  the  beast  dies  in  a  short  time.  If  we  give  the  animal  no  food 
but  see  to  it  that  he  receives  plenty  of  water,  the  animal  will  live  much 
longer.  In  a  test  in  the  writer's  laboratory  in  1912  (Howe,  Mattill,  and 
IIawk(?))),  an  adult  dog  (26  kg. ),  which  was  given  TOO  c.c.  of  water  daily, 
lived  over  100  days  without  food.  Smimov  has  also  demonstrated  that 
fasting  rabbits  which  were  permitted  free  access  to  water  were  less  prone 
to  show  signs  of  fatty  infiltration  of  the  liver  than  were  similar  fasting 
rabbits  which  were  not  permitted  to  drink  water. 

Rubner  says  that  a  fasting  animal  may  lose  all  its  glycogen  and  fat  and 
one-half  its  protein  and  still  live,  hut  if  it  loses  one-tenth  of  its  ivater,  it 
dies.  We  are  continually  losing  water  by  way  of  the  kidneys,  lungs,  skin, 
and  bowel,  and  if  we  do  not  drink  sufficient  water  to  make  good  these  losses, 
our  body  quickly  ceases  to  function  properly  and  death  soon  follows. 
That  the  loss  of  water  through  skin  and  air  passages  may  be  considerable 
has  been  shown  by  direct  determination  (Soderstrom  and  DuBois). 
Normal  men  twenty  to  fifty  years  old  may  lose  by  these  channels  700 
grams  of  water  per  day,  and  the  water  thus  lost  carries  with  it  24  per 
cent  of  the  total  heat  produced  in  the  body.  Typhoid  patients  with  a 
rising  temperature  show  a  decreased  water  output,  while  the  reverse  is 


280  PHILIP  B,  HAWK 

true  wlien  the  temperature  falls.     In  general,  however,  the  output  of 
water  is  very  little  affected  in  disease. 

That  a  lack  of  free  water  in  the  body  may  bring  about  a  rapid  and 
high  increase  in  body  tempc^rature  has  been  demonstrated  (Balcar,  San- 
sum,  and  Wooilyatt,  Woodyatt(^f ) ).  When  sugar,  for  instance,  is  injected 
intravenously  in  a  dog  and  the  animal  is  given  no  water,  high  fever  and 
chills  soon  follow.  Temjxn-atures  as  high  as  120°  F.  have  been  obtained 
by  this  method.  The  sugar  produces  diuresis,  causing  a  lack  of  water  in 
the  dog's  body,  and  the  fever  and  high  temperature  follow. 

Certain  well  known  pathological  conditions  are  associated  with  a  loss 
of  water  from  tbe  body.  In  fatal  cases  of  Asiatic  cholera,  for  example, 
this  desiceaticHi  takes  place  to  such  an  extent  that  we  may  have  a  seruin 
loss  as  high  as  6^  per  cent  (Rogers).  If  isotonic  saline  be  injected  intra- 
venously into  sneh  cholera  patients,  the  fluid  is  immediately  and  com- 
pletely lost  by  \vay  of  the  bowel.  In  cases  of  poisoning  by  war  gas  (Under- 
bill), there  is  also  a  pronounced  loss  of  water  from  the  blood  and  the 
movement  of  water  into  the  lungs.  The  pneumonia  crisis  in  infants 
(Lussky  and  Friedstein)  has  been  shown  to  be  accompanied  by  decrease 
in  body  weight  <lue  to  loss  of  water. 

Water  Drinking  with  Meals. — Beginning  in  1908,  a  long  series  of 
studies  have  been  carried  out  in  the  writer's  laboratory  bearing  upon  the 
question  of  water  drinking  at  meal  time.  At  the  time  our  first  study  was 
made,  the  consensus  of  medical  opinion  was  opposed  to  the  mid-meal 
use  of  water.  Oertel,  who  was  an  advocate  of  fluid  restriction,  says,  '^The 
drinking  of  fluids  with  meals  causes  gi-eat  dilution  of  the  gastric  juice, 
retards  gastrfc  digestion,  and  favors  the  development  of  dyspepsia."  The 
following  quotation  (Carrington)  will  also  serve  to  emphasize,  in  a 
general  way,  some  of  the  reasons  why  physicians  were  opposed  to  the 
drinking  of  water  with  meals: 

"We  can  lay  down  the  definite  and  certain  rule  that  it  (water)  should 
never  be  drunk  at  meals,  and  pieferably  not  for  at  least  one  hour  after 
the  meal  has  been  eaten.  The  effect  of  drinking  water  while  eating  is, 
first,  to  artificially  moisten  the  food,  thus  hindering  the  normal  and 
healthful  flow  of  saliva  and  the  other  digestive  juices ;  secondly,  to  dilute 
the  various  juices  to  an  abnormal  extent ;  and  thirdly,  to  wash  the  food 
elements  through  the  stomach  and  into  the  intestines  before  they  have 
had  time  to  l)ecome  thoroughly  liquefied  and  digested.  The  effect  of  this 
upon  the  welfare  of  the  whole  organism  can  only  be  described  as  direful." 

However,  if  we  search  for  exj)erimental  proof  of  the  above  statements, 
we  fail  to  find  it,  no  matter  how  deeply  we  dig  into  the  musty  volumes  of 
scientific  and  medical  libraries.  In  all  my  search  I  have  never  found  a 
single  ex{)erimental  fact  which  can  rightly  be  interpreted  as  indicating 
that  the  taking  of  water  at  meal  time  is  harmful.  In  none  of  our  tests 
was* water  used  to  wash  do^vn  the  products  of  incomplete  mastication;  the 


/^ 


WATER  AS  A  DIETAEY  CONSTITUENT 


281 


food  was  invariably  masticated  without  the  aid  of  water.  Let  us  follow 
the  various  activities  of  the  digestive  tract,  from  mouth  to  anus,  and  see 
the  actual  influence  of  water  taken  with  meals  upon  these  activities. 

Influence  on  Salivary  Digestion. — It  is  not  necessary  to  believe  with 
Bunge  that  the  main  function  of  the  saliva  is  one  of  lubrication,  in  order 
to  show  that  the  presence  of  w^ater  aids  salivary  digestion.  The  following 
table  (Bergeim  and  Hawk)  shows  that  the  dilution  of  saliva  with  water 
facilitates  the  action  of  the  salivary  amylase: 

ErrecT  OF  Dilution  of  Saliva  in  Concentrated  Mixtures 
Diluent:  Filtered  tap  water.    Time  of  digestion:  10  min.    Temp.:  0*. 


No. 

Amount  of  Starch 
Paste 

>lo.  cc. 
Saliva 

Amount   of 
Water 

Mg.  of 
Maltose 

Dilution 
1: 

1 

1©  cc.  of  10% 
T  cc.  of  10% 
4  cc.  of  10% 
3  cc.  of  io% 
2  cc.  of  10% 
1  cc.  of   10% 
0.4  cc.  of  10% 
0.2  cc.  of  10% 

10 

7 
4 

i 

1 
0.4 
0.2 

'  6  cc. 

12  cc. 

14  cc. 

16  cc. 
18.0  cc. 
19.2  cc. 
19.6  cc. 

378.6 
441.8 
448.6 

458.5 
449.3 
305.4 
28.^.0 
287.6 

2 

2 

3 

3 

5 

4 

5 

7 
10 

6...! 

20 

7 

50 

8 

100 

The  diluent  in  the  ahove  experiment  was  ordinary  tap  water,  and 
the  optimum  dilution  was  six  volumes  of  water. 

Influence  on  Gastric  Digestion. — (Stimulatory  Power  of  Water), — 
The  most  severe  indictment  hrought  against  the  drinking  of  water  with 
meals  was  tiie  claim  that  water  thus  taken  would  dilute  the  gastric  juice 
and  hence  delay  digestion.  Those  who  advanced  this  criticism  overlooked 
the  fact  that  the  gastric  juice  is  manufactured  by  living  cells  which  are 
subject  to  cLemical  and  psychical  stimulation  and  that  water  is  a 
chemical  stimulant.  The  first  experiments  showing  that  water  possessed 
the  power  to  stimulate  the  flow  of  gastric  juice  were  apparently  made 
in  1879  (Heidenhain).  This  observation  was  later  repeatedly  confirmed 
by  other  investigators  (Carlson,  Orr,  and  Brinkman,  Foster  and  Lambei*t, 
King  and  Hanford,  Lonnquist,  Pavlov,  Sanotzky,  Sawitsch  and  Zeliony), 
all  of  whom  used  lower  animals  as  subjects.  Pavlov  was  not  impressed 
with  the  stimulatory  power  of  water — in  fact,  he  found  no  stimulation 
whatever  in  about  50  per  cent  of  his  tests  where  volumes  of  water  ranging 
from  100  to  150  cc.  w^ere  introduced  into  the  stomachs  of  dogs.  He 
says : 

"It  is  only  a  prolonged  and  widely  spread  contact  of  the  water  with 
the  gastric  mucous  membrane,  which  gives  a  constant  and  positive  result." 

Foster  and  Lambert  also  claimed  that  volumes  of  water  below  200  cc. 
exerted  no  appreciable  or  uniform  stimulation  in  the  stomach  of  the  dog. 
According  to  these  investigators  the  increase  in  the  flow  of  gasti-ic  juice 


282 


PHILIP  B.  HAWK 


which  follows  the  introduction  of  water  is  directly  pro[x>rtional  to  the 
volume  of  water  enij>loye(l.  This  point  is  shown  in  the  following  data 
taken  from  one  of  their  tests: 


300  e.c.  water 
500  c.c.  water 
750  c.e.  water 


— -  7.2  c.c.  gastric  juico 
^=^  17.7  c.c.  gastric  juico 
c  juice 


=  25.7  c.c.  gastr 


Chighin 


hatl  previously  shown   a  similar  proportionality.      The  ob- 
servations mentioned  were  made  by  the  use  of  the  Pavlov  pouch. 

The  first  experiments  showing  water  to  be  a  gastric  stimulant  in  the 

human  stomach  Avere  made  in  the 
writer's  laboratory  (Wills  and  Hawk). 
The  ingestion  of  water  at  meal  time 
by  two  men  was  accompanied  by  an 
increase  in  the  excretion  of  ammonia 
which  was  directly  proportional  to 
the  extra  volume  of  water  ingested. 
Inasmuch  as  certain  experiments  have 
demonstrated  that  water  stimulates  the 
flow  of  an  acid  gastric  juice  and  as 
certain  other  experiments  have  demon- 
strated that  the  formation  of  acid  in 
the  body  or  the  introductioa  of  acid 
from  without  produces  an  increase  in 
the  urinary  ammonia  excretion,  we 
feel  justified  in  assuming  that  the 
increase  in  the  ammonia  excretion  ob- 
served in  our  experiments  was  due 
directly  to  the  stimulation  of  gastric 
secretion  by  the  ingested  water.  That 
the  increase  in  the  ammonia  excretion 
did  not  arise  from  intestinal  putrefac- 
tion was  indicated  by  the  finding  of 
lowered  indican  values  during  the 
period  of  high  water  ingestion.  These 
observations  were  verified  by  Ivy  (a)  in  experiments  on  dogs. 

Since  these  observations  gave  only  ^'indirect"  data,  the  pi'oblem  was 
reinvestigated  in  the  writer's  laboratory  and  "direct"  evidence  of  stimula- 
tion obtained.  In  the  latter  investigation  (Bergeim,  Rehfuss  and  Hawk), 
water  was  introduced  into  the  stomachs  of  normal  men  and  samples  of 
gastric  contents  removed  at  intervals  of  ten  minutes  by  means  of  the 
liehfuss  tube  (Rehfuss)  and  analyzed  according  to  the  fractional  method 
C)f  gastric  analysis  (Hawk  (g)).  Figure  1  illustrates  a  pronounced  case  of 
water  stimulation  of  gastric  secretion,  and  Figure  2  illustrates  a  stimula- 


I'l 


-/%^/eF 


1. — Curve  allowing  pronounced 
stimulation  by  water  and  rapid 
'emptyin;,'  of  the  stomacli.  ( Berg- 
eim, Reljfuisa  and  Tlawk;  .Jour. 
Biol.  Cheni.,   1014,  XIX,  Uo.) 


WATER  AS  A  DIETAEY  COXSTITUEKT 


283 


H^nJiM 


eo 


Fig.  2. — Curve  showing  motlerate  stimu- 
lation by  water  (Bergeim,  Reh- 
f UKs  and  Hawk ;  Jour.  Biol.  Chera., 
1914,   XIX,   345.) 


turn  of  inoclcrate  iiitensity,  whereas  Figure  3  shows  but  slight  stimula- 
tion. These  tests  were  made  on  three  men  who  gave  normal  gastric  his- 
tories, and  serve  to  illustrate  the  fact  that  all  normal  stomachs  do  not 
vield  the  same  response  to  chemical 
stinmlation.  This  ix)int  has  been 
emphasized  throughout  our  work  on 
'•Gastric  Uespoiise'^  (Aliller,  Fowler, 
Bergeim,  lichfuss,  and  Hawk).  In 
other  words,  water  is  an  imp<^rtant 
gastric  stimulant,  but  it  does  not  ex- 
ert a  pronounced  stimulatory  effect 
in  every  normal  stomach — neither 
does  any  other  dietary  article.  This 
same  fact  has  also  been  brought  out 
by  Ivy (6).  Other  interesting  water 
experiments  have  also  been  made  by 
Sutherland,  and  by  King  and  Han- 
ford.  The  latter  investigators  say: 
''Water  given  with  meals  or  dur- 
ing digestion  results  in  the  following 
hour  in  an  increase  in  the  amount 

of  juice  secreted  over  that  which  would  be  secreted  on  the  administration 
of  either  water  or  meat  alone." 

Niles,  as  the  result  of  experiments  on  eight  men,  each  of  wliora 
received  one  liter  of  water  at  each  meal  for  one  week,  also  approves  of 
water  drinking  with  meals.     He  says,  "J^J'ot  one  of  the  eight  suffered  a 

single  qualm  of  indigestion, 
either  gastric  or  intestinal." 
That  the  water  some- 
times begins  its  stimulation 
as  soon  as  it  comes  in  con- 
tact with  the  human  gastric 
mucosa  is  illustrated  by 
Fig.  4.  In  this  experi- 
ment, after  removing'  the 
gastric  residuum  (Rehfuss, 
Eergeim  a  n  d  Hawk  (a)  \ 
Fowler,  liehfuss,  a  n  d 
Hawk)  of  a  normal  man, 
100  c.c.  of  water  was  introduced  into  the  empty  stomach  through  the 
Rehfuss  tidie.  That  there  was  no  latent  period  is  shown  by  the  fact  that 
an  acidity  of  15  was  registered  at  the  end  of  one  minute,  and  this  value 
had  risen  to  80  at  the  end  of  a  five-minute  interval.  Pavlov  claims  that 
the  stomach  of  the  dog  shows  a  latent  period  of  five  minutes,  whereas 


Fi<jf.   3.     Curve  showing  sli< 
water    in    the    human    stomacli. 
and  Hawk;   unpublished  data.) 


:ht   stimulation   by 
( Fowler,   Rehfuss 


284 


PHILIP  P.  HzVWK 


other  observers  (Bogcn,  Horiiborg,  Kaznelson,  Sick,  Umber)  claim,  as 
the  result  of  experiments  on  man,  that  the  latent  period  varies  from  3  to 
10  minutes.     Carlson  says: 

*^The  latent  period  of  the  appetite  secretion  varies  indirectly  with  the 
rate  of  continuous  secretion  so  that  when  the  continuous  secretion  is 
abundant,  the  apix?tite  secretion  shows  no  latent  period  at  all,  while  with 
the  lowest  rate  of  the  continuous  secretion,  the  latent  period  varies  from 
2  to  4  minutes." 

That  this  latent  period  does  not  exist  in  certain  human  stomachs  after 
water  stimulation  is  evident  from  our  data. 


'^^iM^ 


Fig.  4. — Curves  showing  immediate  stimulation  by  water  and  rapid  emptying  of  the 
stomach.     (Bergeim,  Rehfuss  and  Hawk;  Jour.  Biol.  Chem.,  1914,  XIX,  345.) 


It  has  also  been  claimed  that  the  gastric  glands  exhibit  a  pronounced 
fatigue  when  subjected  to  repeated  stimulation  (Foster  and  Lambert). 
That  this  pronounced  glandular  fatigue  is  not  always  in<evidenco  is  illus- 
trated in  Fig.  5.  A  nonual  man  was  given  500  c.c.  city  water  (10°-12^ 
C.)  at  1  p.  m.,  five  hours  after  breakfast,  and  samples  of  juice  were 
collected  at  ten-minute  in.tei'vals  until  the  stomach  was  approximately 
empty.  After  an  intermission  of  ten  minutes  the  experiment  was  re- 
peated. It  will  be  observed  that  the  stimulation  was  almost  as  gi-eat  in  the 
repeated  test  as  in  the  initial  one.  A  similar  absence  of  glandular  fatigue, 
in  the  dog,  has  also  been  observed  by  Ivy(Z>)  after  the  injection  of  gastrin 
evei'y  two  hours  over  a  period  of  twenty-six  hours. 

When  gastric  stimulants  are  under  discussion,  much  emphasis  is  in- 
variably placed  upon  the  stimulatory  power  of  meat  extract.  The  com- 
parative stimulatory  power  of  water  and  meat  extract  in  the  same  noraial 


'KiSSi;e^     ^ 


"'mi^Uet     ^    ^ 


Fig.  5. — Curves  showing  no  glandular  fatigue  in  human  stomach.     (Bergeim,  Rehfuss 
and  Hawk;    Jour.   Biol.   Chem.,    1914,   XIX,   345.) 


S 


S 


y^ 


Suhj^ 


^ , — WOO.ccDls6illedUa69K 


^mi»uie^ 


U> 


Fig.  6. — Curves  showing  comparative  stimulatory  power  of  water  and  bouillon  in  the 
human  stomach.     (Fowler,  Rehfuss  and  Hawk;  unpublished  data.) 


285 


286 


PHILIP  B.  HAWK 


stomacli  is  illiii^^trated  in  Fi^*.  6.  It  will  he  observcfl  that  the  gastric 
acidity  was  developed  a  little  more  quickly  in  the  case  of  meat  extract,  and 
the  stomach  emptied  a  little  more  rapidly,  but  that  the  general  stimulatory 
n'sj)niise  was  v(-iy  similar  to  that  of  water.  Fig.  7  shows  the  com- 
parative stimulation  produced  by  water  and  coffee.  Here  again  it  will 
be  observed  that  the  response  is  very  similar  in  the  two  cases.  The  above 
protocols  give  emphasis  to  the  lielief  that  the  stimulation  produced  in  the 
stomach  by  aqueous  solutions  of  various  kinds  is  due  many  times  in  large 
part  to  the  water  alone. 

That  water  may  sometimes  stimulate  the  stomach  fully  as  much  as 
certain  connnon  foods  is  illustrated  in  Fig.  8.     Here  we  have  a  direct 

comparison  with  oatmeal,  a 
good  standard  food,  and  it 
will  be  noted  that  water  ex- 
erted a  greater  stimulation 
than  the  food  in  question. 

That  Pavlov^s  claim, 
based  on  animal  tests,  that 
water  stimulates  gastric  se- 
cretion only  when  there  is 
"widespread  and  prolonged" 
contact  with  the  gastric  mu- 
cosa, does  not  hold,  for  the 
luiman  stomach  has  been 
demonstrated  repeatedly  in 
our  work.  Pronounced  gas- 
tric stimiilation  with  high 
acid  values  and  rapid  stom- 
ach evacuation  have  been 
obtained  after  the  introduc- 
tion of  as  small  a  volume  as 
25  to  50  c.c.  of  water  into  a 
normal  human  stomach. 
Passage  of  Water  from  the  Stomach. — If  water  remained  in  the 
stomach  for  long  periods  of  time  after  its  ingestion,  there  might  be  some 
argiiment  against  its  free  use  with  meals.  However,  there  is  abundant 
evidence  that  it  leaves  very  rapidly  (Cohnheim(a),  Griitzner(a)  (&),  1902, 
11)05,  Grobbels,  Kaufmann,  Leconte,  Scheunert,  Gabrilowitch).  Griitz- 
ner  says : 

"Massiges  Getriink  wahrend  der  Mahlzeit  stort  sicherlich  die  Tatigkeit 

des  gesunden  Magens  in  keiner  Weise,  wie  man  vielfach  angenommen  hat." 

Leconte,  who  fed  two  dogs  normally,  2  hours  later  gave  one  of  them 

water,   and   15   minutes   later   examined  the   stomach   contents   of  both 

animals.     He  found  scarcely  any  difference  between  the  two,  the  water 


SuhjGch^  Han 


mirti 


u6^ 


60 


eo 


Fig.  7. — Curves  showing  comparative  stimulatory 
power  of  water  and  coffee  in  tlie  human 
stomach.  (Fowler,  Rehfuss  and  Hawk;  un- 
published data.) 


WATER  AS  A  DIETARY  COxNTSTITUENT 


287 


having  largely  left  the  stomach  and  even  the  duodenum.  The  general 
consensus  of  opinion  is  that  water  leaves  the  stomach  rapidly,  the  bulk  of 
it  in  the  first  few  minutes  along  the  so-called  ^^Rinne,"  or  trough,  in  the 
less(!r  curvature,  this  being  particularly  true  of  the  empty  stomach. 
Waldeyer  and  Kauffmann  established  the  presence  of  this  trough  on 
anatomical  grounds,  Ernst  contributed  evidence  from  a  pathological  stand- 
point, and  Cohnheim  apparently  succeeded  in  directly  observing  this 
phenomenon  in  his  experiments  on  dogs.  Scheunert,  on  the  other  hand, 
takes  the  opposite  view  and  claims,  from  his  experiments  on  the  horse's 


2^—7^^        '^       eo 


/oo 


no 


Fig.  8. — Curves  showing  comparative  stimulat(ny  powt;r  of  water  and  oatmeal  in  the 
human  stomach.     (Fowler,  Rehfuss  and  Hawk;  unpublished  data. J 


stomach,  that  liquid  in  the  distended  stomach  has  a  tendency  to  permeate 
along  the  gastric  walls. 

The  effect  of  water  combined  Avith  foodstuffs  has  also  been  the  subject 
of  interesting  experiments.  Grobbels  is  authority  for  the  statement  that 
in  dogs  the  digestion  of  bread  followed  by  water  is  shortei-  than  that  of 
bread  alone.  Gabrilowitch  demonstrated  that  in  the  administration  of  a 
mixture  of  meat  and  water  the  water  passes  out  of  the  stomachy  allowing 
the  meat  to  follow  its  customary  digestion.  Certain  experiments  in  the 
writer's  laboratory  also  furnish  evidence  that  water,  at  least  in  some 
cases,  leaves  the  stomach  very  quickly.  In  this  connection  please  refer 
to  Fig.  1,  p.  ^S2.  Tn  this  experiment,  a  normal  nu^u  received  500  c.c. 
of  water  six  hours  aftei*  the  last  meal.  Twenty  minutes  after  tho  water 
passed  into  the  stomach,  the  gastric  contents  showed  an  acid  value  of  111.5, 
and  these  figiues  were  not  subsequently  materially  altered.  We  believe 
that  the  data  from  this  tost  furnish  evidence  of  the  rapidity  with  which 


288  PHILIP  B.  lIxVWK 

the  water  left  the  stomach.  We  may  believe  that  the  500  c.c.  of  water 
upon  reaching  the  stomach  at  once  stimulated  the  gastric  glands  to  greater 
activity,  and  caused  the  contents  of  the  stomach  to  assume  an  acidity 
of  19.0.  Some  time  during  the  next  ten  minutes,  i.e.,  ten  to  twenty 
minutes  after  the  water  first  reached  the  stomach,  practically  the  entire 
500  c.c.  had  passed  into  the  intestine  and  left  behind  a  gastric  juice  of 
high  acid  concentration  (111.5).  That  the  stomach  was  practically 
empty  in  from  10  to  20  minutes,  as  far  as  the  original  water  was  con- 
cerned, is  indicated  by  the  uniform  values  obtained  for  acidity  in  the 
samples  withdrawn  from  the  stomach  during  the  next  half  hour.  In 
other  words,  we  believe  that  the  only  acidity  value  which  was  influenced 
by  the  factor  of  dilution  was  the  acidity  value  of  the  ten  minute  sample. 
Some  time  before  the  next  specimen  was  taken  the  large  volume  of  water 
had  passed  into  the  intestine  and  our  acidity  value  (111.5)  represents 
the  true  stimulatory  power  of  the  water  unmasked  by  the  factor  of  dilution. 
This  is  an  example  of  the  hypersecretory  type  of  stomach  which  we  have 
discussed  in  our  publications  (Rehfuss,  Bergeim  and  Hawk(&)). 

Another  illustration  of  a  stomach  which  rapidly  emptied  after  the 
entrance  of  water  is  given  in  Fig.  4.  Here  we  have  an  acidity  of  80 
developed  in  five  minutes  after  the  entrance  of  100  c.c.  of  water  into  an 
empty  normal  human  stomach.  Inasmuch  as  the  acidity  values  did  not 
materially  change  during  the  next  hour  and  forty  minutes  we  feel  safe 
in  interpreting  the  data  as  indicating  a  practically  complete  emptying  of 
the  stomach  inside  of  ten  minutes.  That  water  and  other  dietary  fluids, 
such  as  coffee  and  tea,  do  not  delay  the  emptying  time  of  the  stomach, 
when  taken  with  food,  has  also  been  shown  in  the  writer's  laboratory 
(Miller,  Bergeim,  Rehfuss,  and  Hawk).  Four  normal  men  were  used 
as  subjects.  The  evacuation  time  after  a  standard  mixed  meal  had  been 
eaten  was  first  determined  and  in  later  tests  the  evacuation  time  of  the 
same  meal  plus  a  liter  of  water,  coffee,  or  tea  was  studied.  The  data  are 
summarized  in  Fig.  9. 

Summarizing  the  various  experiments  which  have  been  made  to  learn 
the  influence  of  water  in  the  human  stomach,  we  may  conclude  as  follows : 
The  introduction  of  water  immediately  stimulates  the  gastric  glands  to 
increased  activity.  In  a  few  minutes,  the  biilk  of  the  water  so  introduced 
leaves  the  stomach  and  does  not  interfere  with  the  evacuation  of  that 
organ  while  its  stimulatory  action  persists,  causing  the  outpouring  of  a 
highly  active  gastric  juice  which  insures  efficient  gastric  digestion.  It  is, 
therefore,  tetter  to  drink  water  with  meals  than  between  meals.  If  taken 
between  meals,  we  have  the  same  stimulatory  effect  on  gastric  secretion, 
but  there  is  nothing  in  the  stomach  to  digest,  and  we  have  thus  a  true 
economic  waste.  A  summary  of  the  experiments  on  water  drinking  with 
meals  is  contained  in  a  publication  by  the  writer   (Hawk  (e)). 


WATER  AS  A  DIETARY  CO:^^STITUENT 


2a9 


Influence  on  Pancreatic  Digestion. — Pavlov  has  shown  that  when  150 
c.c.  of  water  ai*e  introduced  into  the  stomach  of  a  dog,  the  pancreas  ]>egin3 
to  secrete,  or  augments  its  flow,  within  a  few  minutes  after  the  water  has 
entered  the  stomach.  Since  this  investigator  found  150  c.c.  of  water  in- 
sufficient to  excite  a  flow  of  gastric  juice,  the  secretion  of  pancreatic  juice 
is  apparently  not  secondary  to  a  secretion  of  the  other,  but  is  a  direct  result 
of  the  presence  of  water  in  the  stomach.  In  the  case  of  man,  however,  we 
have  shown  that  wafer  is  a  pronounced  gastric  stimulant  and  causes  the 
passage  of  large  quantities  of  acid  chyme  into  the  intestine.  Inasmuch 
as  this  acid  acts  as  a  pancreatic  stimulant,  we  hav^  therefore,  an  indirect 


Comfiteie  T^moi/at 06  3  flours. 


K&j..(Sehoffou^)^^Suhjec-l;e.^  Ca.QLM.Jo. 


Fig.  9. — Chart  illustrating  the  evacuation  of  various  fluids  from  the  human  stomach. 
(Miller,  Bergeim,  Rehfuss  and  Hawk;  Am.  Jour.  Physiol.,  1920,  LII,  28-53.) 

stimulation  of  pancreatic  secretion  (Hawk(c?),  1911).  On  the  basis  of  the 
data  gathered  in  the  investigation  just  mentioned  and  in  associated  investi- 
gations made  in  the  writer's  laboratory  and  elsewhere,  we  are  p'Opared 
to  draw  the  general  conclusion  that  the  ingestion  of  quantities  of  water  at 
mealtime  ranging  in  volume  from  J^a  to  1  1/3  liters  stimulates  the  pan- 
creatic  function  in  two  ways:  first,  a  direct  stimulation  of  the  nervous 
mechanism  of  the  pancreas  brought  about  while  the  water  is  still  in  the 
stomach  and.  second,  an  indirect  stimulation  brou^t  about  on  the  entrance 
of  the  increased  volume  of  acid  chyme  into  the  duodenum.  If  we  have 
this  augmented  pancreatic  activity,  w^e  would  expect  to  find  a  more 
efficient  pancreatic  digestion  when  water  is  taken  with  meals.  Cedain  of 
our  experiments  (Mattill  and  Hawk  (7;))  have  demonstrated  this  point. 
The  experiments  in  question  were  perfonned  on  men  living  on  a  uniform 
diet;  a  preliminary  penod  of  small  water  ingestion  was  followed  by  a 


200  PHILIP  B.  HAWK 

j)erio<:l  of  large  water  ingestion  with  meals,  and  this,  in  turn,  by  a  final 
period  with  the  original  conditions.  When  one  liter  of  water  additional 
was  taken  with  meals  the  average  daily  excretion  of  fat  in  the  feces  was 
ranch  reduced  helow  that  found  when  a  minimum  amount  of  water  was 
taken  with  meals;  one  and  one-third  liters  had  a  like  effect.  A  similar  but 
less  marked  reduction  was  observed  when  500  c.c.  of  water  were  taken 
with  meals. 

The  decreased  excretion  of  fat  observed  during  water  drinking  w^ith 
meals  was  usually  evident  for  a  number  of  days  after  water  had  ceased 
to  be  taken  in  large  or  moderate  amounts  with  meals  indicating  that  the 
beneficial  influence  of  water  was  not  temporary  but  was  more  or  less 
permanent.  After  several  months  of  moderate  water  drinking  with  meals 
a  pronounced  improvement  in  the  digestibility  of  fat  was  observed,  the 
percentage  utilization  having  risen  from  04.3  to  0G.5.  A  slight  gain  in 
weight  accompanied  the  water  drinking,  and  this  gain  was  not  subse- 
quently lost. 

The  better  digestion  and  absorption  of  fat  was  probably  due  to  the 
following  factors: 

(1)  Increased  secretion  of  gastric  juice  and  of  pancreatic 
juice  as  a  result  of  the  stimulating  action  of  water, 

(2)  Increased  acidity  of  the  chyme  bringing  about  a  more 
active  secretimi  of  pancreatic  juice  and  bile, 

(3)  '  Increased  pei-istalsis  due  to  larger  volume  of  material 
in  the  intestine. 

(4)  A  more  complete  hydrolysis  of  the  fats  by  lipase,  due 
to  increased  dilution  {Bradley {a))  of  the  medium  and  C07ise- 
quently  more  rapid  absorption. 

Certain  of  our  experiments  on  carbohydrate  digestion  are  also  of  in- 
terest in  this  connection.  It  has  been  shown  (Mattill  and  Hawk,  1911), 
for  example,  that  in  men  living  on  a  uniform  diet  the  addition  of  1,000  c.c. 
of  water  to  each  meal  causes  a  decrease  in  excreted  carbohydrate  matei-iah 
The  better  utilization  of  food  material  thus  evident  was  not  temporary 
but  appeared  to  extend  for  some  time  following  the  use  of  water.  The 
ingestion  of  a  smaller  amount  of  water  (500  c.c.)  and  die  use  of  a  laige 
volume  of  water  (1,333  c.c.)  by  one  accustomed  to  drinking  water  with 
meals  showed  a  similar  but  less  marked  reduction  in  the  excretion  of 
carbohydrate. 

Other  experiments  on  protein  digestion  and  absorption  point  in  the 
same  direction  (^Fattill  and  Ilawk(^)).  These  stiulies  showed  that  the 
drinking  of  three  liters  of  water  with  meals  caused  a  more  economical 
utilization  of  the  protein  constituents  of  the  diet.  Gains  in  body  weight 
were  also  registered. 


WATER  AS  A  DIETAKV  COXSTITUEXT  291 

Influence  on  Intestinal  Flora  and  Putrefaction. — Since  absorption  is, 
more  rapid  and  complete  when  water  is  taken  with  meals,  there  will  be 
less  food  material  remaining  in  the  intestine  to  furnish  pabulum  for 
intestinal  organisms.  We  would,  therefore,  expect  to  find  a  diminished 
output  of  such  organisms  in  the  feces  and  a  deerease^l  intestinal  putre- 
faction. These  facts  have  been  emphasized  by  certain  of  our  experi- 
mental findings  (llattill  and  Hawk(c),  Fowler  and  Hawk,  Blatherwick 
and  Hawk(a) ).  In  one  instance,  the  excretion  of  bacterial  dry  substance 
in  the  feces  was  reduced  from  8.0  grams  to  6.2  grams  per  day  as  the  result 
of  drinking  about  a  liter  of  water  per  meal  for  a  period  of  five  days. 

That  intestinal  putrefaction  is  reduced  when  water  is  drunk  freely 
at  meal  time  has  also  lx?en  shown  using  indican  as  the  in<lex  (Sherwin 
and  Hawk,  Hattrem  and  Hawk).  The  decreased  intestinal  putrefaction 
brought  about  through  the  ingestion  of  moderate  (500  c.c.)  or  copious 
(1,000  c.c.)  quantities  of  water  at  meal  time  was  probably  due  to 
diminution  in  the  activity  of  indol-fonning  bacteria  following  the  acceler- 
ated absorption  of  the  products  of  protein  digestion,  and  the  passage  of 
excessive  amounts  of  strongly  acid  chyme  into  the  intestine. 

Influence  on  Absorption. — The  better  utilization  of  the  fat,  carbohy- 
drate and  protein  of  the  diet  as  just  discussed  furnishes  proof  that  the 
drinking  of  water  facilitates  the  absorption  of  the  products  of  the  digestion 
of  our  food.  The  drinking  of  water  dilutes  the  material  in  the  intestine 
and  aids  in  its  absorption.  Concentrated  solutions  are  not  readily  absorbed, 
as  is  shown  by  the  experiments  of  London  and  Polovzova(a)  and  others. 
The  latter  investigators  showed  that  when  concentrated  solutions  of  glucose 
are  introduced  into  the  intestine,  a  diluting  secretion  begins  to  flow  from 
the  wall  of  the  intestine.  Its  amount  runs  parallel  with  increasing  con- 
centration of  the  glucose  solution,  and  at  its  maxinmm  it  may  amount  to 
one-half  the  total  quantity  of  blood  in  the  animal.  By  this  dilution  and 
also  by  absorption  of  sugar  the  concentration  of  the  solution  is  brought 
dowTi  to  6-8  per  cent,  a  dilution  at  which  absorption  takes  place  very 
readily  in  the  lower  intestinal  tract.  The  secretion  of  the  diluting  fluid 
begins  with  the  coming  in  of  the  first  glucose  solution  and  continues  fairly 
uniforaily.  Since  absorption  is  going  on  more  or  less  continuously  in 
the  intestine,  the  water  taken  with  one  meal  aids  in  diluting  the  products 
of  the  previous  meal  which  are  in  the  intestine.  Xoi  only  is  euzyrae 
action  more  complete  in  dilute  solutions  but  such  solutions  are  also  bet- 
ter adapted  to  absorption.  When  the  solutions  to  be  absorbed  are  not 
dilute,  the  organism  must  first  make  them  so  by  pfouring  out  a  diluting 
secretion ;  if  they  have  been  made  dilute,  the  organism  is  spared  this  task. 

Influence  on  Blood  Volume  and  Blood  Pressure. — The  practice  of 
drinking  largo  volumes  of  water  is  sometimes  criticized  on  the  theory  that 
it  increases  blood  volume  and  consequently  causes  a  rise  in  blood  pres- 
sure.    However,  some  Yale  experiments  (Bogert,  Underbill  and  Mendel) 


292  PHILIP  B.  HAWK 

have  shown  that  there  is  complete  restoration  of  blood  volume  of  the  do^^ 
and  rabbit  within  thirty  minutes  after  the  intravenous  injection  of  a 
quantity  of  saline  equal  to  the  calculated  blood  volume  of  the  individual. 
Therefore,  after  one  drinks  copiously  of  water,  the  influence  upon  blood 
volume  and  blood  pressure  is  Iwth  slight  and  transitory. 

Distilled  Water. — A  belief  very  widely  held  by  both  the  laity  and  the 
scientific  worker  is  to  the  eli'ect  that  the  ingestion  of  distilled  water  is  a 
bad  procedure.  The  absence  of  inorganic  matter  in  such  water  is  believed 
to  be  the  forerunner  of  various  untoward  influences  upon  the  processes  of 
digestion  and  absorption.  So  far  as  I  am  aware,  there  is  no  experimental 
basis  for  such  a  belief.     One  scientist  (Findlay)  says: 

"If  tissues  or  cells  are  placed  in  distilled  water,  passage  of  water  into 
the  cells  occurs  owing  to  the  difference  of  osmotic  pressure.  The  cells 
swell  up  and  may  finally  burst  and  die.  A  similar  poisonous  action  on  cells 
is  observed  when  distilled  water  is  drunk.  In  this  case  the  surface  layers 
of  the  epithelium  of  the  stomach  undergo  considerable  swelling;  salts 
also  pass  out  and  the  cells  may  die  and  be  cast  off.  This  may  lead  to 
catarrh  of  the  stomach." 

If  this  scientist's  claims  are  true,  then  one  of  our  fasting  tests  is  a 
notable  exception.  This  is  the  fast  which  continued  for  over  100  days 
and  to  which  reference  has  already  been  made  (see  p.  279).  The  fasting 
dog  was  given  TOO  c.c.  of  distilled  water  daily  by  means  of  a  stomach 
tube,  and  yet  at  the  end  of  the  fast  the  post-mortem  examination  failed 
to  show  any  evidence  of  a  deranged  gastric  mucosa.  Certainly  a  ix?i'iod 
of  over  100  days  is  a  sufficiently  long  interval  in  which  to  demonstrate  the 
toxic  influence  of  distilled  water  if  such  an  influence  is  demonstrable. 
Particularly  is  this  tiiie  of  the  fasting  animal,  which  may  possess  a 
lowered  resistance  to  toxic  influences. 

However,  if  we  grant  that  distilled  water,  because  of  the  absence  of 
electrolytes,  does  possess  a  pernicious  influence  upon  the  gastric  mucosa, 
it  iS'  quite  logical  to  believe  that  such  influence  will  be  exerted  to  the  maxi- 
mum by  distilled  w^ater  taken  between  meals.  Because  of  the  electrolyte 
content  of  the  average  diet  distilled  water  taken  along  with  such  a  diet 
will  cease  to  act  as  distilled  water  soon  after  it  reaches  the  stomach.  The 
toxic  action  of  distilled  water,  if  such  action  is  demonstrable,  must  be 
more  in  evidence  when  the  distilled  water  passes  into  the  lelativcly  empty 
stomach.  So  far  as  the  swelling  and  ultimate  bursting  of  the  cells  under 
the  inftaence  of  osmotic  forces  is  concerned,  it  must  be  apparent  that  os- 
motic phenomena  which  are  exhibited  by  non-living,  excised  cells  do  not 
necessarily  hold  for  cells  actually  functioning  in  the  animal  body.  Distilled 
water  in  contact  with  a  cell  of  the  living  body  may,  through  osmotic  influ- 
ence, cause  a  swelling  of  the  cell,  but  the  actual  bursting  of  the  cell  will,  of 
course,  be  pi-evented  by  physiological  factors  which  will  bo  called  into  play, 
thus  causing  the  circulation  to  remove  the  excess  fluid. 


WATER  AS  A  DIETARY  CO]S^STITUEXT  293 

Various  clinical  views  have  been  expressed  as  to  the  influence  of  dis- 
tilled water  ingestion.  Some  clinicians  claim  to  have  found  it  harmful 
in  certain  instances,  others  claim  it  is  harmless,  while  still  others  cxpi-ess 
the  opinion  that  the  question  as  to  its  harmfulness  or  harmlessness  must 
ho  considered  an  open  one.  The  catarrhal  conditions  which  it  is  claimed 
follow  the  drinking  of  water  from  glaciers,  or  the  excessive  ingestion  of 
ice,  may-  possibly  have  had  their  origin  in  the  low  temperature  rather  than 
in  the  absence  of  electrolytes,  although  no  untoward  symptoms  have  re- 
sulted from  the  ingestion  of  ice  water  in  the  writer's  experience  (see 
below) . 

In  our  own  experiments  upon  the  influence  of  distilled  water  ingestion 
with  meals  (Bergeim,  Rchfuss,  and  Hawk,  Blatherwick  and  Hawk,  Mattill 
and  Hawk,  Sherwin  and  Hawk),  we  were  able  to  demonstrate  a  stimula- 
tion of  the  gastric  and  pancreatic  functions,  better  digestion  and  absorp- 
tion of  ingested  food,  a  decrease  in  the  growth  of  intestinal  bacteria,  and 
a  lessening  of  putrefactive  processes  in  the  intestine. 

Ice  Water. — When  we  come  to  ice  water,  we  are  dealing  with  a  slightly 
different  proposition  since  the  question  of  temperature  must  be  considered. 
In  fact,  the  power  of  ice  water  to  chill  the  stomach  and  to  delay  digestion 
is  one  of  the  main  arguments  advanced  against  the  drinking  of  the  cold 
fluid.  In  order  to  study  this  ^^terrible,  chilling  effect"  of  ice  w^ater,  we 
had  skilled  mechanics  construct  a  very  delicate  apparatus  which  enabled 
us  to  follow  the  temperature  changes  in  the  stomach  while  the  food  ^vas 
actually  being  digested  (Smith,  Fishback,  Bergeim,  Rehfuss,  and  Hawk). 
And  this  is  what  we  found.  In  twenty  minutes  after  drinking  a  glass 
of  ice-cold  water  (10°  C.)  the  temperature  of  the  stomach  contents 
w^as  approximately  the  same  as  that  of  the  rest  of  the  body.  And  in  a 
like  period  of  time,  the  temperature  of  hot  coffee  (50°  C.)  was  also  brought 
down  to  that  of  the  stomach  walls.  It  is  truly  wonderful  how  rapidly 
the  stomach  is  able  to  regulate  the  temperature  of  the  things  we  put  into 
it,  whether  they  be  cold  or  hot!  And  the  evacuation  time  is  about  the 
same  for  cold  and  hot  drinks.  Thus  the  "chilling  effect"  of  ice  water  and 
tlie  consequent  delay  in  the  digestion  of  our  food  is  seen  to  be  of  no  real 
significance  under  ordinary  conditions.  However,  there  is  one  time  when 
wo  must  use  discretion  in  the  drinking  of  ice  water.  That  is  immediately 
after  vigorous  physical  exercise,  and  unfortunately  that  is  jiist  the  time 
we  feel  like  emptying  the  ice  cooler.  However,  we  must  not  do  so  foi- 
serious  consequences  may  follow  the  drinking  of  large  volumes  of  ice-<iold 
fluid  (water,  soft  drinks,  etc.)  at  such  times. 

Conclusions 

Before  closing  this  discussion  on  water,  the  writer  would  like  to 
emphasize  the  fact  that,  in  all  of  the  water  studies  made  by  his  associates 


294  PHILIP  B.  HAWK 

and  himself,  normal  subjects  have  been  employed.  We  have  made  no 
clinical  studies  and  have  made  no  clinical  suggestions.  It  may  he  true 
that  a  person  with  a  deranged  circulatory  or  gastric  function,  or  any  pro- 
nounced lesion  of  heart  or  kidney,  should  not  drink  large  volumes  of 
water  at  any  time,  either  with  meals  or  between  meals.  The  ingestion 
of  largo  volumes  of  water  with  meals  may  he  contra-indicated  in  atonic 
or  dilated  stomach,  since  an  excessive  water  ingestion  might  promote 
further  atony  and  dilation.  It  may  also  he  contra-indicated  in  gastroptosis, 
where  the  gastric  support  is  relaxed  and  ijisufficient  and  in  certain  cases 
of  pyloric  colic  and  spasm.  If  contra-indicated  in  these  conditions,  how- 
ever, ice  have  no  experimental  evidence  to  that  effect,  and  it  is  because  a 
large  volume  or  weight  at  any  one  time  is  contra-indicated  and  not  because 
of  the  water  per  se.  The  writer  would  say,  therefore,  that  normal  persons 
may  drink  freely  of  water  at  mealtime,  whereas  those  unfortunate  in- 
dividuals who  possess  lesions  of  heart  or.  kidney  or  who  are  troubled  with 
any  circulatory  or  gastric  disturbance,  should  have  their  fluid  intake  regu- 
lated strictly  according  to  medical  advice.  The  literature  contains  at 
least  two  observations  (Marcus,  Foster  and  Davis),  indicating  that  the 
drinking  of  considerable  water  by  nephritics  causes  no  undesirable  re- 
sults, whereas  the  finding  that  the  introduction  of  an  excessive  volume 
of  fluid  into  the  circulation  causes  no  significant  increase  in  blood  volume 
or  blood  pressure  (Bogert,  Underbill  and  Mendel)  would  seem  to  indi- 
cate that  patients  suft'ering  from  cardiac  disorders  need  not  necessarily 
have  their  water  intake  materially  restricted. 

On  the  basis  of  a  large  number  of  experiments,  made  in  the  writer's 
laboratory  and  elsewhere,  we  feel  warranted  in  concluding  that  the 
average  normal  individual  will  find  that  the  drinking  of  a  reasmiahle  vol- 
ume of  ivaier  ivith  meals  will  promote  the  secretion  and  activity  of  the  di- 
gestive juices,  and  the  digestion  and  ahsorption  of  the  ingested  food,  and 
will  retard  the  growth  of  intestinal  hacteria  and  lessen  the  extent  of  the 
putrefactive  processes  in  the  intestine.  Furthermore,  we  would  place  no 
restriction  upon  the  drinlcing  of  distilled  water  and  none  upon  the  drinking 
of  moderate  rjuantities  of  ice  cold  water,  except  when  one  is  overheated 
following  vigorous  physical  exercise. 

That  Xature  knew  all  these  things  long  before  we  did  is  indicated  by 
the  fact  that  milk,  ]N"ature's  best  food,  contains  87  per  cent  water  and 
by  the  further  fact  that  the  birds  and  the  beasts  (Ev^'ard)  set  man  a  good 
example  to  follow  in  the  matter  of  water  drinking  at  meals. 

There  is  an  old  German  proverb  which  reads  "Alios  Ubel  vergeht 
durch  Wasser  und  Diat."  That  is  a  perfectly  good  proverb,  but  I  suggest 
that  it  be  revised  to  read  "Alles  Ubel  vergeht  durch  reichlich  Wasser  in  der 
Diat/' 


The  Metabolism  of  Alcohol Harold  i.  Higgins 

Introduction — Absorption  of  Alcohol — Excretion  of  AIcohol-^Distribution  of 
Alcohol  After  Absorption — Effects  of  Alcohol  on  '^'otal  Metabolism — 
Effects  of  Alcohol  on  Protein  and  Purin  Metabolism — Combustion  of 
Alcohol — Alcohol  and  Muscular  Work — Alcohol  in  Diabetes. 


The  Metabolism  of  Alcohol 


HAKOLD  L.  HIGGIXS 

CINCINNATI 

Introduction 

Aside  from  the  three  important  gi'oups  of  foodstuffs^  the  proteins, 
the  fats  and  the  carbohydrates,  ethyl  alcohol,  CHg-CHgOH,  is  the  most 
available  nutriment  the  animal  organism  has  to  meet  its  heat  requirements. 
It  is  burned  in  the  body  to  carbon  dioxid  and  water,  and  each  gram  of 
alcohol  when  thus  oxidized  yields  approximately  7.2  calories  of  heat. 
But  while  alcohol  thus  offers  good  possibilities  from  a  nutritive  point 
of  view,  its  status  as  an  altogether  satisfactory  food  is  enhanced  by  its 
pharmacological  and  toxicological  action.  This  action  of  alcohol  at  first 
is  most  marked  upon  the  central  nervous  system;  the  release  of  cerebral 
inhibition  and  the  anesthetic  features  probably  stand  out  foremost.  The 
pathological  changes  as  a  result  of  overindulgence  in  alcohol  are  well 
known.  It  is  quite  universally  recognized  that  too  much  alcohol  is  harm- 
ful to  the  human  organism,  and  that,  to  be  of  any  practical  use  for  nutri- 
tive purposes,  the  quantity  of  alcohol  taken  must  be  small.  Therefore, 
in  discussing  the  nutrition  of  alcohol  in  this  chapter  the  effects  of  mod- 
erate or  small  quantities  will  be  more  particularly  considered. 


Absorption  of  Alcohol 

Alcohol  requires  no  digestion  for  absorption,  but  it  is  absorbed  directlj 
from  the  gastro-intestinal  tract  mainly  into  the  portal  blood  but  also  by 
the  lymphatics  (Dogiel,  1874).  A  considerable  proportion  of  tlie  alcohol 
taken  by  mouth  is  absorbed  in  the  stomach  and  the  remainder  in  the  small 
intestine  (Bodlander,  1883).  The  quantities  or  proportions  absorbed  in 
the  stomach  and  in  the  different  parts  of  the  small  intestine  vary  according 
to  the  rate  with  which  the  alcohol  passes  through  the  pylorus ;  alcohol  taken 
with  food  will  remain  longer  in  the  stomach  and  a  larger  proportion  of  it 
will  be  absorbed  there  than  if  the  alcohol  were  taken  on  an  empty  stomach. 
One  obsers^er  found  that  twenty  per  cent  of  alcohol  was  absorbed  in  the 
stomach,  nine  per  cent  in  the  duodenum,  fifty-three  per  cent  in  the  jejunum 

297 


298 


HAROLD  L.  IIIGGINS 


and  eig:litcen  j>or  cent  in  the  ileum  (^N'cmser,  1907).  Alcohol  is  absorbed 
also  when  given  by  rectum  (Carpenter (5),  1916)  or  when  inhaled  as  vajx>r. 
Alcohol  is  not  absorbed  so  rapidly  when  taken  with  food  as  without;  fat 
esjK^cially  seems  to  delay  the  absorption  (Mellanby(e),  1919)  ;  the  probable 
explanation  for  this  is  that  absorption  from  the  stomach  is  not  so  rapid 
as  from  the  small  intestine. 

While  alcohol  does  nm  require  any  digestion  and  is  readily  absorbed, 
it  does  influence  the  gastric  digestion  of  other  material  (Kast,  1906).  A 
dilute  solution  of  alcohol  increases  the  hydrochloric  acid  cgncentration 
without  affecting  the  pepsin  content  of  the  gastric  juice;  less  dilute  solu- 
tions act  as  irritants  to  the  stomach  and  cause  increased  mucus  fonnation 
and  often  vomiting.  But  while  alcohol  may  influence  gastric  digestion,  yet 
the  net  effects  on  the  availability  of  the  fat,  protein  and  carbohydrate  in 
the  diet  is  not  interfered  with;  i.e.,  the  amount  of  undigested  residue  in 
feces  is  not  essentially  different  when  alcohol  is  taken  from  when  it  is 
not  (Atwater  and  Benedict  (e),  1902).  That  is  seen  in  the  following 
table: 


CoelKcients  of  Availability 

Protein 

Fat 

Carbohydrates 

Energy 

E.xperiments 

Without  alcohol 

With    alcohol 

92.6 
93.7 

Vc 

94.9 
94.6 

% 

97.9 
97.8 

% 

91.8 
82.1 

The  absorption  of  alcohol  is  rapid;  this  has  been  demonstrated  (1) 
by  the  early  psychological  etfects  from  taking  the  drug  (Dodge  and  Bene- 
dict, 1915),  (2)  by  its  beginning  to  be  burned  in  five  to  ten  minutes  after 
ingestion  (Higgins  (a),  1910  ),  and  (3)  by  increase  in  the  concentration  of 
alcohol  in  the  blood  (Mellanby(e),  1919).  Very  soon  after  taking  alcohol 
(one-half  to  two  hours),  the  blood  will  show  the  maximum  concentration. 


Excretion  of  Alcohol 

From  two  to  ten  per  cent  of  alcohol  taken  by  mouth  is  excreted  as 
such  in  the  urine,  the  breath  and  the  sweat  (Atwater  and  Benedict,  1902; 
Voltz,  Baudrexel  and  Deitrick,  1912).  The  remaining  ninety  to  ninety- 
eight  per  cent  is  burned  to  COg  and  ILO.  Alcohol  is -absorbed  di- 
rectly into  the  blood  without  chemical  change,  and  is  excreted  in  part 
unchanged  by  the  kidneys,  the  lungs  and  the  sweat  glands.  Alcohol  is 
also  e.Kcreted  in  the  milk  of  nursing  mothers  (Nicloux(a),  1899).  The 
amount  excreted  in  the  expire<l  air  and  sweat  is  increased  during  muscular 
work,  with  the  increased  respiratory  ventilation  and  sweating.  The 
elimination  of  alcohol  by  the  kidneys  and  lungs,  also  by  the  mammary 
glands,  is  by  diffusion,  the  percentage  of  alcohol  in  the  urine  and  milk 


THE  METABOLISM  OF  ALCOHOL        299 

practically  equaling  that  in  th(3  blood  (Widmark  (a),  1915;  Nicloux  (h), 
1900). 

Distribution  of  Alcohol  After  Absorption 

The  maximum  concentration  of  alcohol  in  the  blood  is  usually  equal 
to  or  slightly  higher  than  one  would  find  if  there  were  even  distribution 
of  alcohol  throughout  all  the  tissues  (Mellanby(e),  1919).  Analysis  of 
various  organs  and  tissues  of  the  body  after  alcohol  has  been  taken  show 
that  alcohol  is  quite  equally  distributed  everywhc^re,  but  apparently  there 
are  some  small  diiferences,  for  the  liver  and  heart  muscle  in  rats  have  been 
reported  as  containing  relatively  low  while  the  brain  and  blood  contain 
relatively  high  percentages  of  alcohol  (Pringsheim,  1908).  This  is  shown 
by  the  following  experiment: 

Alcohol  5  c.c.  per  kilogram  lx)dy  weight  given. 

If  equally  distributed  there  would  be  0.5  per  cent  throughout  the  body. 
There  were  found  in  the 

Blood    0.52% 

Brain .41% 

Kidney    39% 

Liver 33% 

The  percentage  of  alcohol  in  the  blood,  or  in  the  urine,  sliould  prove  a 
good  index  as  to  the  pharmacological  and  psychological  effects  to  be  ex- 
pected; one  observer  states  that  intoxication  does  not  appear  unless  the 
concentration  of  alcohol  in  the  urine  exceeds  one-tenth  of  one  per  cent 
(Widmark  (h),  1917). 


Effects  of  Alcohol  on  Total  Metabolism 

Alcohol  in  moderate  amounts  does  not  increase  the  total  metabolism 
of  the  human  body  (Atwater  and  Benedict  (e),  1902;  Zuntz  and  Berdez, 
1887;  Geppert(aj,  1887;  Higgins(&),  1917).  Both  the. heat  production 
t.nd  the  heat  elimination  are  essentially  unchanged,  for  moderate  quantities 
of  alcohol  cause  no  appreciable  change  in  body  temperature  (Atwater  and 
Benedict,  1902).  However,  large  quantities  of  alcohol  lead  to  marked 
peripheral  vasodilatation  with  fall  in  body  temperature;  this  is  a  cause 
of  increased  heat  elimination,  which  in  turn  is  followed  by  increased 
heat  production  as  the  body  temperature  returns  to  normal.  Alcohol 
in  being  burned  acts  to  replace  some  other  source  of  energy  and  is 
neither  a  stimulant  nor  a  depressor  of  the  metabolism,  and  does  not  serve 
merely  for  '^luxus  consumption.'^ 


800  HAROLD  L.  HIGGmS 


Effects  of  Alcohol  on  Protein  and  Purin  Metabolism 

Alcohol  does  not  appreciably  affect  the  pfroteln  metabolism ;  it  neither 
acts  as  a  protein  sparer  nor,  unless  taken  to  excess,  as  a  protein  destroyer 
(cell-poison)  (Roseniann  (a)).  This  is  shown  by  determinations  of  the 
urinary  and  food  nitrogen  (nitrogen  balance  experiments).  There  is  an 
increase  in  the  nitrogen  output  and  a  negative  nitrogen  balance  for  about 
two  days  after  alcohol  is  added  to  the  diet;  this  is  probably  due  to  the 
change  in  the  water  balance  of  the  body  and  non-protein  nitrogen  content  of 
the  body  fluids  and  is  associated  with  the  diuretic  action  of  alcohol;  the 
nitrogen  balance  is  uninfluenced  by  alcohol  after  the  first  two  days.  Some 
workers  report  that  alcohol  increases  the  uric  acid  excretion,  while  others 
have  claimed  that  alcohol  causes  no  change  at  all  or  an  insignificant  change 
(Rosemann(a)  ;  Mendel  and  Ililditch,  1910).  Changes  in  the  excretory 
action  of  the  kidney  rather  than  in  the  true  uric  acid  metabolism  seem 
to  be  the  cause  of  the  discrepancies  found,  and  supplementary  analyses 
to  determine  the  uric  acid  content  of  the  blood  will  be  necessary  to  deter- 
mine if  the  uric  acid  metabolism  is  affected  by  alcohol. 


Combustion  of  Alcohol 

.  -  Alcohol  is  burned  by  the  body  up  to  a  certain  percentage,  when  avail- 
able in  the  tissues,  in  preference  to  either  fat  or  carbohydrate.  Experi- 
ments with  men  and  animals  show  that  the  rate  of  combustion  of  alcohol 
is  independent  of  the  amount  taken  and  comparatively  constant  (Mel- 
lanby(e),  1919;  Voltz  and  Dietrich,  1912;  Higgins(&),  1917).  Over 
fifty  per  cent  of  the  total  heat  production  of  the  body  seldom,  if  ever, 
comes  from  alcohol.  When  30  c.c.  of  alcohol  were  taken  by  a  man,  the 
percentage  of  the  total  oxygen  consumption  used  in  burning  alcohol  during 
the  first  two  or  three  hours  was  as  high  as  when  45  c.c.  were  taken ;  about 
20  to  40  per  cent  of  the  heat  production  (total  metabolism)  came  from 
the  alcohol,  i.e.  with  a  man  in  the  resting  state,  about  3.5  c.c.  of  al- 
cohol was  burned  per  hour;  thus  if  the  same  rate  of  combustion  of  alcohol 
continued  (which  is  the  case  in  animals)  it  would  require  8  hours  for  all  of 
30  CO.  and  12  hours  for  all  of  45  c.c.  of  alcohol  to  be  burned  (Higgins, 
1917).  The  period  during  which  alcohol -will  stay  in  the  body  when  large 
amounts  are  taken  is  surprisingly  long.  Thus  if  a  physician  desires  to 
give  alcohol  to  a  patient  for  its  nutritive  value,  he  should  obtain  as  satis- 
factory results  nutritionally  and  avoid  many  of  the  untoward  features  of 
alcohol,  by  giving  it  in  small  doses  (10  c.c.  or  less),  which  may  be  repeated. 
Alcohol  displaces  carbohydrate  and  fat  acting  to  spare  them.  •  It  prob- 
ably displaces  a  larger  proportion  of  carbohydrate  than  fat ;  i.e.,  if  there 


THE  METABOLISM  OF  ALCOHOL        301 

is  a  certain  proportion  of  carbohydrate  and  fat  being  buraed,  and  alcohol 
is  ingested,  it  will  be  burned  in  preference  to  either  up  to  about  forty 
per  cent  of  the  total  caloric  expenditure  of  the  body,  and  the  ratio  of 
carbohydrate  to  fat  displaced  in  the  combustion  will  be  greater  than  the 
ratio  of  carbohydrate  to  fat  previously  being  burned  (Mellanby(e),  1919). 

Alcohol  and  Muscular  Work 

While  experiments  have  definitely  proven  that  alcohol  is  burned  in 
the  body,  and  thai  it  displaces  carbohydrate  and  fat,  but  not  protein,  yet 
whether  the  potential  energy  of  alcohol  can  be  changed  into  the  kinetic 
energy  of  muscular  work  in  the  body  is  still  a  matter  of  conjecture  (At- 
water  and  Benedict,  1902;  Chauveau(a)  (6),  1901).  Experimental  evi- 
dence is  not  at  all  conclusive,  although  it  is  generally  believed  probable,  in 
the  absence  of  evidence  to  the  contrary,  that  alcohol  can  be  converted  into 
muscular  energ^%  It  is  true  that  when  alcohol  is  added  to  the  diet  of  a 
person  doing  heavy  muscular  work,  the  work  is  not  so  efficiently  nor  so 
easily  done  (Van  Hoogenhuyse  and  Xieiiwenhuyse,  1913;  Durig(a), 
1906). 

Definite  and  rather  startling  feats  of  endurance  can  be  performed  after 
alcohol  is  taken ;  thus  one  can  hold  the  breath  a  longer  time  after  taking 
alcohol  than  before,  or  one  can  hold  oh  a  bar  longer  or  lift  one^s  weight 
from  the  floor  oftener  at  a  given  rate,  etc  (McKenzie  and  Hill,  1910).  A 
patient  has  been  observed  to  be  able  to  hold  his  breath  fifty-three  seconds 
before  and  one  hundred  and  ^ve  seconds  after  alcohol  (L.  Higgins(&), 
1917).  This  is  probably  to  be  explained  on  the  basis  of  the  dulling  of 
the  nervous  centers  by  alcohol  so  that  the  brain  does  not  react  to  fatigue 
so  readily  as  normally,  and  it  is  not  due  to  the  energy  yielded  from  the 
alcohol.  But  the  fact  stands  out  that  alcohol  gives  one  the  power  to  per- 
form certain  feats  of  endurance  of  short  duration. 


Alcohol  in  Diabeies 

Alcohol  has  been  recommended  in  certain  diseases,  notably  in  diabetes. 
The  diabetic  person  apparently  can  utilize  alcohol  much  as  the  normal 
person,  and  can  obtain  a  food  value  from  it.  Alcohol  does  not,  however, 
act  as  an  antiketogenic  agent,  i.e.,  in  being  burned,  it  does  not  act  to  pre- 
vent the  formation  of  the  acetone  bodies  as  do  carbohydrates  (Higgins, 
Peabody  and  Fitz,  1916).  However,  if  a  diabetic  has  a  change  made  in 
his  diet  so  that  a  given  amount  of  fat  is  substituted  by  an  isod;^Tiamic 
quantity  of  alcohol,  less  acetone  bodies  will  be  formed  in  the  body;  i.e., 
alcohol  does  not  form  acetone  bodies  in  its  intermediary  metabolism  (Bene- 
dict and  Torek,  1906). 


1 


Mineral  Metabolism , 

. Henry  A,  Mattill  and  Helen  7.  Mattill         \ 

% 
Water — Sodium    Chlorid — Alkalies — Calcium — Magnesium — Phosphorus —  | 

Iron — Sulphur — lodin — Xeutrality  Regulation — Disturbances  in  Mineral  ^ 

Metabolism  Accompanying  Pathological  Conditions. 


\ 


Mineral  Metabolism 


HENRY  A.  MATTILL 

AND 

HELEN  I.  MATTILL 

BOCHESTEB 


According  to  Albu-Neuberg  the  mineral  constituents  of  the  adult  hu- 
man body  amount  to  4.3-4.4  per  cent.  In  this  ash  .occur  the  elements  Ca, 
P,  K,  S,  CI,  Na,  !Mg,  I,  F,  Fe,  Br,  Al,  named  in  the  order  of  decreasing 
amounts  (Hackh).  Any  statement  regarding  exact  amounts  of  the  ditfer- 
ent  elements  is  fraught  with  uncertainty  for  two  reasons :  first  the  paucity 
of  reliable  analytical  data,  secondly  the  individual  variability  due  in  part 
to  differences  in  the  organism,  in  part  to  diiTerences  in  food  habits  and 
possibly  to  the  existence  of  pathological  conditions.  The  ash  constituents 
of  the  new-born  have  been  determined  by  Camerer  and  Soldner  with  re- 
sults which  show  considerably  more  uniformity  than  do  those  on  the  adult. 
They  find  2.10  to  2.73  per  cent  ash  of  which*^3S.5  per  cent  is  PjOg,  36.1 
per  cent  CaO,  IM  per  cent  XagO,  7.S  per  cent  Ka^'  "^-'^  pcr  cent  CI,  0.9 
per  cent  MgO  and  0.8  per  cent  Fe^Og.  As  compared  with  the  adult  these 
values  arc  characterized  by  low  total  ash,  CaO  and  P2O5,  and  by  Ligh  Fe. 

About  5/6  of  the  total  ash  occurs  in  the  bones.  Fresh  bones  contain 
about  35  per  cent  ash,  about  84  per  cent  of  which  is  Cag  (P04)2, 1  per  cent 
]\Ig;{(  1^04)2  ^^^  "-^  P^^*  cent  other  Ca  salts.  About  99  per  cent  of  the  Ca 
in  the  organism  is  in  the  bones,  about  70  per  cent  of  the  Mg  and  about 
75  per  cent  of  the  P. 

In  a  comparative  study  of  the  composition  of  the  teeth  of  man  and  dog 
Gassmann(a)  found  74-82  per  cent  ash.  He  w^s  not  able  to  recognize  F. 
He  found  Ca  and  P  most  abundant,  organic  matter  lowest,  in  the  wisdom 
tooth,  while  organic  matter  was  high  and  Ca  and  P  low  in  the  dog's  tooth. 

Cartilage  contains  only  1-6  per  cent  of  mineral  matter  and  its  ash 
is  higher  in  Xa  than  that  of  any  other  tissue  of  the  body,  and  is  also 
characterized  by  a  large  amount  of  sulphates,  which  probably  existed  as 
organically  combined  S  in  the  fresh  tissue. 

It  may  be  safely  assumed  that  the  bone  portion  of  the  ash  constituents 
is  subject  to  less  rapid  metabolic  changes  than  the  remaining  1/6,  of  which 
the  greater  half  is  found  in  the  muscles,  the  lesser  half  in  the  blood  and 

303 


304 


HEXRY  A.  MATTILL  AND  HELEX  I.  MATTILL 


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MINERAL  METABOLISM 


305 


TABLE  IT 

100  gm.  fat-free,  dry  substance  contain 

CI  mg. 

Fe  mg. 

Ca  mg. 

Mg  mg. 

Mu3cle   

302 

769 
1421 

529.8 

859 
1087.5 

525.4 

933 

845 

848 
2545 

125 
39.6 

372 

335.5 

385.6 
82.6 

114.6 
26.1 
34.5 
29.0 
56.9 

33.2 

46.8 

92.3 

39.7 

49.6 

100.4 

116.3 

92.2 

82.4 

169.4 

93.6 

106.4 

Heart    

102.9 

Lunsrs    

40.9 

Liver          

96.6 

Spleen    

75.7 

Kidney    

108.2 

Intestine    

63.7 

Pancreas   

97.4 

Salivary  gland   

Thyroid    

48 
107 

other  fluids,  the  nerves  and  organs.  Dennstedt  and  Eumpf  have  made  an 
exhaustive  study  of  previous  v^ork  on  the  mineral  constituents  of  the  dif- 
ferent organs,  and  from  this  and  their  own  work  have  compiled  a  tahle  (I) 
giving  what  may  he  considered  representative  figures.  These  values  are  of 
interest  chiefly  in  that  they  give  an  idea  of  the  comparative  abundance 
of  the  different  elements,  and  they  are  to  be  considered  as  only  approxi- 
mately expressing  the  composition  of  any  individual  nonnal  organ;  There 
are  no  fixed  relations  in  the  ratio  of  different  elements  to  each  other,  and 
variations  amounting  to  as  much  as  y^  to  2  times  these  average  values  ma^ 
be  found. 

Kecent  work  by  Magnus-Levy  (;)  which  is  summarized  in  Table  II  is  of 
special  interest  when  compared  with  the  values  given  above,  for  while  the 
analyses  are  calculated  to  a  different  basis  they  allow  comparisons  of  the 
relative  amounts  of  the  different  elements,  and  show  rather  wide  differ- 
ences from  the  results  of  Dennstedt  and  Eumpf.  That  much  of  the  nor- 
mal variation  may  be  due  to  variations  in  the  fat  and  water  content  of 
the  organs,  components  which  may  vary  widely  under  physiological  con- 
ditions, is  very  probable,  especially  in  the  earlier  analyses.  Magnus-Levy 
has  eliminated  these  variables  by  calculating  to  a  dry,  fat  free  basis,  and 
has  probably  eliminated  variables  due  to  patliological  conditions,  since 
his  subject  was  a  suicide.  Pathological  conditions  are  usually  char- 
acterized by  increased  water  and  XaCl  content,  and  by  dectreased  Ca  and  P. 

In  the  highly  specialized  cells  the  ratio  of  K  :  Na  is  higher  than  in 
supporting  tissues  (Gerard).  In  muscle,  K  phosphate  is  the  predominant 
constituent  and  Mg  is  more  abundant  than  Ca-  As  the  result  of  analyses 
by  Bunge,  Aron  gives  the  relationship  of  K  :  jN'a  in  muscle  as  5-6  :  1. 
Benedict  concludes  that  there  is  approximately  three  times  as  much  Mg  as 
Ca  in  the  human  muscle.  Heubner  found  0.15  per  cent  P  in  the  fresh 
muscle  of  young  dogs  of  which  70-90  per  cent  was  water  soluble  (phos- 
phates), 0.05  per  cent  P  in  the  skin  and  1.5  per  cent  P  in  bones.  Meigs 
and  Ryan  have  found  the  smooth  muscle  of  the  frog  lower  in  K,  Mg  and 


30G 


IIExXJiY  A.  MATTJLL  AX1>  HELEN  I.  MATTILL 


P,  and  higher  in  Na  and  CI  than  the  striated  muscle.  Since  the  K  and 
P  content  of  muscle  is  gTcater  than  that  of  the  surrounding  fluids,  blood 
plasma  and  lymph,  they  conclude  that  the  fibers  of  muscle  are  not  sur- 
rounded by  a  semipermeable  membrane,  but  that  most  of  the  water  and 
of  the  K,  P,  S  and  Mg  in  the  tissue  is  held  in  colloidal  combination  in  a 
non-difhisable  form.  -Many  of  the  ductless  glands  are  characterized  by 
their  rather  marked  content  of  one  of  the  mineral  elements  in  organic 
combination,  as  the  spleen  by  iron,  the  thyroid  by  iodiii  and  bromin 
(Labat),  the  hypophysis  by  P,  the  tlnnnus  by  arsenic  (Diesing). 

Weil  has  recently  studied  the  mineral  constituents  of  human  nervous 
tissue  (Table  III).  If  the  concentration  of  these  elements  in  the  fresh 
nerve  substance  is  considered,  there  is  a  rather  interesting  classification  into 
two  groups,  the  first  of  which,  comprising  Ca,  ^fg,  P,  S,  CI,  shows  wide 
variations  in  concentration,  and  the  second  of  which,  including  Na,  K, 
and  Fe,  maintains  about  the  same  concentration  in  the  different  nerve 
tissues.  In  view  of  the  effect  of  the  Ca  concentration  on  irritability  (see 
p.  8.3G)  it  is  interesting  to  note  the  lower  concentration  of  Ca  in  gray 
matter.  If  the  analyses  are  calculated  to  a  water-free  basis  the  conditions 
are  reversed,  the  concentration  of  the  first  gi'oup  is  nearly  constant,  of 
the  second  group  variable. 

TABLE  III 


1000  ^n.  Fresh  Xerve 
Substance   Contains 

Gray  Matter 

Cerebellum 

White  :vratter 

Spinal  Cord 

Ca  .              ...      .:   . 

0.104 

0.196 

2..30 

0.56 

1.13 

0.103 

0.203 

2.58 

0.61 

1.08 

0.142 

0.260 

4.21 

0.92 

1.51 

0,179 

Mff 

0.380 

P^::. ..:.:.: 

5.48 

s  

01   

0.85 
1.52 

Sum   (1-5)    

4.380 

4.579 

7.042 

8.409 

Na    

2.03 
3.45 
0.068 

2.20 
3.49 
0.050 

2.25 

3.38 
O.OGJ 

2.01 

K   

3.61 

Fe  

0.055 

Sum  (6-8)    

5.538 

5.740 

5.094 

5.675 

Total   (1-8)    

9.918 

10.316 

12.736 

14.084 

Water   

833 

815 

702 

644 

The  understanding  regarding  the  mineral  constituents  of  the  blood 
is  even  less  satisfactory,  and  is  subject  to  greater  confusion  than  is  that 
of  the  organs  because  in  addition  to  the  application  of  unsatisfactory 
methods,  there  has  been  confusion  as  a  result  of  subjecting  .only  a  part 
of  the  blood,  as  the  serum,  the  red  blood  corpuscles  or  the  plasma,  to  analy- 
sis. Pecent  work  is  bringing  order  out  of  this  chaos,  with  the  result  that 
the  blood  is  coming  to  be  looked  upon  as  that  constituent  of  the  body  .show- 
ing most  constant  composition  with  respect  to  mineral  constituents,  under 
noiinal  conditions  (Table  IV).    From  this  it  is  not  to  be  concluded  that 


MIXERAL  METABOLISM 


307 


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308         IIEXRY  A.  MATTILL  AXD  IIELEX  I.  :\[ATTILL 

the  coniix)sition  of  the  blood  is  fixed,  but  rather  that  it  varies  within  nar- 
rower limits  than  those  for  the  composition  of  the  organ?. 

Of  the  less  abundant  mineral  elements  Gautier  has  called  attention  to 
the  wide  distribution  of  F(<^)  and  As(a)  in  the  org-anism.  F  bears  rather 
a  striking  relation  to  P ;  in  the  soft  tissues  and  glands  P  :  F  is  about  450,  in 
the  supporting  tissue,  bone  and  cartilage  it  is  125  and  in  the  epidermis, 
hair  and  nails  it  is  approximately  4.  Injection  of  XaF  into  rabbits  has 
been  found  to  have  an  undesirable  effect  on  Ca  metabolism  and  F  in  foods 
is  to  be  avoided  (Schwyzer).  Arsenic,  Gautier  found  in  the  thymus  and 
thyroid,  in  menstrual  blood,  in  hair  and  skin.  Bertrand  confirmed  these 
findings,  which  have  been  denied  by  others,  possibly  because  organic  As 
compounds  would  escape  ordinary  analytical  methods.  Van  den  Eeckliout 
found  that  ingestion  of  As  promoted  growth  and  well-being  in  animals. 
Bang(/)  found  that  As  in  the  urine  varies  greatly,  depending  on  the 
amount  in  the  foodstuffs,  and  may  reach  0.5  mg.  daily.  Fish  is  especially 
high  in  As  and  on  a  fish  diet  he  found  0.78  mg.  As  daily,  while  on  a  vege- 
tarian diet  the  urine  was  As-free. 

Silica  is  noi-mally  present  in  the  urine  and  feces  in  amounts  fluctuating 
with  the  intake  (Schulz(a)).  It  is  widely  distributed  in  the  body  and 
comprises  40  per  cent  of  the  ash  of  hair  and  seems  to  be  an  essential  con- 
stituent of  the  pancreas.  Kahle  calls  attention  to  the  loss  of  SiOg  by  the 
pancreas  and  its  increase  in  the  lymph  glands  of  tubercular  cattle,  and  to 
its  increase  in  the  pancreas  in  carcinoma.  He  found  that  the  administra- 
tion of  the  organic  preparation  of  silica  made  by  Weyland  had  a  beneficial 
influence  on  the  formation  of  connective  tissue  in  the  affected  organs  of 
tubercular  guinea  pigs.  Schulz(c)  considers  that  Kahle  is  not  justified 
in  his  generalizations  since  there  is  a  wide  variation  in  the  SiOg  content  of 
glands  of  tuberculous  and  carcinomatous  patients.  He  found  0.0084  per 
cent  SiOg  in  the  normal  dry  thyroid  and  a  larger  amount  in  pathological 
th\Toids(&).  Ga?smann(&)  has  identified  selenium  in  teeth  and  bones. 
Mn  (Reiman  and  Minot;  Bertrand  and  Medigreceanu)  is  widely  dis- 
tributed in  the  human  organism  and  is  highest  in  the  liver,  averaging 
O.lT  mg.  per  100  g.  moist  tissue.  The  blood  contains  0.004-0.024  mg,  Mn 
per  100  g.,  its  function  is  probably  catalytic.  Small  amounts  of  Cu  and 
Zn  are  widely  distributed  in  the  body  and  always  presejit  in  the  urine  and 
feces,  their  sources  being  undoubtedly  the  ingested  foods  (Van  Itallic  and 
Van  Eck ;  Rost  and  Weitzer). 

Older  conceptions  of  the  relative  unimportance  of  salts  for  nutrition 
and  the  easy  assumption  that  a  normal  mixed  diet  always  supplied  what- 
ever need  there  might  be  for  inorganic  elements  have  recently  given  way  to 
a  recognition  of  the  very  definite  needs  of  the  body  with  respect  to  min- 
eral constituents.  Forster  first  established  the  fact  that  salt-poor  diets 
led  to  faulty  nutrition.  What  little  work  has  been  done  on  the  ingestion  of 
a  salt-free  diet  leads  to  the  conclusion  that  salts  in  the  food  are  not  pri- 


MINERAL  METABOLISM  309 

marilj  necessaiy  for  the  digestion  or  utilization  of  the  foodstuffs,  but 
that  their  lack  even  over  a  brief  period  leads  to  unpleasant  nen-ous  phe- 
nomena such  as  sweating,  lack  of  appetite,  listlessncss  and  disturbed 
sleep  and  to  fatal  results  if  long  continued  (  Lunin).  Taylor(6)  in  a  0-day 
experiment  on  himself  during  which  he  ingested  a  ration  consisting  of  TO- 
TS g.  washed  white  of  egg,  120  g.  of  fat  and  200  g.  sugar  and  containing 
less  than  0.1  g.  of  salts,  per  day,  noticed  especially  the  nervous  symptoms 
and  a  general  muscular  soreness.  On  the  9th  day  acetone  was  noticed  in 
the  hreath,  and  acetone  and  diacetic  acid  in  the  urine,  whereupon  the  diet 
was  discontinued.  The  elimination  of  Ca  and  Mg  through  the  urine  ceased 
entirely  after  four  days ;  CI  reached  a  minimum  of  0.2  g.  daily,  phosphates 
were  constant  and  conjugated  sulphates  were  abnormally  high;  urinary 
ammonia  rose  only  on  the  appearance  of  diacetic  acid,  suggesting  that  the 
fixed  alkalies  are  required  for  the  neutralization  of  the  strong  acids  of  S 
and  P.  Urinary  acidity  was  constant.  Diuresis  and  a  loss  in  body 
weight  (which  was  quickly  regained  on  return  to  a  normal  diet)  indicated 
a  loss  of  water  from  the  body.  Goodall  and  Joslin  repeated  Taylor's  experi- 
mental procedure  on  two  subjects,  and  in  both  cases  failed  to  confirm  the 
appearance  of  either  acetone  or  diacetic  acid  in  the  urine,  although  the 
nervous  symptoms  were  similar,  and  they  agree  with  Taylor  in  finding 
extremely  low  urinary  chlorin,  and  considerable  loss  of  weight  due  to  a 
loss  of  body  water.  Unfortunately  no  complete  study  of  the  mineral  bal- 
ance was  made  and  the  opportunity  which  these  conditions  gave  for  throw- 
ing light  on  the  fundamental  mineral  exchange  in  the  body  was  lost.  That 
the  undesirable  symptoms  are  in  part  though  not  entirely  due  to  the  acid- 
forming  S  and  P  present  in  the  protein  seems  clear  from  the  early  worb 
of  Lunin,  who  found  that  NagCOa  added  to  a  salt-free  diet  prolonged 
the  life  of  mice  to  about  double  its  duration  without  the  Na2C03  but  did 
not  prevent  death  with  the  usual  symptoms. 

Fasting  experiments  have  long  been  used  to  obtain  fundamental  infor- 
mation upon  the  metalx)lism  of  organic  matter.  The  excretion  of  inor- 
ganic material  during  fasting  gives  similar  information  on  mineral  econo- 
my. In  the  study  of  prolonged  fasting  made  at  the  Nutrition  Laboratory 
of  the  Carnegie  Institution  (Benedict  (/i))  it  appeared  that  the  excretion 
of  ^IgO  (per  kg.  of  body  w^eight)  was  practically  constant,  especially  after 
the  first  six  days,  and  was  about  one  third  of  the  Ca  excretion.  There  was 
a  notable  parallelism  between  the  daily  loss  of  Mg  and  of  body  protein 
although  the  Mg  was  always  slightly  gi-eater  than  the  calculated  value  from 
catabolized  protein,  using  Magnus-Levy's  figure  of  0.106  per  cent  for  the 
Mg  content  of  dry  muscle.  Sodium  elimination  gradually  fell  during  the 
first  fifteen  days,  thereafter  it  was  constant  at  a  very  low  level  (about 
0.0011  g.  Xa  per  kg.  body  wt.)  After  the  fifth  day  KgO  formed  80-90 
per  cent  of  the  total  alkali  excretion  (Xa  and  K).  If  muscle  has  three 
times  as  much  Mg  as  Ca  and  5  or  6  times  as  much  K  as  N^a,  mineral  elimi- 


310  •      IIEXRY  A.  MATTILL  AXD  HELEX  I.  :^rATTILL 

nation  in  fasting  cannot  bo  regarded  simply  as  waste  products  from  protein 

catabolism.     After  15  days  CI  elimination  was  practically  constant  at  0.15 

g.  daily  and  was  derived  for  the  most  part  from  disinte2:rated  muscle  sub- 

X 
stance.     The  ratio  was  always  lower  than  the  accepted  value  for 

flesh,  QSiy  the  excess  of  PoOg  undoubtedly  resulting  from  the  metabolism 
of  bones.     Elimination  of  S  was  always  less  than  would  be  expected  from 

the  ratio  ^=  13.3  in  protein,  and  Benedict  considers  this  an  indication 

of  the  catalx)lism  of  some  substance  high  in  nitrogen  and  low  in  sulphur. 
The  elimination  of  Ca  and  P,  and  to  a  less  extent  of  K,  in  excess  of  that 
accounted  for  by  muscle  catabolism  may  be  intei-preted  as  an  indication 
of  a  metabolic  need  for  these  elements  which  when  not  met  by  a  proper 
intake  is  in  normal  cases  met  by  the  reserves  in  bone. 

In  their  book  published  in  1906  Albu-Xeuberg  repeatedly  deprecate 
the  lack  of  sufficiently  complete  metabolism  experiments  to  enable  them 
to  come  to  any  reliable  conclusions  regarding  the  mineral  requirements  of 
the  adult  organism.  Most  of  the  work  up  to  that  time  had  been  limited 
to  the  investigation  of  urinary  excretion,  and  because  of  the  lack  of  any  ap- 
proximately fixed  relation  between  urinary  and  fecal  output  of  Ca,  Mg 
or  P,  was  valueless.  They  point  out  that  only  by  a  painstaking  investiga- 
tion not  only  of  the  urinary  output  but  also  of  the  fecal  output  and  of  the 
food  intake,  can  any  reliable  data  regarding  minimum  requirements  for 
normal  conditions  be  obtained.  Furthermore,  in  such  controlled  experi- 
ments, in  which  the  intake  is  varied  by  the  addition  to  the  food  of  the 
mineral  constituents  sometimes  in  inorganic,  sometimes  in  organic  com- 
bination, another  element  of  uncertainty  is  introduced  in  that  the  ab- 
sorption and  hence  availability  to  the  body  of  the  minerals  is  not  inde- 
pendent of  the  form  in  which  they  are  ingested,  and  also  the  absorption  of 
one -mineral  constituent  depends  to  a  degree  on  the  quantities  of  other 
food  materials  ingested,  e.  g.,  a  condition  of  Ca  equilibrium  may  he  con- 
verted to  a  minus  balance  by  the  ingestion  of  an  increased  amount  of  P, 
of  carbohydrate  or  of  fat.  We  have  only  made  a  beginning  in  the  acquisi- 
tion of  data  which  will  finally  lead  to  as  definite  an  understanding  of 
the  mineral  requirements  as  we  now  have  of  protein  and  energy^  require- 
ments. With  the  recently  attained  success  in  feeding  mixtures  of  puri- 
fied foodstuffs  to  experimental  animals  has  come  a  new  method  of  deter- 
mining the  mineral  needs.  McCollum  and  Davis (/)  have  by  this  method 
shown  that  a  ration  in  which  the  acid  forming  elements  far  outweigh  the 
basic  elements  may  support  growth  but  is  quite  inadequate  for  reproduc- 
tion. Osborne  and  Mendel (e)  have  varied  the  mineral  content  so  as  to  re- 
duce the  quantity  of  one  element  after  another,  or  of  several  at  once,  to  a 
minimum,  and  they  find  that  rats  grow  normally  and  equally  well  whether 


MIXERxVL  METABOLISM  3li 

deprived  of  Mg,  Na  or  CI  or  of  all  three.  If  deprived  of  K  growth  is  not 
very  satisfactory  and  when  deprived  of  both  Xa  and  K  it  ceases.  Lack 
of  Ca  or  P  is  promptly  followed  by  a  slowing  of  growth. 


Water 

Of  all  the  body  constituents  water  is  present  in  greatest  proportion 
and  except  in  the  bones  and  fat  it  comprises  more  than  one  half  the  weight 
of  tlie  fresh  substance.  Three  factors  exert  their  influence  on  the  water 
content  of  the  body  and  of  the  individual  organs.  First,  the  age.  The 
fetus  has  the  highest  percentage  of  water,  at  the  third  month  94  per 
cent,  which  falls  rapidly  so  that  by  the  fifth  month  it  is  approximately  the 
same  as  at  birth,  66-69  per  cent  (Camerer  and  Soldner).  In  the  adult  it 
is  oS-63  per  cent.  Second,  the  nutritional  condition  of  the  organism. 
With  poor  nutrition  the  water  content  of  the  body  increases,  as  a  result  of 
loss  of  fat,  since  water  and  fat  are  present  in  the  tissues  in  quanti- 
ties which  vary  inversely  (Voit(&)).  The  ingestion  of  carbohydrates 
(Weigert(a))  and  of  NaCl  favors  water  retention.  Strauss(6f)  claims 
that  for  every  10  to  15  grams  of  salt  retained  1^/4-2  kg.  of  water  are 
retained,  and  he  considers  this  a  "sero"  rather  than  a  tissiie  retention. 
Third,  a  pathological  condition  is  in  many  cases,  especially  in  fibrile  dis- 
eases, accompanied  by  water  retention.  Balcar  et  ah  consider  this  to  be  the 
result  of  a  poisoning  of  the  tissues  which  causes  them  to  combine  with 
excessive  quantities  of  water,  thus  interfering  with  regulation  of  body 
temperature  by  surface  evaporation.  By  the  injection  of  a  solution  con- 
taining 5  per  cent  XaCl  and  1  per  cent  N'asCOg  until  diuresis  deprived  the 
body  of  large  quantities  of  water  they  were  able  to  produce  fever  experi- 
mentally, and  they  compare  this  fever  with  the  salt  or  inanition  fever  of 
new-born  infants,  both  of  which  disappear  on  the  administration  of  water. 

Sakai's  analyses  of  the  blood  of  new-bom  infants  as  compared  with 
that  of  nursing  infants  and  adults  show  a  lower  percentage  of  water,  and  a 
higher  percentage  of  salt  in  the  new-born,  HgO  :  XaCl  ^=  122,  than  in 
either  of  the  others,  Ha^^  :  NaCl  ^^  140  —  142.  The  maximum  water  con- 
tent of  the  blood  occurs  at  about  three  months  of  age  and  a  too  long  con- 
tinued liquid  diet  for  babies  is  apt  to  prolong  the  period  of  high  blood 
dilution  with  pathological  consequences  (Lederer;  Widmer(&)).  The 
normal  water  content  of  the  blood  is  occasionally  decreased  in  diabetes  but 
pathological  conditions  usually  result  in  its  increase. 

Edema  is  a  water  retention  accompanied  by  salt  retention  which 
Fischer (?>)  considers  the  result  of  an  accumulation  of  acid  in  the  body 
(acidosis)  since  he  has  shown  experimentally  that  increased  H  ion  concen- 
tration promotes  the  absorption  of  water  and  of  ISTaCl  by  protein.  Hender- 
son does  not  consider  this  explanation  adequate  because  he  finds  no  in- 


312        HENRY  A.  MATTILL  AND  HELEN  I.  MATTILL 

creased  colloidal  swelling  in  H  ion  concentrations  within  the  ranges  that 
occur  in  the  body  or  the  urine,  and  because  acidosis  is  not  always  accom- 
panied by  edema. 

The  requirement  of  the  body  for  water  is  of  course  dependent  to  a 
degree  on  climatic  and  occupational  variations,  bvit  under  comparable  con- 
ditions a  child  requires  more  water  per  kg.  of  body  weight  than  an  adult. 
Bartlett  is  of  the  opinion  that  a  child  6  months  old  needs  122  g.  water 
per  kg.  and  an  adult  35  g.  Widmer(Z>)  considers  that  a  child  6  months  old 
should  receive  115  g.  per  kg. ;  a  child  1  to  2  years  old  65-110  g.  water  per 
kg.  and  that  85  g.  is  the  optimum  ingestion  for  a  2-year-old  child.  The 
daily  loss  of  'Water  through  the  lungs  is  400-500  g.  for  adults.  Lack  of 
water,  if  accompanied  by  the  ingestion  of  food,  results  in  increased  pro- 
tein metabolism  (Spiegler).  A  fasting  animal  is  supplied  with  water  for 
its  body  needs  by  the  catabolism  of  its  own  tissues,  and  usually  shows  little 
inclination  to  drink.  Excessive  water  drinking,  in  fasting  or  with  food, 
causes  temporarily  increased  N  elimination  followed  by  improved  protein 
economy  (Fowler  and  Hawk,  Orr). 


Sodium  Chlorid 

In  how  far  sodium  chlorid  is  a  food  and  in  how  far  it  is  a  condiment, 
is  a  question  which  is  open  to  discussion  and  which  is  not  of  particular  im- 
portance. A  certain  amount  of  it  must  be  considered  a  necessary  food 
constituent  for  all  but  strictly  carnivorous  animals  who  suck  the  blood, 
as  well  as  eat  the  flesh  and  bones  of  their  prey,  but  thei-e  is  no  doubt  that 
habit  has  resulted  in  the  use  of  much  more  NaCl  in  the  human  dietary 
than  is  physiologically  necessary.  Albu-Neuberg  state  that  1-2  g.  of  NaCI 
daily. is  sufficient.  While  custom  varies  considerably  the  average  daily 
intake  is  probably  nearer  8-10  gr.  Bunge's  explanation  that  the  need  of 
!N*aCl  by  herbivora  and  animals  living  on  a  mixed  diet  is  due  to  the  pre- 
ponderance of  K  over  Na  in  grains,  vegetables  and  flesh  and  that  the  ab- 
sorption by  the  blood  of  the  salts  from  these  foods  leads  to  a  loss  of  blood 
Na  and  CI  which  must  be  compensated  by  ingestion  of  NaCl,  is  still  gener- 
ally accepted.  According  to  this  theory  the  K  and  Na  salts  from  the  food 
enter  the  blood  as  organic  salts  or  as  phosphates  and  since  the  ratio  of 
K  to  Na  is  higher  than  in  the  blood,  the  excess  of  K  salt  reacts  with  NaCl 
in  blood,  producing  IvCL  and  a  Na  salt,  both  of  which  are  excreted  by  the 
kidneys  thereby  impoverishing  the  body  of  NaCl.  Koppe  has  added  to 
this  the  theory  that  salt  hunger  may  be  due  to  a  lack  of  ionized  salts  in  vege- 
table foods. 

The  relation  of  salt  to  water  retention  has  already  been  mentioned 
(p.  311).  This  matter  has  been  attacked  experimentally  from  difi*erent  di- 
rections with  interesting  results.    Cohnheim  and  his  co-workers  have  shown 


:NrTXERAL  ]\rETABOLIS:M 


313 


that  the  water  lost  on  profuse  sweating  is  much  more  rapidly  regained  on 
a  salt-rich  than  on  a  salt-poor  diet,  when  water  and  food  intake  are  other- 
wise unchanged.  They  hold  that  the  largo  amount  of  dilute  urine  follow- 
ing mnscular  exertion  is  due  to  the  thirst  which  prompts  w^ater  drinking 
and  since  no  salt  is  taken  with  the  water  it  cannot  be  incorporated  into 
the  body.  The  fact  that  thirst  is  only  transitorily  slaked  by  water  drink- 
ine:  under  such  conditions  is  also  a  result  of  the  lack  of  XaGl. 

Workinir  from  the  other  direction  Belli  reduced  his  ]SaCl  intake  to 
a  minimum  during  10  days  of  a  metabolism  experiment  which  consisted 
of  4  days  preliminary  period  (10.2  g.  XaC'l  daily)  10  days  salt-poor 
(1.03  g.)  and  3  days  final  (9.32  g.).  His  decreased  w^ater  intake  during 
period  II  (2000  g.)  w^as  enough  to  account  for  his  loss  of  weight  (1.3  kg.) 
since  water  excretion  was  practically  unchanged,  and  in  the  final  period 
he  rapidly  regained  weight  with  water  balances  as  follows : 


Last  day,  period  II. 
1st  day,  period  III 
2nd  day,  period  III 
3rd  day,  period  III 


Water  Intake 


2102 
2279 
2292 

.20S7 


Water  Loss  in 
Urine  and  Feces 


1517 

950 

1327 

1833 


Body  Weight,  Kg. 


64.8 
65.6 
66.2 
66.2 


During  period  II  the  urinary  CI  fell  to  0.04  per  cent  and  in  the  last  five 
days  there  was  CI  equilibrium.  Klein  and  ^^erson  in  1867  found  a  similar 
loss  of  weight  in  a  period  without  salt  and  in  the  following  period  a  large 
gain  which  they  ascribed  to  water  retention. 

In  experimental  work  on  a  diet  free  from  all  mineral  constituents 
similar  losses  of  weight  have  been  followed  by  a  rapid  gain,  in  one  case 
4.1  kg.  in  72  hours,  on  a  return  to  a  normal  diet  or  on  the  addition  of 
only  XaCl  (Taylor(6)  ;  Goodall  and  Joslin). 

There  is  apparently  no  continuous  storage  of  XaCl  in  the  body,  an 
increased  intake  may  result  in  slight  retention  for  a  few  days,  but  equilib- 
rium is  soon  established  on  the  higher  level.  In  work  on  dogs  v.  Hoesslin 
established  that  on  an  intake  sufficient  to  exceed  the  minimum  needs  all 
the  ingested  XaCl  w^as  eliminated  by  the  kidney,  not  equally  on  all  days 
but  with  daily  and  periodic  variations.  On  a  quantity  of  salt  nuich  ex- 
ceeding the  minimum  needs  there  was  likewise  equilibrium  over  a  long 
I>eriod,  but  from  day  to  day  the  capacity  of  the  organism  for  water  and 
salt  varied  within  limits  which  were  about  10  per  cent  each  way  from  the 
average.  The  water  content  of  the  feces  is  less  the  greater  the  salt  intake, 
CI  and  w^ater  secretion  by  the  kidney  run  approximately  parallel. 

Urinary  elimination  of  CI  undergoes  a  rapid  rise  upon  ingestion  of 
food  (Dobrovici;  Ilermannsdorfer),  due  to  absorption  of  XaCl  b}^  the 
stomach,  followed  by  a  fall  representing  secretion  of  TICl  in  the  gastric 
juice,  which  is  accompanied  by  increased  alkalinity  of  the  blood  (Van 


314         lIEXPvY  A.  MATTILL  AXD  HELEN  I.  MATTILL 

Slyke,  Ciillen  and  Stillinan),  and  then  a  slow  rise  representing  absorp- 
tion from  tho  intestine. 

On  a  salt-free  diet  and  in  fasting  tlie  salt  elimination  soon  falls  to  a 
very  low  level,  Ix-low  0.3  g.  chlorin  daily,  and  remains  there.  It  is  im- 
possible to  lose  more  than  10-14  per  cent  of  tho  body  chlorids  and  Rose- 
man  n  has  shown  that  the  body  husbands  its  supply  of  chlorids  so  thor- 
oughly that  only  by  removal  of  the  IICl  of  the  gastric  juice  by  fistula  or 
stomach  tube  can  s\Tnptoms  of  CI  hung-er  and  malnutrition  be  produced. 
The  ingestion  of  XaCl  after  fasting  is  followed  by  retention  for  a  few 
days  and  then  the  equilibrium  is  reestablished.  Recent  work  indicates  that 
the  skin  is  an  important  storage  place  for  chlorids  (Padtberg(a)  ;  Wahl- 
gi-en). 

Early  work  on  the  influence  of  XaCl  on  metabolism  led  to  the  con- 
clusion that  it  stimulated  protein  metabolism  but  later  work  on  sheep,  dogs 
and  men  has  proven  that  moderate  quantities  of  jSTaCl  act  as  a  protein 
sparer  (Belli)  reducing  the  N  elimination  2-6  per  cent  without  affecting 
the  total  energy  exchange.  Pescheck  (a)(5)  has  shown  a  similar  protein 
sparing  action  of  Xa  acetate,  citrate,  lactate  and  Mg  acetate,  in  some  cases 
accompanied  by  diuresis.  The  ingestion  of  XaCl  increases  the  renal  and 
decrease's  the  intestinal  elimination  of  Ca,  probably  without  changing  the 
total  excretion  (Towles;  v.  Wendt(a)). 

The  blood  is  characterized  by  a  greater  constancy  in  NaCl  concentra- 
tion than  is  any  other  body  constituent  (Biemacki,  Gerard).  In  children 
the  plasma  XaCl  varies  between  0.536-0.626  per  cent,  avg.  0.587  per  cent, 
and  in  disease  it  is  usually  below  normal.  Veil  found  that  in  adults  the 
plasma  X^aCl  varied  between  .575  and  .637  per  cent  with  an  average  of 
0.61  per  cent.  The  corpuscles  contain  about  40  per  cent  as  much  as  the 
serum  (Snapper (6)).  Authorities  differ  as  to  the  influence  of  the  diet, 
Veil  found  plasma  chlorids  decreased  on  a  salt-poor  diet,  increased  on  a 
salt-rich  diet,  Arnoldi(Z>)  found  the  opposite  unless  a  large  ingestion  of 
water  accompanied  the  high  XaCl  intake,  when  chlorids  might  be  in- 
ci-eased.  Austin  and  Jonas  found  chlorids  independent  of  diet  and 
Barlocco  found  that  the  administration  of  XaCl  per  os  resulted  in  a  transi- 
torily increased  concentration  of  blood  salt  followed  by  a  decrease  which 
continued  imtil  compensated  by  kidney  activity,  when  it  again  increased; 
while  intravenous  injection  did  not  produce  the  preliminary  rise,  but  ' 
caused  reduced  XaCl  concentration  followed  by  a  rise  unless  nephrectomy 
had  been  performed.  In  view  of  recent  findings  on  the  tendency  of  the 
organism  to  maintain  constant  blood  volume  and  concentration  (Bogert, 
Underbill  and  ^Mendel;  Smith  and  Mendel)  the  question  deserves  further 
investigation.  Gastric  secretion  does  not  appreciably  affect  blood  chlorid 
concentration  (Rosemann(/)).  Ingested  salt  seems  to  be  without  effect 
on  the  gastric  secretion  judging  from  the  work  of  Rosemann  and  from 
the  normal  food  utilization  found  in  salt-free  diets.     On  the  other  hand 


MINERAL  METABOLISM 


315 


there  is  evidonce  that  loss  of  salt  through  excessive  perspiration  leads  to 
liypoaciditv  (Cohnheiin  and  Kreglinger). 

Work  by  Froivin  and  Gerard  on  a  dog  with  Pawlow  stomach  may  bear 
upon  this.  liavinL'  usually  received  10  g.  XaCl  daily,  the  dog  was  re- 
dm'cd  to  a  salt-free  diet  of  200  g.  rice  and  TOO  g.  horse  meat  cooked  in 
water  with  the  following  results : 


NaCl 

Gastric   Seer. 

Aciditv  as  g.  ' 

Total  Chlorids 

K  per 

Xa   per 

Intake 

24  Hrs. 

HCl  per  liter 

asg.  HCl  per  1. 

liter 

liter 

Jan.  12 

0 

3.50  c.c. 

2.81 

.5..55 

13 

0 

2:.> 

3.32 

.5..57 

14 

0 

11.-) 

3.28 

.5.07 

15 

0 

113 

1.97 

5..57 

16 

0 

06 

1.38 

5.84 

0.15 

2.21 

17 

5  ^• 

18.5 

3.39 

5.98 

18 

5  g. 

190 

3.06 

5.39 

0.22 

0.96 

19 

0 

90 

1.20 

5.90 

which  are  striking  f<;r  the  constancy  of  the  total  chlorid  content  and  tlic 
decreased  acidity  of  the  secretion  with  lack  of  XaCl  in  food.  The  ingestion 
of  a  chlorid,  whether  XaCl,  KCl  or  CaCl2  brought  the  quantity,  acidity 
and  concentration  of  Xa  and  K  in  the  gastric  juice  back  to  normal.  Batke 
found  a  similar  decreased  gastric  acidity  in  salt  hunger. 

Since  ingestion  of  acids  causes  loss  of  alkalies  from  the  body  the  Xa 
and  K  elimination  in  hypo-  and  hyperchlorhydria  has  been  the  subject  of 
some  investigation,  and  has  been  found  to  be  unaffected  by  such  gastric 
disturbances  (Secchi(6)).  Blood  chlorid  in  hypoacidity  may  be  higher 
than  in  hyperacidity  (Arnoldi(a),  Strauss (c).  Veil).  However,  in  dis- 
eased conditions  which  affect  kidney  permeability,  notably  in  nephritis, 
high  blood  chloride  usually  occur  and  at  the  same  time  hyperchlorhydria — 
the  stomach  apparently  taking  on  the  excretory  function  which  the  kidney 
has  lost  (Goyena  and  Petit;  Crosa). 

Alkalies 


The  alkali  metals  Xa  and  K  are  present  in  all  organs  and  tissues. 
Those  tissues  having  important  functions,  and  which  are  rich  in  cells 
have  a  higher  ratio  of  K  to  Xa  than  the  tissues  of  conduction  and  suppoi't 
or  the  body  fluids  Init  there  is  no  absolute  specificity  between  Xa  and  K 
in  any  organ,  and  the  blood  alone,  of  all  the  tissues  and  fluids,  conserves 
its  ratio  of  Xa  :  K  in  spite  of  regime  or  food.  The  ratio  of  K  :  Xa  is 
highest  in  the  vertebrates  and  is  normally  about  2%  :  1. 

This  difference  between  the  quantities  of  Xa  and  K  in  the  body  is 
reflected  in  most  fo^Dds  especially  in  milk  and  vegetables,  and  in  infancy 
the  retention  is  in  approximately  the  same  ratio  as  the  occurrence  in  human 
milk  (Cronheim  and  MUller(c),  Mcycr^h)).'  In  the  usual  mixed 
diet  the  ration  of  Xa   :  K  is  reversed,  because  of  the  addition  of  XaCl 


31G        IIEXKY  A.  MATTIl.L  AXD  IIELEX  I.  MATTILL 

to  the  food  and  what  little  metabolism  work  has  bceu  done  on  alkali 
•balance,  does  not  give  conclusive  results  regarding  their  retention  chiefly 
because  the  loss  of  the  alkalies,  especially  Xa,  through  sweat  makes  the 
determination  of  total  excretion  difficult. 

An  abnormally  high  ratio  of  X  :  Xa  (22:1)  in  the  food  of  puppies 
has  been  shown  to  result  in  a  strong  positive  K  balance  and  a  slightly 
negative  Xa  balance,  and  when  long  continued,  to  stop  growth.  The  ratio 
of  K:Xa  in  the  liver  and  kidney  was  1.5  to  1  while  in  control  animals  (re- 
ceiving K:Xa  2  :1)  it  was  1.24  :  1  and  in  rats  a  very  high  K  diet  brought 
the  ratio  of  K  :  Xa  in  their  ash  up  to  2.41  :  1,  when  it  is  normally 
1.5  :  1  (Gerard(6)).  Osborne  and  Mendel(Z)  have  found  K  more  essen- 
tial than  Xa  in  the  diet  of  rats.  The  bones  of  calves  receiving  a  high  K 
diet  showed  retarded  development  even  with  a  plentiful  supply  of  Ca  and 
PaOg  in  the  diet,  though  the  cortiposition  of  the  bones  was  normal  (Aron 
(a) ).  An  eifort  to  confirm  these  results  on  children  by  studying  the  CaO 
balance  on  diets  high  and  low  in  K  (K:  Xa  2: 1  and  1: 17)  has  been  un- 
successful (Adler). 

The  ingestion  of  a  diet  rich  in  fat  aifects  the  alkalies  in  the  same 
way  that  it  affects  Ca,  and  may  lead  to  a  negative  balance  (Hellesen).  In- 
gestion of  acids  has  a  similar  effect  (Secchi(a)).  Elimination  of  the 
alkalies  is  principally  through  the  urine.  The  feces  usually  contain  more 
K  than  Xa,  but  only  in  cases  of  diarrhea  does  the  quantity  of  either  become 
a  considerable  proportion  of  the  total  excretion.  There  are  3-4  gi-ams 
KgO,  5-8  g.  XagO  daily  in  the  urine  of  the  normal  adult,  though  these 
quantities  are  subject  to  wide  variations  depending  on  the  diet.  In  stai-va- 
tion  the  elimination  of  X^'a  rapidly  decreases,  of  K  less  rapidly,  and  after 
a  few  days  the  K  elimination  is  six  to  nine  times  as  gi'cat  as  the  Xa,  a 
proportion  which  exceeds  that  found  in  muscle  substance.  On  breaking 
a  fast  and  in  convalescence  there  is  a  very  marked  K  retention. 

The  coincidence  of  glycosuria  and  acidosis  has  resulted  in  the  develop- 
ment of  an  alkali  therapy  in  diabetes  for  which  a  considerable  success 
is  claimed  (IJndcrhill(r/)  ).  In  opposition  to  this  claim  must  be  mentioned 
the  findings  of  others,  that  XallCO.t  administration  is  sometimes  followed 
by  retention  of  chlorids  and  water  resulting  in  edema,  and  that  the  ap- 
parently improved  carhjhydrato  utilization  may  be  only  a  result  of  its  stor- 
age in  the  increased  body  water  (Levinson;  Hertz  and  Goldberg;  Beard). 

Calcium 

The  distribution  of  Cat)  between  urine  and  feces  is  too  variable  to 
permit  of  any  even  approximate  statement.  The  urinary  CaO  may  com- 
prise 5-64  per  cent  of  the  total  CaO  excreted  in  the  normal  cases  (Xeurath, 
Towles).  A  milk  diet  is  apt  to  result  in  a  lower  proportion  of  urinary 
CaO  to  total  CaO  than  a  mixed  diet  (Secchi(fe))  in  spite  of  the  fact  that 


MINERxVL  METABOLISM!  317 

urinary  CaO  is  higher  on  a  milk  diet  than  on  a  mixed  diet;  and  milk  is 
more  effective  than  Ga  lactate  in  increasing  urinary  CaO  (Givens(6)). 
Breast-fed  infants  usually  show  higher  urinary  CaO,  in  terms  of  per  cent 
of  total  CaO,  than  the  artificially  fed.  NaCl  and  IICl  increase  the  per 
cent  of  urinary  CaO  but  do  not  affect  the  Ca  balance  (Givens(6),  v. 
Wendt(a))  while  bases  are  without  effect  (Givens)  except  in  pathological 
conditions  (Eppinger  and  Ullmann).  An  increased  urinary  CaO  is 
usually  accompanied  by  diuresis  (Schetelig). 

Calcium  in  the  food  is  usually  in  organic  combination,  as  in  milk,  eggs, 
vegetables  and  cereals,  though  there  is  a  not  unimportant  intake  of  lime 
from  drinking  water,  in  inorganic  combination.  Tim  question  as  to  the 
relative  availability  of  these  two  forms  has  not  yet  been  settled  (Bunge(c?)  ; 
McCluggage  and  Mendel;  Rose  (6)  ;  Aron  and  Frese).  Givens  found 
that  0.34  g.  CaO  in  the  form  of  dried  skim  milk  when  added  to  a 
Ca  poor  basal  ration  would  produce  a  positive  Ca  balance,  while  1  g.  of 
CaO  in  the  form  of  lactate  was  necessary  to  accomplish  the  same  end.  In 
two  cases  of  exophthalmic  goiter  Towles  found  that  the  addition  of  Ca  lac- 
tate to  a  Ca  poor  diet  which  was  giving  a  negative  balance,  resulted  in  a 
positive  balance  which  soon  reverted  to  negative,  whilo  the  addition  of  the 
same  amount  of  CaO  in  the  form  of  milk  gave  a  higher  and  a  lasting 
CaO  retention.  That  inorganic  Ca  salts,  especially  the  soluble  ones,  are 
absorbed  is  indicated  by  Kost  who  found  notable  increased  Ca  in  the 
bones  of  rabbits  fed  CaClg  for  a  long  period,  as  compared  with  control 
animals.  Orgler,  supplying  Ca  in  the  form  of  Ca  phosphate,  found  equally 
good  retention  whether  the  salt  was  given  in  raw  milk  or  in  sterilized  milk. 

The  adult  normal  requirement  for  Ca  has  been  variously  estimated 
3.3  g.  (Bunge)  to  0.38  g.  CaO  per  day.  Bertram  maintained  equilibrium 
on  0.38  g.  CaO.  Renvall  required  1.19-1.26  g.  CaO.  Von  Wendt(a)  con- 
siders 0.8  g.  CaO  daily  sufficient  and  Xelson  and  Williams  by  studying  the 
total  elimination  of  four  subjects  on  normal  unrestricted  diet  found  0.95- 
1.43  g.  CaO  excreted  daily.  Sherman (c)  considers  0.9-1  g.  CaO  per  day 
sufficient,  since  it  is  considerably  above  the  average  amount  found  by  him 
in  a  compilation  of  97  experiments  in  which  a  minimum  CaO  for  equilib* 
rium  was  determined  (0.63  g.  CaO  per  70  kg.  body  weight)  (e).  He  states 
*'the  case  of  Ca  is  the  one  which  would  seem  to  call  for  the  most  liberal  mar- 
gin in  intake  over  the  estimated  average  maintenance  requirement  if  indi- 
vidual variability  is  to  be  covered  by  an  ample  factor  of  safety."  He  holds 
that  1  g.  of  Ca.  should  accompany  every  100  g.  of  protein  intake.  A  suffi- 
cient Ca  supply  is  so  important  that  some  investigators  have  recommended 
the  addition  of  Ca  salts  to  bread  and  others  the  direct  ingestion  of  1  to  1.5 
g.  CaCl,  or  Ca  lactate  daily  (Heinze;  Bertram;  Loew).  Such  an  addi- 
tion does  not  affect  the  arteries  (Kost)  and  has  been  shown  in  animal 
experimentation,  to  have  beneficial  results  (Emmerich  and  Loew(&)  ;  Ev- 
vard;  Dox  and  Guernsey).     Pellagra  producing  diets  have  been  shown  to 


318         IIEXRY  A.  MATTILL  AXD  IIELEIsT  I.  MATTILL 

be  deficient  in  Ca  (!McCollum,  Simmonds  and  Parsons).  The  ingestion  of 
excessive  quantities  of  fat,  protein  or  carlx)hydrate  increases  lime  ex- 
cretion (Koclimann(a)  (&)  ).  X  and  Ca  balances  show  no  parallelism  wliat- 
ever. 

Albii-Xenberg  state  that  XaCl  increases  and  that  alkalies  reduce  CaO 
resorption:  neither  v.  Wendt  nor  Givens  support  this  statement,  Aron 
found  that  hioh  K  and  low  Xa  intake  decreased  Ca  absorption,  but  Adler 
was  not  able  to  confirm  this.  Dubois  and  Stolte  by  adding  alkali  to  the 
diet  of  rachitic  children  were  able  to  convert  a  negative  to  a  positive  lime- 
balance,  but  if  the  balance  was  originally  positive  the  addition  of  alkali  had 
little  effect.  Xeitlier  Givens  nor  Granstrom  were  able  to  show  any  effect  of 
alkali  or  acid  administration  on  the  lime  balance  of  a  dog.  Sccchi  on  the 
other  hand  found  in  dog  and  man  an  increased  Ca  output,  especially  in  the 
feces,  when  HCl  was  administered.  Undoubtedly  the  nutritive  condition 
of  the  individual  at  the  time  such  an  experiment  is  initiated  influences 
the  result ;  Givens'  dogs  Avere  on  a  minimum  or  even  inadequate  Ca  intake, 
while  Secchi's  subjects  showed  a  positive  Ca  balance.  An  addition  of 
H3PO4  causes  an  increased  CaO  output  in  both  urine  and  feces. 

In  the  adult  there  is  a  tendency  to  Ca  equilibrium.  Renvall  increased 
the  lime  intake  over  the  amount  necessary  for  equilibrium  by  ingesting 
CaC03  and  found  a  retention  of  CaO  for  several  days,  followed  by  equilib- 
rium on  a  higher  level  of  intake  and  output.  This  is  strikingly  like  pro- 
tein and  XaCl  metabolism,  and  is  confirmed  by  Sherman  and  by  Ilerbst. 

In  infancy  and  childhood  tlie  question  of  lime  metabolism,  as  of  phos- 
phorus, becomes  one  of  especial  importance  because  of  the  need  of  the 
body  for  these  elements  in  growth  and  especially  in  bone  fonnation. 
Weiser  has  shown  in  work  on  dogs  that  gain  in  w^eight,  on  a  diet  poor 
only  ill  Ca,  is  below  normal,  and  surprisingly  enough,  the  bones  make  up 
a  larger  percentage  of  the  total  body  weight  than  in  the  control  animals. 
The  water  content  of  the  bones  was  20-30  per  cent  higher  than  that  of 
the  controls,  the  ash  content  lower,  and  the  fat  content  about  the  same. 
The  composition  of  the  ash  varied  from  the  nonnal  and  the  variation  was 
greatest  in  the  ribs  and  least  in  the  skull,  and  was  characterized  by  de- 
creased Ca,  P2O5  and  SOo,  and  by  the  appearance  of  3-5.5  per  cent  XagO 
and  0.35-1.25  per  cent  Iv^O.  Aron  and  Sebauer  confirm  this.  E.  Voit 
found  the  breast  bone  and  skull  of  pigeons  to  be  most  affected  by  a  Ca  free 
diet.  Aron(c/)  and  Briining  in  work  on  growing  rats  which  they  main- 
tained at  constant  weight  by  imderfeeding  on  an  otherwise  adequate  diet, 
or  by  food  containing  only  carbohydrate,  found  a  markedly  increased 
percentage  of  ash  in  the  total  body,  as  compared  with  control  animals  of 
the  same  weight  but  younger. 

The  amounts  of  the  mineral  elements  required  to  make  a  gain  of  100 
g.  in  the  body  weight  of  infants  have  been  calculated  from  various  angles. 
Camerer  and  ScHdner  based  their  estimate  on  the  composition  of  new-bom 


MIXEKAL  METABOLISM 


319 


TABLE  V 


Grams   Going-   to   jVIakc 
100  '^..  Gain  in  Weight 

K,0 

rr. 

NajO 

CuO 

g- 

PA 

CanK-rcr  and  Soldncr    . . 
CronlR-im    and     [Miiller 

.*>  4  months  ohl   

">-0  months  old   

Alcvfr    

0.20 

1.53 
1.20 
0.73 

0.C9 

0.24 

0.06 
0.40 
0.17 

0.82 

1.00 

1.97 
0.48 
0.3 

0.21 

0.04 

0.18 
0.12 

1.04 

1.77 
0.78 
1.17 

Tobler    and    Noll,    2\U 
months  old         

0.47 

1 

infants,  Cronhcim  and  ^liillcr  on  the  retention  found  in  metal)olism  ex- 
periments extending  over  ']5  days,  and  Meyer  on  the  metabolism  of  fast- 
ing. Tobler  and  Xoll  report  a  metabolism  experiment  on  a  21^  months 
old  baby  giving  the  average  retention  per  day  on  an  average  daily  gain  of 
24.3  g.,  and  for  the  sake  of  comparison  their  values  for  retention  have  been 
multiplied  by  4,  to  make  ap])roximately  a  100  g.  gain  in  weight,  and  aro 
included  in  Table  V.  Bartlett's  estimate  that  1.7  g.  ash  must  accompany 
every  gi*am  of  K  laid  down  is  probably  within  these  limits.  He  considers 
0.05-O.S  g.  Ca  per  day  a  noimial  deposit:  Herter  considers  0.1  g.  CaO  the 
daily  depf>sit  necessary  for  normal  growth.  Apparently  gain  in  weight 
is  due  to  such  variable  proportions  of  l>one,  protein,  water  and  fat  that 
only  an  approximate  estimate  of  the  mineral  need  can  Ik?  made  on  this 
basis.  Children  0-7  years  old  should  get  0.-3-0,5  g.  CaO  per  clay,  14  yeai-s 
old,  0.6-0.1)  g.,  in  order  to  support  normal  growth  of  Ixmes  (Ilerbst). 

It  is  generally  conceded  that  human  milk  contains  the  mineral  con- 
stituents in  the  ideal  proportions  for  growth,  although  Dibbelt  and  Aron(6) 
point  out  that  the  breast-fed  baby's  need  of  lime  may  exceed  its  supply  in 
the  first  six  months  of  life,  and  thereafter  the  supply  exceeds  the  need.  In 
this  connection  it  is  worth  while  to  refer  to  recent  very  painstaking  analyses 
of  woman's  milk  by  Schloss(a)  and  Holt (6)  and  of  cows'  milk  by  Triinz 
who  show  a  colostrum  period  consisting  of  the  fii'st  12  days  and  charactei^ 
ized  by  high  ash  content,  a  transition  pta-iod  to  the  end  of  the  4th  week  after 
which  the  composition  remains  about  constant  until  the  10th  month.  This 
can  best  be  summarized,  and  the  difference  lietween  human  and  cow's  milk 
displayed  in  the  following  table  (VI).  Scliloss  compared  the  complete 
24-liour  samples  of  milk  from  (S  wet  nurses  and  found  a  marked  pa]-al- 
lelism  between  the  X  and  total  ash.  The  lower  content  of  Ca  in  human 
milk  is  compensated  by  a  much  better  absorption. 

The  feeding  of  vegetables  to  young  babies  (6-7  months  old)  has  recently 
been  shown  to  exert  a  favorable  influence  on  their  gTOwth.  The  increased 
quantity  of  salts,  their  especially  favorable  chemical  natui*e,  or  the  vitamin 
content  are  variously  suggested  to  explain  this  effect.  Since  boiling  vege- 
tables in  water  causes  a  considerably  greater  loss  of  salts  than  steaming,  tlie 
latter  method  of  cooking  is  recommended  (Courtney;  Fales  and  Bartlett). 


320         HEJN^KY  A.  MATTILL  AXD  llELEX  I.  MATTILL 

TABLE  VI 


G.  in  100  cc.  Milk. 

Ash 

CaO 

MgO 

PA 

Na,0 

K,0 

CI 

Human    Milk 

Ifolt — col6strurn      . . 

0.3077 

0.0446 

0.0101 

0.0410 

0.0453 

0.0938 

0.0568 

Holt— early    mature. 

1  -4  mos 

.20o(5 

.0486 

.0082 

.0342 

.0154 

.0539 

.0351 

Holt. — middle        ma- 

ture. 4-9  mos.    . . . 

.2000 

.0458 

.0074 

.0345 

.01.32 

.0609 

.0358 

Schloss— mature     . . 

M83J) 

.0376 

.0080 

.0405 

.0189 

.0529 

.0522 

Cows'  ^tilk 

Trunz — colostrum, .  . 

.760 

.194 

.027 

.238 

.052 

.174 

.092 

Trujiz     —     mature, 

period  II    

.714 

.174 

.019 

.205 

.042 

.176 

.101 

Ascheiiheirn(6)  found  that  the  addition  of  fat  to  the  diet  of  infants  in- 
creased the  fecal  CaO  at  the  expense  of  the  urinary  and  that  if  the  child 
was  sick  or  convalescent  the  drain  on  CaO  might  he  so  great  as  to  establish 
a  negative  balance.  Meyer  and  Birk  and  Rothberg  found  a  like  effect  of 
fat  on  the  balance  of  Na,  K,  Mg,  and  Ca.  Herter  showed  that  the  loss 
of  CaO  in  infantilism  was  connected  with  poor  utilization  of  fat^  and  the 
excretion  was  in  the  fonn  of  a  Ca  soap.  He  also  concluded  that  a  small 
increase  of  fat  in  the  food  might  convert  a  positive  CaO  balance  to  a 
negative. one.  Recent  work  (McCrudden  and  Fales)  has  not  substantiated 
Herter,  ]N^iemann(6)  in  a  metabolism  experiment  on  a  normal  10-months' 
old  infant  varied  the  fat  content  of  milk  from  1.13  per  cent  to  3.97  per 
cent  and  foimd  a  constant  excretion  of  CaO  throughout,  on  an  intake  of 
1.8  g.  CaO  per  day.  Ho  concludes  that  in  normal  infants  the  change  from 
a  fat-poor  to  a  fat-rich  diet,  so  long  as  the  fat  content  remains  within 
physiological  limits,  does  not  interfere  with  CaO  absorption  and  does  not 
increase  tlie  fecal  CaO  although  the  typical  fat  stools  are  present.  Others 
confirm  this  (Wolff;  Holt,  Courtney  and  Fales(c?)).  Hoobler(a)  goes 
even  further  and  shows  that  a  high  fat  content  if  within  normal  physi- 
ological limits  favors  retention  of  Ca  and  P  but  this  is  not  the  case  if  the 
fat  rises  above  the  normal  quantity  in  human  milk  (Lindberg).  For  in- 
fants on  modified  cow's  milk  Holt  and  his  co-workers  found  the  best  ab^ 
sorption  of  Ca  w-hen  the  food  contained  0.045-0.060  g.  CaO  for  every  gi-am 
of  fat  and  when  the  fat  intake  was  not  less  than  4  g.  per  kg.  body  weight. 
For  young  children  on  a  mixed  diet  the  absorption  was  best  w^hen  the  fat 
intake  was  not  less  than  3  g.  per  kg.  body  weight  and  there  was  0.003-0.005 
g.  CaO  to  every  gram  of  fat. 

In  artificial  feeding  with  cows'  milk  the  intolerance  for  fat  often  noticed 
may  be  caused  by  the  excessive  amount  of  calcium  present  which  for  lack 
of  sufficient  CI  or  phosphate  for  its  excretion  as  a  salt  of  either  of  these 
acids  may  be  excreted  as  a  Ca  soap  or  may  accumulate  in  the  tissues  caus- 
ing fever  and  finally  being  excreted  as  Ca  lactate.  The  dilution  of  the 
milk  with  whey,  thus  supplying  a  large  proportion  of  acid  elements,  or 


:NriXERAL  :metaboltsm 


321 


^^decalcifying"  of  the  casein  improves  the  fat  and  mineral  utilization  in 
such  cases  (iiosworth,  Bowditch  and  Giblin;  Eosvvoith  and  Bowditch; 
Forbes  (  c )  ;  C/] i\\ n  )rn  ) . 

The  mineral  requirements  of  childhood  and  adolescence  have  Leen  sub- 
jected to  metabolism  studies  by  llerbst(a)  and  Jundelt  with  the  following 
results : 


PjOj  retention  per  kg.  body  weiglit  per  day. 
CaO  retention  per  kg.  body  weight  per  day. 
3IgO  retention  per  kg.  body  weight  per  day. 


Herbat 


(Gboys— e-iayrs.) 


0.027— <).0.*J7  g. 
0.01  —0.02  g. 
0.002—0.007  g. 


Jundelt  (2  boys) 


Slit  yrs.         7%  yrs. 


.0315  .0207 

.0029      1      .0204 
.0140  .0159 


In  another  12-day  study  of  two  rapidly  growing  adolescent  boys  Ilerbst 
(b)  found  a  daily  exchange  per  kilogi-am  of  Ix^dy  weight  as  follows: 


Subject  I. 
Subject  II 


CaO 

Retained 
g- 


0.0075 

.0042 
.0118 

.0093 


CaO 

Excreted 
g- 


0.0146 

.0204 
.0075 

.0128 


PA 
Retained 

g- 


0.0148 

.0138 
.0039 

.0111 


N 

Balance 

g- 


+  0.013 

-f  .045 
—  .020 

+  .029 


6  days  of  muscular  ex- 
ertion 

6  days  of  rest 

t>  days  of  muscular  ex- 
ertion 

6  davs  of  rest 


These  values  are  of  interest  in  showing  the  relation  of  CaO  deposit  to 
bodily  activity  and  the  lack  of  any  parallelism  between  CaO  and  X. 
Hoppe-Seyler  and  v,  Noorden  have  noticed  increased  CaO  elimination 
in  bodily  inactivity. 

Eecent  work  has  greatly  extended  our  information  regarding  the  cal- 
cium of  the  blood.  That  calcium,  though  preseut  in  small  amount,  is 
one  of  the  important  constituents  of  the  blood  because  of  its  effect  on  co- 
agulation and  heart  irritability,  has  long  been  acknowledged.  We  are  inv 
debted  to  Jansen(&)  for  a  review  of  previous  work,  the  development  of  an 
analytical  method  and  analytical  results.  Previous  investigatoi's  have 
found  4.0  to  11.9  mg.  CaO  per  100  c.c.  blood  (using  strictly  chemical 
methods),  with  variations  for  a  given  species  as  great  as  the  difference 
between  various  species.  Semi-exact  methods,  devised  by  Blair  Bell  and 
Wright,  have  resulted  in  such  wide  variations  in  findings  when  employed 
by  different  investigators  (Katzenellenbogen;  Morley;  Midlik)  that 
these  results  will  not  be  considered  in  the  following  summary.  Jansen, 
Voit,  Dhere  and  Grimme,  and  Dennstedt  and  Rumpf  agi-ee  in  finding 
a  variation  in  blood  calcium  dependent  on  ago  and  independent  of  sex. 
At  birth  the   infant's   and  mothei-'s  blood   are   about  the  same  in   Ca 


322  IlEXRV  A.  MATT[]J.  AND  IIELEX  I.  MATTILL 

content.  The  Ca  in  infant's  blood  increases  during  several  months  after 
birth ;  it  reaches  a  maximum  which  varies  but  may  be  as  much  as  double 
that  at  birth,  and  thereafter  there  is  a  gradual  decrease.  Jansen  in  the 
analvsis  of  the  blood  of  33  men  and  women  found  an  average  of  12.46 
mg.  per  100  c.e^^of  whole  blood  at  20-30  years  of  age,  12.25  mg.  at  30-40 
years,  11.3  mg.  at  40-50  years,  and  10.95  mg.  above  50  years.  Dennstedt 
and  Kumpf  found  11.0  mg.  the  average  of  many  determinations  on  adults. 
Using  a  nephelometric  method  Lyman(a)  found  about  half  this  amount, 
and  slightly  higher  in  women  than  in  men.  There  is  a  difference  of  opinion 
regarding  the  distribution  of  the  blood  Ca  between  the  plasma  and  coi^ 
puscles,  some  (Lamers)  considering  that  all  the  Ca  is  in  the  plasma, 
others  (Ileubner  and  Rona ;  Cowie  and  Calhoun)  that  it  is  in  both 
plasma  and  corpuscles.  Jansen  found  that  if  he  ^vashed  the  corpuscles 
free  from  plasma  with  isotonic  sugar  solution  they  usually  contained  some 
Ca  (1-3.5  mg.  CaO  per  100  c.c,  whole  blood),  but  if  they  were  washed  with 
hypotonic  XaCl  solution  they  were  free  from  Ca,  and  he  concluded  that 
the  Ca  is  dissolved  in  a  diffusible  fonn  in  the  corpuscles.  Heubner  and 
Rona  found  a  similar  distribution  between  plasma  and  corpuscles  in 
cat's  blood.  The  fibrin,  Jansen  found,  contained  0.34  mg.  CaO  per  100 
c.c.  whole  blood.  The  Ca  content  of  the  cerebrospinal  fluid  is  about  half 
that  of  the  blood  and  is  less  subject  to  fluctuations  in  pathological  condi- 
tions (Halverson  and  Bergeim). 

The  calcium  content  of  the  blood  during  pregnancy  and  lactation  has 
been  the  subject  of  considerable  investigation  because  of  the  unusual  drain 
on  lK)dy  Ca  at  such  times.  During  pregnancy  and  the  puerperium  Jansen 
found  an  average  of  12.5  mg,.CaO  per  100  c.c,  whole  blood,  a  normal 
value  for  the  age.  Lamers  found  0.8-1  mg.  higher  CaO  in  pi-egnant 
and  lactating  women,  but  he  found  high  blood  CaO  in  women  4-8  wrecks 
after  delivery,  regardless  of  whether  they  were  lactating  or  not.  Possibly 
this  illustrates  the  lag  in  adjustment  after  pregnancy  which  McCrudden 
considers  an  explanation  of  osteomalacia  (see  p.  339).  Lamers  and  Mul- 
lik  suggest  that  a  rise  in  blood  CaO  causes  the  onset  of  labor.  The  in- 
gestion of  a  Ca-poor  or  Ca-rich  diet  or  of  Ca  salts  seems  not  to  affect  the 
blood  Ca  (Clark;  Denis  and  lMinot(7t)). 

The  important  role  which  the  Ca  ion  plays  in  controlling  the  permeabil- 
ity of  colloidal  membranes  leads  Brinkman(?>)  to  the  conclusion  that  the 
Ca  ion  concentration  of  the  blood  is  as  constant  at  H  ion  concentration,  and 
that  the  distribution  of  the  Ca  in  the  blood  between  a  protein  compound 
(25  per  cent)  and  Ca  (HC03)o  and  its  ions  (75  per  cent)  supplies  the 
necessary  mechanism  for  its  adjustment.  Rona  and  Takahashi  place 
this  Ca  ion  concentration  at  30  mg.  per  liter  of  serum.  The  increased 
blood  calcium  which  has  been  found  on  subcutaneous  injection  or  in- 
halation of  CaClo  (Clark;  Ileubner  and  Rona)  and  which  Yoorhoeve 
claims  to  have  found  on  ingestion  of  large  amounts  of  Ca  in  food,  cannot 


MINERAL  METABOLIS:\[  323 

(according  to  Eona  and  Takahashi)  affect  the  Ca  ion  concentration  of  the 
blood  to  any  degree. 

Magnesium 

!^^agne3inm  has  not  so  far  taken  on  the  importance  that  the  other  min- 
erals have  in  a  consideration  of  mineral  nietaholism,  possibly  bccanse 
the  lx)dy  need  is  relatively  small  and  always  sufficiently  covered  by  the 
food  supply  so  that  the  nutritive  disturbances  which  might  follow  lack 
of  ^Ig  are  not  observed.  Osborne  and  ^Mendel  found  that  a  diet  poor  in 
]Mg  supp)rted  growth  of  rats  as  well  as  one  richer  in  ^fg  but  in  tJie  Mg- 
poor  diet  they  may  not  have  gotten  below  the  minimum  requirement.  The 
very  small  amount  of  Mg  in  human  milk,  which  is  not  compensated  by 
a  storage  in  the  infant's  body  as  is  Fe,  leads  to  the  conclusion  that  'Mg 
needs  are  at  least  extremely  low,  Bertram  found  that  0,73  per  day  more 
than  covered  the  body  needs,  and  resulted  in  storage  of  ^fg  for  a  few 
days,  after  which  equilibrium  was  established.  Renvall  found  a  balance 
established  on  an  intake  of  about  0.45  g.  Mg;  on  0.25  g.  there  was  a  loss 
of  Mg  by  the  body.  Von  \Vendt(a)  found  in  one  case  a  alight  storage  on 
0.20  g.  ^IgO  daily  and  in  another  a  loss  of  Mg  on  0.33  g.  Sherman  in 
studies  on  150  American  dietaries  found  an  average  intake  of  0.34  g.  Mg 
per  day,  which  probably  expresses  a  little  more  than  the  minimum  require- 
ment. Xeither  Mg  (Wheeler)  nor  Sr  (Lehnerdt)  can  replace  Ca  physio- 
logically. 

In  bones  the  amount  of  Ca  is  8  to  9  times  that  of  Mg,  in  muscle  the 
Mg  is  2  to  3  times  the  Ca,  in  nerves  the  amount  of  IMg  is  about  twice  that 
of  the  Ca.  In  fasting  the  elimination  of  Ca  is  3-4  times  that  of  Mg,  indicat- 
ing a  catabolism  of  both  bone  and  body  protein. 

Absorption  of  ]\[g  is  similar  to  that  of  Ca,  though  it  seems  to  suffer  less 
interference  by  the  presence  of  other  substances.  Its  distribution  in  the 
urine  and  feces  is  subject  to  the  same  variations  as  that  of  Ca  under  similar 
conditions  though  a  larger  proportion  of  the  total  Mg  is  urinary;  urinary 
^[g  is  usually  lower  than  urinary  Ca  (Giveu8(&)  ).  The  ingestion  of  large 
amounts  of  Mg  salts  has  been  found  to  increase  the  Ca  elimination,  but  Mg 
elimination  seems  to  be  independent  of  Ca  ingestion  (Malcolm;  Hart  and 
Steenbock(a').  Fats  and  carbohydrates  decrease  Mg  retention  in  infants 
(Birk). 

Phosphorus 

Xone  of  the  other  inorganic  elements  has  so  wide  a  distribution  in 
various  forms  in  the  animal  body  as  has  phosphorus.  Its  importance  in 
life  processes  is  reflected  in  the  great  volume  of  literature  that  has  been 
contributed  upon  its  occurrence,  its  nutritive  history  and  its  functions. 


321         HENRY  A.  jMATTILL  AND  HELEN  I.  MATTILL 

A  compilation  and  review  of  the  information  available  in  1914  forms  a 
compendious  monograph  embracing  about  3,000  titles,  and  it  would  seem 
unnecessary,  indeed,  if  not  impossible  to  refer  individually  even  to  the 
more  important  contributions  before  that  time  (Forbes  and  Keith), 

In  inorganic  fonn  phosphorus  is  found  in  animal  and  plant  tissues 
chiefly  in  the  form  of  K  and  Ca  salts  of  phosphoric  acid  and  in  the  organic 
forms  in  the  generally  familiar  classification  as  nucleoproteins,  phos- 
phoproteins  and  lecithoproteins  or  phosphatids.  To  these  should  be  added 
the  phosphoric  acid  esters  of  carbohydrates  and  related  substances  which 
may  be  found  increasingly  .impoi-tant  as  investigation  continues;  for 
example,  a  phosphorus-containing  carbohydrate  is  regularly  found  as  a  con- 
stituent of  starch  (Northrup  and  Nelson). 

The  distribution  of  the  different  foiTns  of  P  in  the  organs  and  tissues 
has  claimed  the  attention  of  several  investigators  recently  and  the  resulting 
outstanding  facts  are  that  inorganic  phosphates  make  up  the  greater 
amount  of  muscle,  bone  and  blood  phosphorus  (Heubner;  Greenwakl(/), 
that  the  important  substance  for  muscular  activity  is  a  compound  of  lactic 
and  phosphoric  acids  which  is  derived  from  organic  P  compounds 
(Embden),  that  in  smooth  muscle  the  protein  P  is  more  abundant  than  in 
striated  (Costantino),  that  lack  of  P  in  the  food  affects  first  the  in- 
organic P  of  the  bones  and  liver  and  that  of  the  other  organs  only  very 
gi'a dually.  The  brain  and  heart  lose  total  P  under  no  conditions  of  dieting 
(^lasslowfa)),  exceptional  ingestion  of  P  as  phosphates  seems  to  decrease 
the  P  content  of  the  central  nervous  system,  although  it  does  not  seem  to 
influence  the  deposit  of  phosphatids  in  muscle  and  bone,  the  percentage 
of  which  is  remarkably  constant  throughout  life;  possibly  it  does  affect 
the  nucleoproteins  (Heubner). 

An  estimate  of  the  phosphorus  requirement  is  rendered  doubly  difficult 
because  of  the  uncertainty  which  sui-rounds  the  question  of  the  availability 
of  the  different  fonns  of  phosphonis  in  foods.  Unquestionably  there  is' 
a  dift'erence  between  the  phosphates  and  the  organic  P  compounds  both 
in  the  rate  and  the  percentage  of  absorption.  Experimental  studies  in 
which  phosphates  have  been  added  to  a  diet  poor  in  P  can  therefore  hardly 
be  compared  with  those  in  which  an  ordinary  mixed  diet  has  been  used. 
Sherman  found  from  a  study  of  9.5  balance  experiments  that  the  minimum 
requirement  averaged  0.88  g.  P  per  day  per  70  kg.  body  weight,  and  he 
considers  3.50  g.  P2O5  per  day  a  sufficient  intake.  Berg  maintained 
equilibrium  on  2.25  g.  P2O5  daily  at  the  same  time  that  Ca  equilibrium  was 
maintained  on  O.^^S  g.  CaO,  and  he  showed  that  the  addition  of  10  g. 
CaHP04  to  this  diet  not  only  resulted  in  no  retention  of  either  P  or  Ca, 
but  caused  a  loss  of  Ca  from  the  body.  Von  Wendt  on  the  other  hand  was 
able  to  convert  a  negative  CaO  balance  to  a  positive  balance  by  the  addition 
of  3g.  CaHP04.  Any  definition  of  the  P  requirement  without  at  the  same 
time  taking  into  consideration  the  Ca  supply,  or  vice  versa,  is  unsafe. 


^•^ 


MINERAL  METABOLISM  325 

The  inquii-y  into  P  metabolism  is  still  centered  about  the  question  of 
the  avaihibility  of  inorganic  forms  of  P  for  the  animal  organism.  De- 
terminations of  the  P  and  'N  exchange  usually  indicate  better  retention 
when  the  P  is  supplied  in  organic  combination  (Masslow(a)  ;  LeClerc  and 
Cook ;  Ilirschler  and  Terray)  and  this  is  likewise  the  case  for  Ca  retention, 
but  in  work  on  cows  it  has  recently  be<»n  shown  that  if  the  ingestion  of  a 
Ca  rich  food,  as  hay,  is  alternated  daily  with  the  ingestion  of  a  food  low  in 
Ca  and  to  which  inorganic  phosphates  have  been  added,  there  is  good 
retention  of  both  P  and  Ca  (Meigs,  Blatherwick  and  Gary).  Berg  in  a 
metabolism  experiment  on  himself  could  show  no  P  retention  on  addition 
of  Ca(H2P04).  or  Ca(H2P02)2  to  a  diet  supplying  3.04  g.  HPO4  daily. 
On  the  other  hand  Forbes (6)  in  experiments  on  swine  finds  orthophos- 
phates  and  hypophosphites  as  satisfactory  forms  in  which  to  supply  P  as 
are  nucleic  acid,  phytin  or  glycerophosphates.  Fingerling  found  the  same 
for  ruminants  and  ducks.  Osborne  and  Mendel  were  able  to  supply  prac- 
tically all  of  the  mineral  constituents  in  the  form  of  inorganic  compounds 
and  still  get  normal  growth  in  rats.  Experimental  work  is  somewhat  incon- 
clusive because  the  effort  to  prepare  a  diet  supplying  enough  protein  and 
energy-  with  a  minimum  of  P  in  organic  combination  may  result  in  an 
insufficient  supply  of  the  animo  acids  or  of  the  food  accessories  (vitamins) 
and  nutritive  failure  follows  irrespective  of  the  form  of  P.  That  inor- 
ganic phosphates  are  utilized  to  a  degree  is  unquestionably  established,  but 
there  is  still  a  lack  of  quantitative  work  which  would  establish  the  percent- 
age of  absorption  from  each  source.  That  this  is  different  seems  clear  from 
the  fact  that  the  percentage  of  the  ingested  P  retained  by  infants  is  higher 
when  they  are  breast-fed  (human  milk  contains  about  77  per  cent  of  its 
P  in  organic  combination)  than  when  fed  on  cows^  milk  which  contains 
about  27.9  per  cent  of  its  P  organically  combined  (Keller;  Schlossmann). 
Marshall  in  a  review  of  the  subject  concludes  that  inorganic  fonns  are  as 
satisfactory  as  organic,  but  others,  notably  Sherman  and  Forbes,  take  the 
more  conseiTative  view  and  (are  walling  to)  gTant  an  advantage,  though 
possibly  not  indispcnsability,  to  the  organic  forms. 

Of  the  mineral  constituents  of  the  liody  P  is  the  most  universally  re- 
quired, by  lx)ne,  muscle,  gland  and  nerve;  P  retention  is  the  rule  and 
in  this  respect  and  because  its  retention  is  frequently  independent  of  the 
X  balance.  Albu-Xeuberg  compare  P  whh  fat  In  infants  P  retention  is 
0.02-0.03  g.  PoOg  per  kg.  body  weight  per  day,  in  growing  children 
it  is  0.027-0.042  g.  per  kg.  (Herbst(a)  (&)),  in  adolescent  boys  it  is 
0.004-0.015  and  may  be  said  to  be  independent  of  the  X  balance,  al- 
though the  low^est  P  retention  found,  0.04  g.  PoOg  per  kg.,  accompanied  a 
negative  X  balance.  The  retention  of  P2O5  was  twice  as  great  as  would 
have  been  required  by  the  retained  X  and  Ca  for  building  bone  and  muscle. 
Cronheim  and  ^fiiller(fe)  found  a  similar  retention  of  P  in  excess  of  the 
amount  required  by  the  retained  Ca  and  X  and  conclude  "P  rich  nerves 


326 


HENRY  A.  MATTILL  AND  HELEN  I.  ]\rATTILL 


and  tissues  rich  in  nuclear  material  must  play  an  important  part  in  the 
gi-owth  of  the  early  years."  rnsufficient  P  in  the  food  during  growth  re- 
sults in  serious  underdevelopment  of  the  bones  (Schmorl;  jMasslow(&)). 
The  partition  of  the  excreted  P  between  urine  and  feces  depends 
largely  on  the  nature  of  the  diet.  A  meat  diet  gives  rise  to  high  urinaiy 
P  and  a  vegetable  diet  to  a  largo  excretion  through  the  intestine.  The 
urinary  excretion  is  normally  2-2.5  g.  P2O5  as  primary  and  secondary 
phosphates  of  the  alkali  and  alkaline  earth  metals.  Intestinal  excretion 
of  Cfl  and  P2O5  usually  nin  parallel.  Phosphaturia,  which  is  character- 
ized by  a  cloudy  urine  or  one  which  becomes  cloudy  on  heating,  is  not  al- 
ways due  to  increased  amounts  of  phosphates  in  the  urine^  but  frecjuently 
to  their  insolubility  in  an  alkaline  urine,  and  may  result  from  a  vege- 
table diet  or  an  ingestion  of  quantities  of  alkali  or  following  the  increased 
alkalinity  (so-called)  of  the  blood  during  digestion  or  loss  of  the  acid 
stomach  juices  by  vomiting  or  by  removal  with  stomach  pump.  Patho- 
logical phosphaturia  follows  an  increased  alkalinity  of  the  blood  as  a  re- 
sult of  disease,  or  of  increased  elimination  of  P  and  Ca  by  way  of  the  kid- 
neys because  of  some  interference  with  the  excretory  functions  of  the 
intestinal  membranes  (Soetbeer).  P  is  present  in  the  blood  in  three  forms 
— lipoid,  phosphorus,  inorganic  phosphates  and  a  form  soluble  in  acids  but 
not  precipitated  by  the  ordinary  phosphate  reagents.  *'Acid  soluble  P" 
includes  the  latter  two  and  is  2-4.5  mg.  P  (6.4-14  mg.  H3PO4)  per  100 
cc.  plasma  (Feigl(a) ;  Greenwald(/))  of  which  1-3.5  mg.  P  (3.2-12  mg. 
H...PO4)  is  in  the  form  of  inorganic  phosphates  (Marriott  and  Haessler; 
Denis  and  Minot(^)  in  nonnal  individuals.  The  phosphorus  concentra- 
tion in  corpuscles  is  about  7  times  as  great  as  in  plasma  and  shows  less 
individual  variations  (Bloor ;  Porte).  As  a  result  of  many  analyses  using 
his  nephlelometric  method  Bloor (^)  gives  the  following  table  of  average 
P  distribution  in  the  blood  of  normal  men  and  women : 


IVIgs.  HjPOj  in  100  cc.  Plasma 

In  100  cc 

Corpuscles 

Men 

Women 

]Men 

Women 

Total    

32 
10.4 

8.7 
22.1 

1.72 

3G.2 
12.4 
11.2 
24.9 
1.26 

248. 

188. 
18.7 
57. 

172. 

240. 

Acid  soluble 

Inorfranic    

Lipoid    

187. 
15.7 
56.6 

Other  forma 

167. 

Iron 

Iron  occupies  a  unique  position  among  the  mineral  constituents  of 
the  body  since  its  presence  in  hemoglobin  endows  the  blood  with  oxygen- 
carryuig  capacity.  The  blood  of  a  man  is  said  to  contain  about  three 
grams  of  iron.    The  liver  and  spleen  contain  perhaps  0.02  per  cent  of  their 


MINERAL  METABOLISM  .  .327 

fresh  substance;  iron  is  likewise  found  in  bone  marrow  and  in  muscles. 
As  a  constituent  of  nucleoprotcins  iron  has  the  function  of  a  catalyst 
(Spitzcr)  particularly  of  oxidations,  and  its  presence  in  most  (Mouneyrat; 
Jones)  if  not  in  all  cells  (biasing)  both  animal  and  vegetable  has  gen- 
erally been  accepted.  It  has  been  demonstrated  in  the  liver  and  other 
organs  of  animals  whose  blood  pigment  is  not  hemoglobin  (Baldoni ;  Dastre 
and  Floresco).  The  cell  nuclei  of  vegetable  tissues  also  contain  iron,  and 
the  decorticated  and  enucleated  form  in  which  most  cereals  are  used  for 
human  food  makes  them  relatively  poor  purveyors  of  this  element.  Some 
fruits  and  vegetables,  especially  the  chlorophyll-containing  ones,  such 
as  spinach  and  cabbage,  are  richest  in  iron.  The  amount  of  iron  necessary 
to  meet  the  daily  requirements  of  man  cannot  be  stated  dogmatically  since 
it  depends  on  the  kind  and  amount  of  other  foods,  organic  a&  well  as  in- 
organic, ingested  with  it  (Kochrnann(c) ).  In  view  of  our  meager  knowl- 
edge Sherman  in  his  review  of  the  functions  of  iron  in  nutrition  states  that 
the  daily  intake  ought  to  be  not  less  than  12  mg.  of  food  iron,  a  figure 
which  should  be  increased  during  pregnancy  and  lactation.  Milk  is  one 
of  the  poorest  sources  of  iron  (Jolles  and  Friedjung;  Langstein;  Edelstein 
and  v.  Czonka).  The  relative  amount  of  iron  in  the  body  of  an  animal 
varies  with  its  age;  thus  Meyer  (a)  showed  that  in  calves  the  iron  of  the 
liver  decreases  with  increasing  age;  he  found  that  the  fetus  contained 
ten  times  as  much  iron  (relatively)  as  the  grown  animal,  most  of  which 
is  accumulated  during  the  last  three  months  before  birth  (Hugounenq). 
This  question  was  especially  dealt  with  by  Bunge(6)  and  Abderhalden 
(e){a){g)f  who  found,  in  rabbits  and  in  rats,  that  the  relative  amounts  of 
iron  and  hemoglobin  in  the  body  decreased  progressively  during  lactation, 
at  the  end  of  wdiich  it  was  at  a  minimum.  Thereafter,  on  the  mixed  food 
of  the  mother  tlie  iron  again  increased.  In  guinea  pigs  whose  lactation 
period  is  extremely  short,  this  relation  was  not  observed.  Abderhalden 
therefore  points  out  the  undesirability  of  restricting  an  infant  to  milk  diet, 
beyond  the  period  of  lactation,  and  the  necessity  of  abundant  iron-cx)utain- 
ing  foods  for  growth  and  increasing  blood  volume. 

In  iron-containing  foods  the  element  is  usually  in  complex  organic 
combination ;  only  in  drinking  water  and  in  medicinal  iron  preparations 
is  iron  ingested  in  inorganic  form.  The  course  which  iron  follows  in  the 
digestive  tract  has  been  of  special  interest  because  of  a  possible  difference 
in  behavior  between  the  two  forms,  and  in  contradiction,  to  the  first  pro- 
nouncements of  J^unge(a)  on  the  toxicity  of  inorganic  iron  and  the  good 
fortune  of  its  non-absorption  there  has  come  a  general  acceptance  of  the 
view  that  both  forms  are  absorbed  in  the  same  way.  The  toxicity  of  iron 
salts  given  intravenously  was  demonstrated  long  ago,  but  since  inorganic 
iron  per  os  has  no  toxic  effects  unless  the  doses  are  large  enough  to  erode 
the  epithelium,  iron  salts  are  in  some  way  modified  in  the  stomach 
(Gaule).   A  part  of  the  ingested  iron,  either  organic  or  medicinal,  is  set 


328         HP:XKY  a.  MATTTLL  and  TIRLEX  I.  MATTILL 

free  (Schirokaiicr)  forming  a  loose  combination  with  peptone,  perhaps  of 
the  nature  of  an  albuminate.  Hemoglobin,  nueleic  acids,  and  related  com- 
pounds, on  tlie  other  hand,  are  probably  not  decomposed  until  after  they 
have  left  tho  stomacli. 

The  further  course  of  iron  has  been  followed  histologically  in  the  in- 
testinal tract  and  in  organs  and  tissues  by  means  of  a  microchemical 
test  \vith  ammonium  sulphid  (and  heat),  sometimes  with  the  addition  of 
potassium  ferrocyanid  and  IICl ;  only  the  loosely  combined  iron  responds 
readily  to  this  test,  the  "organic"  iron  only  after  long  standing  under 
ammonium  sulphid  or  not  at  all  (Quincke;  Matzner).  While  the  mechan- 
ism of  absorption  has  not  been  completely  outlined  it  appears  that  most 
of  the  iron  enters  the  system  in  the  duodenum,  either  in  soluble  foim  in 
the  plasma  or  through  the  phagocytic  action  of  leucocytes.  In  dogs  pro- 
vided with  various  intestinal  fistulas  it  w^as  observetl  (Rabe)  that  87  per 
cent  of  the  ingested  (inorganic)  iron  was  absorbed  before  reaching  the 
ileum  and  a  large  percentage  in  the  duodenum;  but  such  a  study  of  the 
absorpftion  of  iron  is  complicated  by  the  fact  that  iron  is  also  largely 
excreted  by  the  intestine;  this  was  shown  as  early  as  1852  by  Bidder  and 
Schmidt  (a).  They  found  it  in  all  stages  of  fasting  and  later  work  on 
fasting  (Lehmann,  Miiller,  et  aL),  as  well  as  the  experiments  of  Forster  and 
Voit(a)  showed  that  iron  was  constantly  eliminated  by  the  intestinal  traet, 
whether  iron-containing  food  was  ingested  or  not.  The  length  of  time 
elapsing  between  the  ingestion  of  a  given  amount  of  iron  and  its  gradual 
elimination  extending  over  a  period  of  days  or  even  weeks  (Gottlieb (a.), 
Hamburger),  clearly  indicated  its  absorption  and  also  its  excretion. 
Direct  experiments  on  isolated  loops  of  the  intestine  were  even  more  final 
in  this  rt^gard  (Kobei-t  and  Koch;  Honigmann). 

The  fact  that  iron  in  process  of  excretion  cannot  be  demonstrated  rai- 
crochemically — the  reaction  is  never  obtained  in  fasting  animals  (Tarta- 
kowsky(a))  and  disappears  in  guinea  pigs  after  24  hours  of  fasting 
(Swirski) — suggests  that  all  the  iron  demonstrable  by  this  test  is  on  its 
way  to  absorption.  This  reaction  is  reg-uhnly  obtained  in  the  duodenal 
epithelium  and  in  the  submucosa  of  the  ascending  colon ;  it  is  seldom 
obtained  in  the  gastric  mucosa  (Hochhaus  and  Quincke;  Hari(a))  or  in 
tho  low^er  small  intestine  except  in  cases  of  abundant  iron  feeding 
(Macallum(a))  or  delayed  absorption  (Cloetta).  Xor  was  Abderhalden 
able  to  find  any  essential  difference  in  manner  of  absorption  between  or- 
ganic and  inorsranic  iron  in  animals  on  a  vegetable  or  meat  diet  and  a 
more  recent  investigation  by  means  of  the  microchemical  method  (Hueck) 
has  confirmed  these  statements.  Because  of  the  gradual  elimination  of 
iron  the  usual  balance  experiment  of  short  duration  (Stockman  and  Greig) 
no  matter  how  accurate,  cannot  afford  far-reaching  data  on  the  metabo- 
lism of  iron. 

The  intestinal  elimination  of  iron  takes  place  through  tho  epithelium 


]MKVEKAL  METABOLISM  320 

of  the  colon,  perhaps  in  very  small  part  by  way  of  the  bile.  That  bile 
may  contain  iron  has  lon^;  been  known,  but  the  figures  given  show  a  wide 
variation  which  may  be  ascribed  in  part  to  faulty  methods  of  analysis,  in 
part  perhaps  to  a  different  behavior  of  various  forms  of  iron  (  Leone).  The 
clear  connection  between  hemoglobin  and  the  bile  pigments  and  the  place  of 
formation  of  the  latter,  unquestionably  the  liver,  need  not  l)e  reviewed 
here.  The  iron  tluis  set  free  is  deposited  in  the  organs  or  gradually  elimi- 
nated, but  whether  the  amount  of  urobilin  in  the  feces  is  a  reliable  index 
of  blood  destruction  in  health  and  in  disease  is  uncertain  (^Ic  Crudden(c?)  ; 
Kobertson(a)  ;  Whipple  and  Hooper(a)).  Bunge's  theory  of  a  protective 
action  of  iron  salts  against  hydrogen  sulphid  in  the  intestine  has  been 
discarded  because  of  the  proven  absence  of  hydrogen  sulphid  in  the  small 
intestine  (^lacfayden,  Xencki  and  Sieber). 

The  urinary  elimination  of  iron  has  been  the  subject  of  many  investi- 
gations with  widely  different  results  (earlier  literature  cited  by  Socin)  but 
by  the  method  of  Xeumann  which  gave  constant  results  it  apj>eared  to  be 
about  1  mg.  in  24  hours,  perhaps  much  less  (Marriott  and  Wolf)^  a  small 
fraction  of  which  is  decomposable  by  (XIl4)2S  and  heat,  the  rest  being 
in  complex  organic  combination,  perhaps  of  the  nature  of  a  pigment  or 
of  a  non-coagulable  protein  compound  (Monier).  A  small  proportion 
of  intravenously  or  subcutaneously  injected  iron  appears  in  the  urine 
(Damaskin),  most  of  it,  however,  is  eliminated  by  way  of  the  intestine 
(Lipski).  The  urinary  excretion  of  iron  varies  in  some  pathological 
conditions  (the  literature  is  cited  by  Goodman),  but  the  kidneys  play  a 
minor  part  in  the  excretion  of  iron  (Fini ;  Lapicque;  Woltering). 

Experiments  on  iron  metabolism  date  back  as  far  as  IS-ii)  when  Ver- 
deil  showed  that  the  ash  of  dogs  fed  meat  contained  more  iron  than  that 
of  dogs  given  bread  (for  the  early  literature  see  Hall)  ;  the  accumulation 
of  iron  in  the  liver  after  intravenous  injection  (Zaleski;  Gottlieb(a))  and 
after  ingestion  in  organic  or  inorganic  form  (Kunkel;  Salkowski(c)  ; 
Tartakowsky(&)  ;  Oerum(a) ;  Bonanni(6))  especially  after  the  organic 
(Samoljoif)  not  only  in  liver  but  also  in  spleen,  muscles  and  bones  has 
been  determined  repeatedly.  The  iron-free  feeding  experiments  of  v. 
Iloesslin  are  the  earliest  of  their  kind.  By  such  food  and  by  bleeding  he 
deprived  growing  dogs  of  iron ;  their  hemoglobin  fell  and  anemia  was  also 
evident  in  a  paleness  of  the  mucous  membranes,  but  gTOWth  was.  not  inter- 
fered with;  similar  results  were  obtained  on  rabbits.  The  interesting 
experiments  of  Schmidt  on  mice  showed  that  iron-poor  food  clid  not  produce 
anemia  or  a  fall  in  hemoglobin  in  full-grown  animals  but  that  the  offspring 
of  such  animals,  on  the  «ame  iron-free  food,  Vv^ere  retarded  in  growth  and 
developed  severe  anemia,  with  disapjx^arance  of  iron  stores  in  the  liver  and 
their  diminution  in  the  spleen.  i\.ccording  to  Fetzer  the  adnnnistration 
of  iron-poor  food  to  pregnant  rabbits  and  guinea  pigs  caused  a  depletion 
of  the  iron  supplies  of  the  mother  up  to  a  certain  point,  but  the  maternal 


330  IIEXRY  A.  MATTILL  AXD  IIELEX  I.  MATTILL 

organism  did  not  sacrifice  the  iron  required  for  its  own  vital  functions. 
After  blood  deprivation  it  appeared  (Eger;  Haussennan(a))  that  animals 
returned  to  normal  hemoglobin  slowly  on  inorganic  iron,  more  quickly 
on  food   rich   in   iron,   and  most  quickly  on   both.     The  conclusion  of 
Abderhalden   that   tho   addition    of    iron    ]/reparations   to   food    rich    in 
iron   is   more  stimulating  to   the  hemopoietic  organs   than   when    it   is 
added  to  iron-poor  food,   was  not  universally  accepted;   an  interesting 
debate  ensued  between  Abderhalden  on  the  one  hand  and  Jaquet  and 
Tartakowsky  on  the  other,  a  summary  of  which  is  given  in  Meinertz' 
excellent  review  of  iron  metabolism.     From  Abderhalden's  own  figures 
Tartakowsky   showed   that  the  differences   in   hemoglobin   produced  by 
adding  inorganic  iron  to  iron-rich  and  to  iron-poor  diets  were  very  small, 
and  when  taken  absolutely  were  rather  in  favor  of  the  iron-poor  diet  with 
the  accompanying  relatively  smaller  total  amount  of  hemoglobin.     From 
histological    studies    on    bone    marrow    of    dogs    that    had    been    bled, 
Hoffmann  concluded  that  the  stimulating  effect  of  iron  was  in  speeding 
up  the  development  of  red  cells,  and  Muller(6)  indeed  foimd  more  nu- 
clear erv'throcytes  in  the  bone  marrow  of  iron-fed  animals,  but  not,  he 
concluded,  as  a  result  of  stimulation  (similar  to  that  of  arsenic,  perhaps) 
but  simply  because  of  the  presence  of  more  raw  material.     Tartakowsky 
was  able  to  show  that  the  feeding  of  iron  preparations  to  anemic  dogs  on 
iron-poor  food  prevented  a  fall  in  hemoglobin;  iron  was  still  present  in 
liver  and  spleen  two  months  after  "beginning  the  iron-poor  food,  and  he 
maintained  that  the  blood  of  full-grown   dogs  cannot   be   deprived  of 
iron  by  feeding  iron-poor  food.     Only  bleeding  accomplished  this  and 
hemoglobin  was  brought  back  to  normal  on  iron-poor  food  by  the  addition 
of  iron,  but  not  without  it.    Lack  of  material  is  the  whole  explanation  and 
bleeding  in  itself  is  the  stimulus.    Later  results  reported  by  Oenmi  indi- 
cated a  distinct  superiority  of  organic  iron  over  the  inorganic  in  restor- 
ing loss  of  hemoglobin  although  the  iron  content  of  liver  was  greatest  in 
the  inorganic  iron  animals.     Zahn  on  the  other  hand  reports  findings  in- 
dicating that  in  animals  (made  anemic  by  bleeding)  hemoglobin  did  not 
increase  any  more  rapidly  with  than  without  medicinal  iron  addition  to 
the. food.     He  fed  iron-rich  food  to  both  groups  and  this  he  considers  the 
important  difference  between  his  own  and  previous  experiments ;  perhaps 
other  dietary  factors  are  also  involved  (Hooper  and  Wliipple(6)).     Chis- 
toni(5)    found  that  organic  iron   preparations   possessed  a   superiority 
over    inorganic   wheii   given   intravenously    to    dogs    with    experimental 
anemia ;  hemoglobin  and  erythrocytes  increased  less  rapidly  with  inor- 
ganic, and  the  other  pathological  indications  did  not  disappear  under 
inorganic  iron  administration  as  they  did  imder  the  organic.     More  re- 
cently the  value  of  inorganic  iron  in  the  treatment  of  secondarj^  anemia 
has  been  questioned  because  Blaud's  pills  were  found  to  be  inert  when 
added  to  various  diets  whether  these  favored  blood  regeneration  or  not. 


MINERAL  METABOLISM  331 

Hemoglobin,  on  the  other  liand,  exerted  a  distinctly  favorable  influence 
(Hooper,  Robsclieit  and  Whipple). 

V.  Xoorden  points  out  that  artificially  produced  anemia  is  not  compa- 
rable with  chlorosis,  nor  are  the  conclusions  from  exjKn-imental  results  in- 
terchangeable, because  in  this  disease-  it  is  not  a  matter  of  lack  of  food 
iron,  and  the  stimulus  required  by  the  blood-forming  organs  seems  to 
be  more  powerful  in  inorganic  iron  preparations  than  in  iron-containing 
proteins.  Evidently  no  general  conclusions  can  as  yet  be  drawn.  From 
the  standpoint  of  the  physiology  of  nutrition  the  whole  question  is,  accord- 
ing to  Albu  and  Xeuberg,  of  minor  imix)rtance  since  the  iron  of  foods 
is  almost  entirely  in  organic  combination.  Sherman  voices  the  opposite 
opinion  and  considers  that  it  is  of  gTcat  importance  to  know  whether  the 
iron  in  natural  waters  can  supplement  an  inadequate  supply  of  food  iron. 
To  what  extent  the  full-grown  organism  can  husband  its  resources  of  iron 
is  still  uncertain  but  there  is  no  question  as  to  the  need  of  abundant  iron 
in  growth  and  in  pregnancy.  The  retention  of  iron  observed  at  high  alti- 
tudes and  considered  as  evidence  of  the  need  of  additional  iron  supplies 
(v.  Wendt(^))  requires  conumiation  (Sundstroem (?>)). 

The  role  of  the  spleen  in  iron  metabolism  is  uncertain  and  many  of 
the  conclusions  reached  are  quite  contradictory.  The  iron  content  of  the 
spleen  is  decreased  by  repeated  bleeding  and  during  pregnancy,  and  is 
increased  by  hemolytic  processes  and  by  the  administration  of  iron. 
Investigations  on  splenectomized  animals  indicated  that  the  fecal  iron 
in  such  animals  was  considerably  above  noimal  ( Asher  and  Grossenbacher ; 
Chevallier(c) ;  Bayer(a)),  especially  when  loss  of  body  protein  was  caused 
by  underfeeding,  and  remained  so  for  many  months  (Asher  and  Zimmer- 
mann),  though  these  findings  have  recently  not  been  corrolx)rated  (Austin 
and  Pearce).  There  was  some  loss  of  hemoglobin  (Pugliese)  or  none  at 
all  unless  the  food  was  poor  in  iron  (Tcdcschi;  Asher  and  Vogel).  Such 
anemia  in  dogs  was  more  marked  on  a  diet  of  cooked  meat  than  when  the 
meat  was  fed  raw  (Pearce,  Austin  and  Pepper).  Examination  of  differ- 
ent organs  and  tissues  microchemically  and  analytically  indicated  a 
changed  distribution  of  iron,  the  liver  of  gitinea  pigs  containing  less  than 
normal  (Pana)  although  an  increase  is  also  reported;  in  frogs  a  decrease 
was  obseiTed  in  all  tissues  and  organs  (Gambarati).  The  various  changes 
develop  gradually,  persist  for  several  months,  and  finally  diminish  (Cheval- 
lier((i)(6))  as  if  other  organs  developed  a  vicarious  activity.  It  would 
seem  that  the  spleen  is  an  organ  for  the  assimilation  of  iron,  and  is  not 
necessar}'  for  the  process  of  blood  destruction  (!Meinertz(a.)),  but  that  it 
retains  for  the  body  the  iron  that  has  been  set  free ;  but  whether  it  does 
this  for  the  iron  resulting  from  the  destniction  of  erythrocivtes  (Bayer (c)) 
or  for  that  originating  in  food  is  not  determined.  In  cases  of  .pernicious 
anemia  and  hemolytic  icterus  splenectomy  has  been  of  advantage ;  in  these 
cases,  however,  a  previously  abnormally  large  loss  of  iron  in  the  feces  was 


HENRY  A.  MATTILL  AXi)  HELEN  I.  MATTILL 

very  greatly  reduced  (Goldschinidt,  PepjKT  and  Pearce;  Pepper  and 
Austin),  a  result  directly  opposite  to  that  obtained  in  normal  animals. 
In  experimental  anemia  the  store  of  iron  in  the  liver  and  spleen  increases 
(Muir  and  Dunn),  hut  some  factor  other  than  blood  destruction  is  opera- 
tive, perhaps  a  derangement  of  the  mechanism  for  retaining  iron  (Dubin 
and  Pearce(a)). 

Sulphur 

In  a  discussion  of  mineral  metabolism  sulphur  requires  only  a  passing 
mention,  for  the  amounts  of  this  element  ingested  in  inorganic  form  are 
very  small.  The  various  forms  of  sulphur  found  in  the  urine  (inorg-anic 
and  ethereal  sulphates,  neutral  and  basic  sulphur),  and  in  the  feces  (sul- 
phids)  originate  in  the  processes  of  digestion  and  utilization  of  the  sulphur- 
containing  proteins  in  the  food  and  from  the  catabolism  of  sulphur-contain- 
ing tissue  proteins.  Since  sulphates  are  thus  always  available  in  the  body 
it  is  obviously  impossible  to  determine  the  requirements  of  the  organism 
for  inorganic  sulphur.  That  the  organic  form  is  necessary  is  indicated 
by  the  experiments  of  Osborne  and  ]Mendel((7).  It  appeared  that  cystin 
was  a  limiting  factor  in  growth  of  rats  on  a  diet  containing  9  per  cent  of 
casein,  since  the  addition  of  cystin  without  any  other  modification  made  the 
ration  decidedly  more  adequate.  The  addition  of  cystin  to  diets  low  in 
protein,  Lewis  (a)  found,  diminished  the  elimination  of  nitrogen  in  dogs 
while  the  equivalent  amount  of  nitrogen  in  sulphur-free  compounds  sucb 
as  tyrosin  and  glycocoU  had  no  such  effect.  It  has  recently  been  shown 
that  rats  cannot  use  inorganic  sulphates  in  place  of  the  necessary  amino- 
acid  cystin  (Daniels  and  Rich;. 

lodin 

lodin  was  discovered  in  the  thyroid  by  Baumann  in  1895  in  amounts 
from  2  to  7  mg.j  in  the  nonnal  gland;  much  higher  values  (3-44  mg.) 
have  been  reported  recently  by  Zunz  whoso  data  were  obtained  during  the 
war,  and  the  literature  contains  widely  divergent  figures.  It  is  present 
in  the  thyroid  of  cattle  long  before  birth,  the  female  containing  more 
than  the  male,  and  it  is  present  in  the  new-born  infant  and  in  the  human 
fetus  at  least  during  the  last  three  months  of  intrauterine  life  (Fenger(a.) 
(b)  (d)  ;  Pellegi'ini).  The  amount  of  iodin  gTadually  increases  with  age, 
being  most  abundant  at  about  the  age  of  50.  There  is  also  a  seasonal 
variation  in  the  iodin  content  of  the  thyroid  (in  cattle,  sheep  and  hogs) ; 
in  the  summer  and  fall  the  amount  of  iodin  is  considerably  greater  than 
in  winter  and  spring  (Seidell  and  Fenger;  Fenger(e)),  and  is  to  be 
associated  with  external  temperature  and  change  in  the  size  of  the  gland. 
In  cattle  no  difference  was  found  between  pregnant  and  nonpregnant  ani- 
mals.    The  iodin  content  of  the  thyroid  may  also  }ye  increased  by  increas- 


MINERAL  METABOLISM  333 

ing  the  iodin  content  of  the  food  and  is  probably  closely  dependent  iij>:>n 
it  normally  (Hunter  and  Simpson;  Strauss;  Cameron(a)).  (For  a  dis- 
cussion of  iodin  in  foods  see  Forbes  and  Beeij^le ;  for  its  distribution  in 
plant  and  animal  tissues  see  Cameron.)  Its  absence  in  the  pituitary  lias 
very  recently  bef'u  confirmed  (Seaman)  as  well  as  its  presence  in  the  blood 
(Kendall  and  Iticbardson).  The  complex  organic  combination  in  which 
iodin  is  found  in  tlie  thyroid  has  been  isolated  and  identified  by  Kendall 
as  4,  5,  G  tri-hydro-4,  5,  6,  tri-iodo-2-oxy,-lK'ta  indobpropionic  acid,  con- 
taining 65  per  cent  iodin  and  to  which  most  if  not  all  of  the  physiological 
effects  of  tho  thyroid  gland  can  be  ascribed,  particularly  the  stimulation 
of  basal  metabolism  (Kendall(G)  (c)  (^)  ;  Kendall  and  Ilichardson  ;  Cam- 
eron and  Carmichael). 

Iodin  compounds  are  absorbed  by  the  intestine  and  since  iodids  are 
sometimes  excreted  after  administration  of  organic  iodin,  while  ingested 
iodids  may  serve  to  increase  the  amount  of  thyroid  complex,  the  body 
possesses  the  ability  to  ionize  and  also  to  deionize  iodin  (Buchholtz;  Blum 
and  Griitzner).  Inorganic  iodids  are  excreted  mostly  by  the  kidneys,  and 
the  time  of  their  appearance  after  ingestion  may  be  used  as  the  basis  of 
absoi-ption  tests  though  marked  variation  in  different  individuals  is  re- 
ported. Ingested  iodin  (element)  is  quickly  bound  in  the  blood  by  protein 
and  the  absorption  of  iodids  by  the  thyroid  is  very  rapid,  but  the  iodin 
complex  is  formed  more  slowly  (Sollmann(&)  ;  Marine  and  Rogoff  (a)  (c)). 
The  administration  of  various  forms  of  iodin  (non-toxic  dose)  has  caused 
temporary  infertility  in  animals  (Adler(a)(6)  ;  Loeb  and  Zoppritz). 

Lack  of  iodin  in  food  and  drinking  water  is  considered  the  cause  of 
fetal  and  maternal  athyrosis  and  as  the  result  of  successful  treatment  in 
animals  the  administration  of  potassium  iodid  has  been  recommended 
(Smith;  Hart  and  Steenbock(6)  ;  Welch).  The  administration  of  small 
amounts  of  iodid  prevents  simple  goiter  in  man  (Kimball  and  Marine), 
and  while  this  condition  has  been  associated  with  a  lack  of  iodin  (Hun- 
ziker),  a  voluminous  literature  has  established  no  clear  coimection 
between  endemic  goiter  and  water  supplies  (Clark  and  Pierce).  The 
literature  upon  metabolism  in  diseases  of  the  thyroid  and  in  thyroid  feed- 
ing is  reviewed  by  Halverson,  Bergeim  and  Hawk, 


Neutrality  Regulation 

The  maintenance  of  neutrality  is  one  of  the  functions  of  the  inorganic 
constituents  of  the  body.  The  production  of  acids  in  the  body  is  contin- 
uous, and  the  oxidation  products  of  carbon,  sulphur  and  phosphonis  are 
neutralized  in  the  body  by  the  alkali  metals  (to  some  extent  probably  by 
the  alkaline  earths),  by  ammonia  resulting  from  protein  decomposition  and 
by  the  proteins  (Klein  and  IMorit^;  Robertson  (a)).     The  elimination  of 


■I 


334         HEXRY  A.  MATTILL  AND  HELE:N^  I.  MATTILL 

carbonic  acid  as  such  hy  the  lungs  docs  not  involve  a  ponuanciit  with- 
drawal of  alkali  from  the  body,  and  hy  virtue  of  the  peculiar  ability  of 
the  kidney  only  a  portion  of  the  alkali  used  to  neutralize  phosphoric  acid 
is  lost.  The  inorganic  sulphates  of  the  urine,  on  the  other  hand,  represent 
a  complete  loss  to  the  body  of  the  alkalies  required  in  their  formation. 
The  presence  of  bicarlx)nate  and  of  phosphates  in  the  blood  in  optimum 
concentration  is  the  basis  for  the  delicate  mechanism  of  neutrality  repda- 
tion  which  Henderson  has  so  fundamentally  conceived.  Because  of  this 
mechanism  assisted  by  the  acid-alkali  exchanges  between  the  plasma  and 
the  erythrocytes  as  well  as  the  tissues  (Collip;  Haggard  and  Henderson 
(b)  ;  Henderson  and  Haggard),  an  overproduction  of  acid,  even  though 
it  is  considerable,  does  not  change  the  hydrogen-ion  concentration  of  the 
blood  (Sonne  and  Jarlov)  ;  the  alkali  reserve,  as  measured  by  the  carbon 
dioxid  capacity,  is  decreased  (Van  Slyke  and  Cullen)  and  urinary  acidity 
and  ammonia  are  increased.  The  character  of  the  food  influences  these 
relations,  foods  high  in  protein  and,  therefore,  containing  a  preponderance 
of  acid-forming  elements  decrease  the  alkali  reserve  and  increase  urinary 
acidity  and  ammonia,  those  containing  a  preponderance  of  base-forming 
elements  (vegetables,  fruits),  decrease  the  latter  two  and  increas(}  the 
former  (Kastle;  Forbes(«)  ;  Sheraian  and  Gettler;  Hasselbalch;  Elather- 
wick;  McClendon,  et  aZ.). 

Prolonged  administration  of  acids  or  of  acid-foi-ming  foods  tends  to 
deprive  the  organism  of  alkalies.  Thus  acidosis  produced  in  children  by 
an  acid-forming  diet  caused  a  loss  of  Ca  and  Mg  (Sawyer,  Baumann  and 
Stevens),  and  in  observations  on  animals  with  experimental  acidosis  the 
alkaline  phosphates,  especially  the  potassiinn  phosphate  of  the  muscles, 
and  the  calcium  carbonate  of  the  bones  were  the  first  major  reserves  drawn 
upon  after  the  bicarlx)uates  of  body  fluids  (Goto(c)).  ]\rcCollum(ri)(/) 
found  that  rats  could  grow  and  be  maintained  for  fairly  long  periods 
on  acid-forming  and  also  on  base-forming  rations  though  reproduc- 
tion was  usually  not  successful.  Lamb  and  Ervard  determined  that 
the  addition  of  sulphuric  acid  to  the  ration  of  swine  did  not  inter- 
fere with  gi'OAvth  but  prevented  reproduction.  Of  the  ingested  sul- 
phuric acid  only  61  per  cent  was  neutralized  by  ammonia,  and  their 
conclusion  (that  there  was  no  marked  loss  of  calcium)  is,  according  to 
Forl)es,  not  justified.  To  what  extent  these  reserves  are  called  into  action 
in  daily  dietary  fluctuations  in  man  cannot  be  stated ;  in  the  exj>erimeiit 
of  Sherman  and  Gettler  the  substitution  of  isodynamic  quantities  of  rice 
in  place  of  potato  in  an  otherwise  constant  diet  caused  an  increase  in 
■urinary  acidity  and  ammonia,  but  the  combined  increase  in  both  could 
account  for  only  about  two  thirds  of  the  acid  involved.  They  suggest 
that  most  of  the  excess  might  be  accounted  for  by  a  change  in  the  balance 
of  acid  and  base-forming  substances  in  the  feces,  but  unfortunately  they 
were  imable  to  make  a  complete  study  of  the  feces.     It  is  significant  that 


MINERAL  METABOLIS.AI  335 

the  increased  acidity  was  not  accompanied  by  an  increase  in  urinar\^ 
pliospliorus. 

The  administration  of  alkalies  to  man  depresses  urinary  ammonia  and 
the  urine  may  be  made  alkaline  like  that  of  herbivora  (Janney(a)  Hender- 
son and  l*almer) ;  the  complete  suppression  of  ammonia  cannot  be  secured 
in  normal  subjects  though  it  is  possible  in  nephritis  (Denis  and  Minot(6  ) ). 
The  benefit  resulting  from  the  giving  of  alkali  in  a  number  of  pathological 
conditions  in  which  acidosis  exists,  such  as  diabetes,  infantile  diarrhea 
(Ilowland  and  Marriott),  cholera  (Rogers),  is  temporary  and  the  value 
of  the  practice  is  questioned,  but  a  critical  loss  of  alkali  from  the  blood  and 
tissues  is  thereby  prevented.  The  acidosis  of  nephritis  (Palmer  and  Hen- 
derson )  accompanied  by  decreased  KH.  excretion  is  a  result  not  of  over- 
production but  of  kidney  insufficiency  and  a  consequent  retention  of  acid 
phosphate;  this  may  even  be  increased  by  giving  sodium  bicarbonate. 
For  this  reason  the  value  of  Ca  in  this  condition  is  emphasized  (Marriott 
and  Howland(«))  because  Ca  leaves  the  body  largely  by  way  of  the  intes- 
tine ;  the  value  of  lime  in  correcting  the  acidosis  of  diabetes  has  also  been 
indicated  (Kahn  and  Kahn(a)).  The  influence  of  alkalies  on  the  course 
of  sugar  utilization  and  on  lactic  acid  formation,  and  the  effects  of  acids  on 
nitrogen  metabolism,  may  be  cited  as  further  instances  ont  of  many  others 
indicating  a  regulation  of  the  processes  of  metabolism  by  the  alkaline  re- 
serve of  the  blood  and  tissues  (IJnderhill(i) ;  Murlin  and  Graver ;  MacLeod 
and  Fulk ;  McCollum  and  Hoagland(/i)  ;  Steenlx)ck,  Nelson  and  Hart). 

The  important  role  of  ionic  substances  in  life  processes,  in  the  be- 
havior of  the  individual  cell  and  in  the  activity  of  various  isolated  tissues, 
such  as  nerves,  muscles,  and  especially  the  heart,  need  not  be  considered 
in  a  discussion  of  the  metabolism  of  mineral  matter.  For  normal  dis- 
charge of  its  functions  every  tissue  seems  to  require  a  properly  balanced 
adjustment  of  ions  in  its  fluids  and  membranes  and  the  source  of  these 
mineral  substances  is  the  ingested  food ;  but  to  what  extent  the  processes 
involving  ion  interactions  consume  the  minerals  involved  and  thereby  re- 
quire their  constant  renewal  in  the  food,  and  where  the  accumulated  body 
reserves  are  stored,  and  by  what  mechanism  the  physiologically  proper  pro- 
portions of  the  various  ions  are  selected  by  the  tissues  from  the  hetero- 
geneous supply  brought  to  them  by  the  blood  and  lymph,  are  imanswered 
questions.  The  tetany  following  parathyroidectomy  may  be  an  example 
of  the  unbalancing  of  ionic  equilibrium  necessary  for  nonnal  muscular  or 
nervous  activity.  Decreased  blood  calcium  accompanies  the  tetany  and 
administration  of  calcium  relieves  it ;  but  the  calcium  reserves  of  bone  seem 
not  to  be  available  for  this  purpose.  To  calcium  has  been  ascribed  a  very 
important  role  in  correcting  almost  all  kinds  of  disturbances  in  inorganic 
equilibrium,  but  the  translation  of  inorganic  equilibrium  into  the  language 
of  inorganic  metal)olism  must  await  more  knowledge  of  the  terms  under 
which  the  processes  of  each  are  carried  on. 


336         IIEXRY  A.  :\IATTILL  AXD  HELEN  I.  MATTILL 

Disturbances  in  Mineral  Metabolism  Accompanyin;^ 
Pathological  Conditions 

Fevers  are  usually  accompanied  by  a  retention  of  chlorids.  Snapper 
(a)  (c)  and  Peabody  bave  sliown  that  the  blood  clilorids  are  below  nomial, 
and  the  retention  is  due  not  to  a  failure  of  kidney  function  but  to  a  change 
in  cell  penneability.  A  similar  retention  of  chlorids  in  fever  produced 
artificially  by  injection  of  B.  pyocyaneus  in  dogs  has  been  noticed  (Griiu- 
baum).  Such  chlorid  retention  is  not  always  accompanied  by  water  re- 
tention (Leva(6)). 

Tuberculosis  is  accompanied  by  an  abnormal  loss  of  calcium  (Croftan; 
Voorhoeve(6) ;  Sarvonat  and  Kebattu). 

Typical  hereditary  hemophilia  is  not  associated  with  deficiency  in 
blood  Ca,  or  with  irregular  Ca  metabolism  but  there  is  a  type  of  hemo- 
philia "calcipriva"  in  which  the  blood  calcium  is  low  and  in  which  an 
increased  Ca  intake  changes  a  negative  to  a  positive  balance  with  bene- 
ficial effects  on  the  blood  coagulability  (Hess). 

Leprosy  seems  to  be  associated  with  a  disturbance  in  Ca  metabolism 
(Underbill  (p)). 

The  kidney  insufficiency  in  some  types  of  nephritis  is  marked  by  re- 
tention of  chlorids  (Gluzinski;  Ceconi). 

In  nephritis  without  acidosis  the  inorganic  phosphate  of  the  blood  is 
normal,  but  with  acidosis  it  may  rise  to  8-23  mg.  per  100  c.c.  (Denis  and 
Minot((7) ;  ^Marriott  and  Ilowland(a) ),  due  to  a  specific  disturbance  of 
kidney  function  which  prevents  the  elimination  of  phosphates;  at  the 
same  time  there  is  a  marked  reduction  of  blood  calcium.  Ingestion  of 
calcium  salts,  thus  diverting  the  excretory  function  to  the  intestine,  is 
recommended  as  a  therapeutic  measure. 

Attempts  to  prove  an  interdependence  of  mineral  metabolism  and  the 
endocrin  glands  have  not  thus  far  produced  proof  of  any  very  definite 
relationships  (Droge)  with  the  exception  of  a  well-established  connection 
between  the  parathyroid  and  Ca  metabolism.  Underbill,  and  ]!dcCallum 
with  Voegtlin  and  ^vith  Vogel  found  that  the  tetany  resulting  from  thyreo- 
para  thyroidectomy  was  accompanied  by  decreased  calcium  in  the  blood  and 
that  injection  of  Ca  lactate  would  temporarily  abolish  the  tetany.  "JsTu- 
merous  researches  have  shown  the  important  relation  of  the  Ca  salts  to 
the  excitability  of  the  central  nervous  system.  Their  withdrawal  leaves  the 
nerves  in  a  state  of  hyperexcitability  and  tetany  may  be  regarded  as  an 
expression  of  hyperexcitability  of  the  nerve  cells  from  some  such 
cause.  The  mechanism  of  the  parathyroid  action  is  not  detennined,  but 
the  result,  the  impoverishment  of  the  tissues  with  respect  to  calcium  and 
consequent  tetany,  is  proven."     Injections  of  Ca  or  Mg  salts  check  the 


MINERAL  METABOLISM  337 

s\'Tnptoms  of  tetany,  injection  of  neutral  or  alkaline  salts  of  ISTa  or  K 
intensifies  them. 

By  intravenous  injection  of  phosphoric  acid  and  its  Xa  salts  Binger 
has  been  able  to  reduce  the  Ca  of  the  seniin  from  10  mg.  to  6  mg.  per 
1<>0  c.c.  Tetany  results  at  this  point  luiless  the  pH  is  aV)ove  6;  if  the 
solution  injected  has  a  pll  greater  than  this  no  tetany  results.  A  similar 
marked  reduction  of  blood  Ca  to  as  low  as  1.5  mg.  per  100  c.c.  without 
tetany  occurs  in  nephritis  where  the  blood  is  extremely  high  in  acid 
phosphates.  Parathyroidectomy  is  accompanied  by  an  increase  in  the 
acid  phosphates  of  the  blood  and  during  a  tetanic  seizure  the  ammonia  of 
the  blood  is  about  twice  normal,  while  injection  of  ammonium  carbonate 
into  normal  animals  will  bring  on  symptoms  of  tetany  immediately  (Green- 
wald(a)(6);  Watanabe(c) ;  Jacobson).  That  the  hydrogen  ion  con- 
centration is  a  determining  factor  is  clear  from  the  work  of  Binger  and  of 
Marriott  and  Howland,  and  from  recent  work  which  showed  increased 
alkalinity  of  the  blood  following  parathyroideetomy  and  just  before  con- 
vulsions began  (Wilson,  Stearns  and  Thurlow)  ;  also  from  the  coincidence 
of  tetany  and  increased  alkalinity  of  the  blood  as  a  result  of  intravenous 
infusion  of  NallCO.j  (Harrop(a)),  and  of  operations  on  the  stomach 
which  exclude  the  acid  secretion  from  the  duodenum  (McCann).  On 
the  other  hand,  blood  w^hich  has  been  dialyzed  against  a  solution  contain- 
ing ever}^thing  normal  to  blood  except  calcium  when  transfused  into  the 
isolated  leg  of  a  dog  resulted  in  over-stimulation  of  the  nerves  (MacCallum, 
Lambert  and  Vogel). 

There  is  some  difference  of  opinion  regarding  the  blood  Ca  in  infantile 
tetany,  Longo  (quoted  by  Ilowland  and  Marriott),  finding  a  normal  con- 
tent in  eight  cases  wdiile  others  have  found  it  much  reduced  (K'eurath ; 
Bro\\'n,  MacLachlan  and  Simpson),  and  Ilowland  and  Marriott  say  "con- 
%iilsions  may  be  expected  when  the  Ca  of  the  seriun  becomes  less  than  7 
mg.  per  100  c.c."  They  find  the  Mg  and  inorganic  phosphates  of  the 
blood  remain  normal.  Calcium  absorption  is  little  if  at  all  affected  in  in- 
fantile tetany  (Schwarz  and  Bass)  and  while  the  Ca  content  of  nervous 
tissue  has  been  found  (post  mortem)  below  normal  (Quest;  Weigert(?>)) 
it  is  not  invariably  so;  but  in  cases  Avhere  the  Ca  is  normal  the  ^a  and 

]^a  +  K 
K  are  abnormally  high,  and  the  ratio  ^        ^.     is  high(Aschenheim(a)). 

A  metabolism  study  of  a  baby  having  rickets  and  tetany  (Fletcher) 
has  brought  out  a  similar  relation  in  the  retention  of  these  elements;  while 
the  disease  was  in  active  progi-ess  the  retention  of  CaO  was  0.39  gr.  daily 

and  the  ratio  — —  =  1.5,  during  the  later  period  during  which  there 

was  marked  improvement  in  the  s\inptoms  the  i*etention  of  CaO  was  0.44 

-XI-  I  -TT 

gr.   daily,   and   the  ratio  -tt—t-tt-  =    0.72,     Howland  and   Marriott 

Ca  +  Mg 


338         HEXRY  A.  MATTILL  AND  HELEN  I.  MATTILL 

have  not  been  able  to  show  alkalosis  in  cases  of  infantile  tetany, 
but  medication  with  NallCO.-j  for  other  causes  has  in  four  cases  resulted 
in  tetany  convulsions  accompanied  by  low  blood  Ca,  both  of  which  were 
corrected  when  the  NaHCOa  was  stopped.  They  conclude  '^it  is  apparent 
that  the  symptoms  of  tetany  and  the  lowering  of  the  Ca  content  of  the 
sei-um  may  be  produced  in  a  variety  of  ways,  but  we  have  not  been  able  to 
show  that  any  of  these  means  is  operative  in  infantile  tetany." 

Administration  of  Ca  salts  per  os  may  or  may  not  (Haskins  and  Ger- 
stenberger)  have  a  beneficial  effect  on  infantile  tetany.  Injection  of 
calcium  lactate  gives  temporary  relief  and  if  accompanied  by  administra- 
tion of  phosphorized  cod  liver  oil  it  speeds  the  recovery  which  phosphorized 
cod  liver  oil  alone  will  accomplish  (Brown,  et  al.). 

There  is  apparently  an  intimate  relation  between  blood  sugar  and  cal- 
cium. Thyreoparathyroidectomy  is  accompanied  by  a  decrease  in  both, 
and  the  injection  of  Ca  will  temporarily  restore  blood  sugar  to  normal 
( Underbill  (/<) ;  Underbill  and  BJatherwick).  The  question  as  to  whether 
the  hypoglycemia  is  a  result  of  the  thyreoparathyroidectomy  or  of  the  re- 
sulting reduction  in  blood  caleium  is  still  unanswered.  Hyperglycemia 
occurs  in  pneumonia,  tuberculosis  and  especially  diabetes,  and  each  of  these 
diseases  is  characterized  by  loss  of  calcium  (Kahn  and  Kahn;  Loeper  and 
Bechamp)  and  upon  injection  of  calcium  salts  the  glycosuria  is  decreased. 
Administration  of  CaCla  to  diabetics  is  claimed  to  reduce  the  glycosuria 
(Phocas).  Urinary  elimination  of  phosphorus  is  about  normal,  that  of  Ca 
and  especially  of  !Mg  is  high  in  diabetes  (Euler  and  Svanberg;  Nelson). 
In  expenmental  diabetes  in  rabbits  a  decalcification  has  been  obsei*ved 
(Bobert  and  Parisot).  There  is  possibly  some  connection  between  the 
diabetes  of  pregnancy  and  the  unusual  drain  on  calcium  (Kahn  and  Kahn 
(a)  ).  In  the  acidosis  of  diabetes  the  loss  of  Ca  may  Ik*  due  to  the  elimina- 
tion through  the  urine  of  Ca  salts  of  volatile  fatty  acids  (Palacios). 

Because  of  the  marked  changes  in  mineral  metabolism  and  in  the 
composition  of  the  bone  in  rachitis  and  osteomalacia  (Goldthwaite,  et  ah; 
Holt,  Courtney  and  Fales(^)(e);  Schabad(a)  (2>) ;  Schloss(6) ;  Bru- 
backer;  McCrudden(a)(c))  these  have  often  been  considered  diseases  of 
lime  metabolism.  There  is  usually  a  negative  lime  balance  in  the  active 
stage  of  rachitis,  but  rachitis  does  not  always  result  from  a  low  Ca  intake 
and  it  frtxjucntly  occurs  in  children  receiving  plenty  of  CaO.  The  blood 
Ca  is  not  invariably  abnormal  in  rickets  or  osteomalacia  (Stheeman  and 
Arntzenius).  Attempts  to  establish  a  relation  between  the  thyroid^thy- 
mus,  or  sex  glands  and  rickets  or  osteomalacia  are  not  convincing  (Sarvonat 
and  Roubier;  Zuntz(c)  ;  Bieling;  Claude  and  Rouillard;  Rominger; 
Aschenheim(c)).  The  seasonal  variation  of  rachitis,  its  incidence  being 
greatest  in  the  spring  and  least  in  the  early  fall  months,  has  heen  associated 
with  the  increased  Ca  retention  shown  by  lactating  cows  when  changed 
from  a  dry  to  a  fresh  gi*een  ration  containing  the  same  amount  of  Ca. 


MTXERAL  METABOLISM  339 

Possibly  the  lack  of  some  food  accessory  which  aifects  mineral  metabolism 
(jKs  for  example  the  antiscorbutic  vitamin)  and  which  is  reduced  by  dry- 
ing, is  reflected  in  the  milk  and  results  in  the  appearance  of  a  patholo^cal 
condition  in  a  young  animal  subsisting  on  that  milk  (Baumann  and  How- 
ard; Halt,  Steenbock  and  iloppert;  Rol>b). 

The  disturljance  of  phosphorus  metabolism  accompanying  that  of  cal- 
cium metabolism  in  rachitis  has  been  considered  a  secomlary  effect.  The 
fact  that  phosphorus  therapy  is  frequently  successful  (Koclmianu(^)  ; 
'Mcyerib) )  suggests  that  phosphorus  may  be  more  fundamentally  involved 
than  it  is  generally  thought  to  Ix). 

Osteomalacia,  on  the  other  hand,  is  more  generally  considered  a  disease 
of  calcium  metabolism,  occurring  usually  as  a  result  of  the  drain  on  body 
lime  during  pregnancy.  McCrudden(6')  considers  that  the  normal  "fliix" 
of  calcium  is  increased  in  pregnancy,  that  because  of  functional  inertia  it 
may  continue  too  long  after  the  demand  has  ceased,  and  become  patho- 
logical, and  that  ovariotomy  effects  a  cure,  not  because  of  any  functional 
relation  between  the  ovaries  and  Ca  metabolism,  but  because  it  removes 
the  possibility  of  further  drain  on  calcium  by  pregnancies.  The  effect 
of  castration  on  rats  bears  this  out  since  the  lime  content  of  females  is 
unchanged  by  castration,  but  that  of  males  is  reduced  10-20  per  cent 
(Keachj. 


The  Metabolism  of  Vitamins Carl  Voegtiin 

Discovery  of  Vitamin* — Chemical  Nature  aiitl  Physical  Properties  of  Vitamins 
— Antineuritie  Altamin  (Water-soluble  B) — Fat-soluble  Vitamin  (Fat- 
soluble  A) — Antiscorbutic  Vitamin  (C  Factor) — Distribution  of  Vita- 
mins in  Food — Digestion  and  Absorption  of  Vitamins — Intermediary 
Metabolism  and  Physiological  Action — End  Metabolism  of  Vitamins — 
Special  Feature  of  Vitamin  Metabolism. 


The  Metabolism  of  Vitamins 


CAKL  VOEGTLIX 

WASIIIXCTOX 

Discovery  of  Vitamins 

Until  a  few  years  ago  it  was  generally  assumed  that  a  complete  diet 
for  purposes  of  proper  growth  and  maintenance  of  health  of  the  animal 
body  should  consist  of  proteins,  fats,  carbohydrates,  inorganic  salts  and 
water  in  sufficient  quantities  to  funiish  an  adecjuate  supply  of  energy  and 
material  for  the  building  up  of  the  body  tissues.  The  discovery  of  certain 
other  substances  not  related  to  the  above-mentioned  food  factors,  and 
now  considered  just  as  essential  for  the  mainteiiiiuce  of  normal  metabolism, 
can  be  traced  back  to  two  distinct  lines  of  invesvtigation ;  first,  the  study 
of  scurvy  and  beriberi,  and,  second,  feeding  experiments  with  highly 
purified  diets. 

!N'umerous  clinical  observations  on  scurvy'  and  beriberi,  and  especially 
the  experimental  production  of  these  diseases  in  the  lower  animals  by 
Eijkman(c)  (1807),  and  Hoist  and  Frohlich(rt)  (1007),  called  attention 
to  the  importance  of  the  diet  in  the  causation  of  these  diseases.  Thus  it  was 
found  that  scurvy  does  not  occur  if  the  diet  contains  an  adequate  amount 
of  either  fresh  meat,  fresh  vegetables  or  fresh  fruits,  and  that  the  disease 
can  be  successfully  treated  by  the  administration  of  relatively  small 
amounts  of  certain  fresh  fruits  and  vegetables.  These  observations,  and 
the  fact  that  prolonged  exposure  of  these  foods  to  temperatures  of  100^  0. 
destroyed  their  prophylactic  and  curative  proj>erties,  suggested  that  the 
fresh  foods  contained  some  hitherto  unrecognized  food  constituents.  Ex- 
perience with  beriberi  showed  furthermore  than  this  disease  appears  if 
the  diet  is  restricted  to  highly  milled  cereals,  whereas  people  living  on 
foods  made  from  the  whole  grain  are  immune  against  beriberi.  -Small 
amounts  of  an  extract  of  the  portion  of  the  grain  removed  in  the  milling 
process  proved  to  be  a  powerful  curative  agent.  This  led  to  the  conclu- 
sion that  the  whole  gi-ain  and  the  extracts  made  from  the  offal  contained  a 
substance  or  substances  which  later  on  were  shown  by  Fimk(a)  (1911)  not 
to  be  related  to  any  of  the  well-known  food  factors. 

Independent  of  this  work  on  scurvv'  and  beriberi,  some  investigators 
attempted  to  feed  animals  on  purified  diets  containing  an  adequate  pro; 

341 


342  CAKL  VOEGTLIA^ 

portion  of  the  well-known  food  factors  (purified  proteins,  fats,  carbo- 
hydrates and  inorganic  salts).  These  attempts  invariably  resulted  in 
failure,  as  the  animals  after  a  certain  period  declined  in  weight  and  ex- 
hibited symptoms  of  malnutrition.  Pioneer  work  on  this  subject  was 
doneby  Lunin  (1881),  Stepp(^/)(^)  (11)00,  11)12),  II(»pkins(«)  (11)12), 
Osborne  and  Mendel  (1011),  and  McCollum  and  Davis(r/)  (1012,  1015).^ 
The  addition  of  small  quantities  of  milk  or  certain  other  natural  foods  to 
the  purified  diet  rendered  the  latter  physiologically  complete.  The  purified 
diet,  as  the  diet  which  causes  beriberi  or  scurvy,  was  evidently  lacking  in 
some  food  constituents  which  are  essential  for  normal  metabolism.  These 
substances  of  unknown  chemical  composition  were  termed  by  Funk  "vita- 
mins." Hopkins  refers  to  them  as  "accessory  food  factors,"  and  IMcCollum 
speaks  of  the  "Fat-soluble  A"  (fat-soluble  vitamin),  "Water-soluble  B" 
(antineuritic  vitamin),  to  which  Drummond  has  added  the  "Water-soluble 
C"  (antiscorbutic  vitamin). 

There  can  be  little  doubt,  if  any,  about  the  identity  of  the  antineuritic 
vitamin  with  the  water-soluble  B.  The  proof  for  this  assumption  is 
based  upon  two  well  established  facts:  (1)  the  solubilities  in  various 
solvents  and  the  resistance  towards  heat,  exposure  to  alkali  and  other 
agents  is  identical  for  both  substances;  and  (2)  the  distribution  of  these 
two  factors  in  various  foodstuffs  is  the  same,  whether  established  by 
means  of  gi-owth  experiments  on  rats  or  whether  the  antineuritic  power  is 
determined  in  pigeons.  Both  pigeons  and  rats  develop  pol;)Tieuritis  if  the 
diet  is  lacking  in  either  water-soluble  B  or  antineuritic  vitamin. 

All  the  various  terms  applied  to  these  substances  have  been  justly 
criticized  for  one  reason  or  another.  The  terminology  adopted  in  this 
chapter  should  therefore  be  considered  as  more  or  less  arbitrary. 

Chemical  Nature  and  Physical  Properties  of  Vitamins 

The  chemical  composition  of  vitamins  is  unknown,  principally  on 
account  of  past  failures  to  isolate  these  substances  in  pure  form  from  the 
natural  foods.  The  work  so  far  done  on  this  subject  is,  hov/ever,  not 
without  interest,  both  from  a  theoretical  and  practical  aspect,  and  will 
therefore  be  briefly  reviewed. 

Antineuritic  Vitamin  (Water-soluble  B). — The  early  researches  on 
beriberi  and  polyneuritis  gallinarum  showed  that  the  antineuritic  vitamin 
can  be  readily  extracted  by  means  of  water  or  hot  ethyl  alcohol  (Eijkman 
(e),  1006)  from  rice  polishings,  yeast,  and  other  material  rich  in  this  sub- 
stance.    Acetone,  ether,  chlorofonn,  benzene,  and  petrolether  fail  to  ex- 

*  For  a  historical  review  of  the  earlier  experiments,  the  reader  is  referred  to  the 
monograph  by  Osborne  and  Mendel  (1911).  The  later  development  of  the  subject  is 
admirably  presented  in  the  "Report  on  the  Present  State  of  Knowledge  Concerning 
Accessory  Food  Factors  (Vitamins),"  Medical  Research  Committee,  1919,  H.  M.  Sta- 
tionery Office,  Imperial  House,  Kingsway,  London,  W.  C.  2. 


1 


TnE  METABOLISM  OF  VITAMINS  343 

tract  this  vitamin  (McCollum  and  Simmonds(a),  1918).  The  addition  of 
a  small  amount  of  hydrochloric  acid  to  alcohol  increases  the  efficiency  of 
the  extraiction  and  the  best  results  are  obtained  by  using  acid  methylalcobol 
(Voe^itlin  and  flyers  (J),  1920).  If  the  alcoholic  extract  is  deposited 
upon  dextrin  and  the  mixture  dried,  the  deposited  vitamin  may  be  dissolved 
by  benzene,  but  not  by  acetone  (^fcCollum  and  Simmonds(a),  1918). 
Voegtlin  and  Myers (^/)  (1920)  showed  that  olive  oil  or  oleic  acid  extracts 
the  antineuritic  vitamin  from  autolyzed  yeast,  thus  proving  that  at  least 
under  certain  conditions  this  vitamin  is  fat-solnble,  as  well  as  water-soluble. 
The  gTcat  water-solubility  of  this  vitamin  siigjrests  that  in  the  cooking  of 
fresh  foods  in  water  a  considerable  amount  of  this  substance  may  pass 
into  the  water,  and  that  the  latter  should  therefore  be  consumed  w^ith  the 
cooked  food  whenever  possible.  The  active  substance  diffuses  easily 
through  the  ordinary  semi-permeable  membranes  (Chamberlain  and  Ved- 
der(a)(&),  1911,  and  Sugiura,  1918),  a  fact  which  indicates  that  the  anti- 
neuritic vitamin  very  probably  has  a  relatively  small  molecular  weight. 
It  is  safe  to  regard  the  antineuritic  vitamin  as  it  occurs  in  the  natural 
foods  as  resistant  to  drying  or  moderate  heating,  up  to  100°  0.  Prolonged 
heating  of  foods  above  100°  C,  as  used  in  the  process  of  commercial 
canning,  appears  to  destroy  a  variable  proportion  of  this  factor  (Grijns, 
1901;  Eijkman(e),  1906;  Hoist,  1907;  McCollum  and  Davis((if),  1915). 
In  an  alkaline  medium  destruction  proceeds  much  more  rapidly,  es{)iecially 
if  the  temperature  is  raised  to  100°  C.  (Cooper(a),  1913;  Vedder  and 
Williams,  1913;  Sullivan  and  Voegtlin(a),  1916;  Steenbock(a),  1917; 
Drummond(a),  1917;  Chick  and  Hume((i),  1919).  For  example,  it  was 
found  that  cornbread  made  from  low  extraction  commeal,  baking  soda, 
salt  and  water  w^as  deficient  in  antineuritic  vitamin,  whereas  cornhread 
made  without  the  addition  of  sodium  bicarbonate  still  contained  this  vita- 
min (Voegtlin,  Sullivan  and  Myers,  1916).  The  use  of  baking  soda  in 
cooking  is  therefore  contraindicated  unless  proper  provisions  are  made 
to  neutralize  the  free  alkali,  as  for  instance  by  the  addition  of  buttermilk 
in  bread  making.  Several  obseiTCi's  (Cooper  and  Funk,  1911;  Sullivan 
and  Voeg'tlin(a),  1916)  have  noted  that  the  antineuritic  substance  is  higlily 
resistant  to  acids,  as  prolonged  boiling  with  10  p.c.  sulphuric  or  hydro- 
chloric acid  does  not  seem  to  lead  to  any  appreciable  deterioration;  on  the 
contrary,  the  physiological  activity  of  crude  extracts  of  foods  containing 
this  vitamin  was  greatly  increased  by  this  treatment,  as  shown  by  the 
prompt  relief  of  the  symptoms  in  polyneuritic  birds  (Vedder  and  Williams, 
1913;  Sullivan  and  Voegtlin,  1916). 

Zilva  (1919)  has  demonstrated  that  the  antineuritic  vitamin  in 
autolyzed  yeast  is  not  destroyed  when  exposed  for  six  hours  to  ultraviolet 
rays,  nor  does  radiimi  emanation  seem  to  have  any  deleterious  action  upon 
this  substance  (Funk(e),  1916).  Sugiura  and  Benedict  (1919)  claim  that 
the  growth-promoting  factors  in  yeast  may  be  partially  inactivated  by  this 


3U  CARL  VOEGTLIISr 

treatment,  an  obsei-vation  which  these  observers  consider  as  a  possibla 
explanation  of  the  therapeutic  effect  of  radium  upon  neoplasms. 

Cooper  and  Funk  (li>ll)  discovered  that  the  active  substance  is 
precipitated  by  phosphotungstic  acid,  and  that  the  precipitate  tlius  ob- 
tained yields  a  highly  active  preparation  after  decomposition  of  the  pre- 
cipitate and  removal  of  the  phosphotungstic  acid.  Later  work  by  Funk 
(1012,  1913)  then  showed  that  this  preparation  can  bo  further  purified 
by  treatment  with  silver  nitrate  and  baryta,  which  precipitates  the  vitamin. 
By  repeated  recrystallization  of  this  fracticn  (pyrimidin  fraction),  a  sub- 
stance was  obtained  which  melted  at  233^  C.  to  which  Funk  gave  the 
fomiula  Ci7ll2o07T^2-  The  crystals,  for  unknown  reasons,  very  often 
lose  their  physiological  activity  on  recrystallization  from  water,  a  fact 
which  has  been  most  troublesome  in  the  isolation  of  this  vitamin.  The 
principal  observations  of  Funk  were  confirmed  by  Edie,  Evans,  Moore, 
Simpson  and  Webster  (1011-12),  Cooper(a)(6)  (1013),  Vedder  and 
Williams  (1016),  Williams  (1016),  Voegtlin  and  Myers(^)  (1020j,  and 
others.  The  last  two  investigators  carried  the  purification  a  little  further 
by  the  use  of  mercuric  sulphate,  and  obtained  a  product  free  of  purins,  hi&- 
tidin,  proteins,  albumoses  and  lipoids.  Suzuki,  Shinamura  and  Odaki 
(1912)  claim  to  have  prepared  a  picrate  of  the  antineuritic  vitamin,  but 
their  work  could  not  be  verified  by  Drummond  and  Funk  (1014).  Hof- 
meister (a)  (d)  (1018,  1020)  claims  that  the  antineuritic  vitamin  belong*s 
to  the  pyrimidin  series  (OgHnXO^)  and  that  it  yields  a  crystalline  hydro- 
chlorid  and  gold  salt.  Williams  and  Seidell  (1016)  obtaineil  adenin  from 
autolyzed  yeast,  and  found  that  it  had  powerful  curative  properties  when 
tested  on  j)ioly neurit ic  birds.  The  sample  lost  its  physiological  propei-ties 
on  standing.  They  furthermore  found  that  inactive  adenin  submitted  to 
treatment  with  sodium  ethylate  assumed  antineuritic  properties,  observa- 
tions which  led  these  authors  to  regard  the  antineuritic  vitamin  as  an 
isomer  of  adenin.  However,  Voeg-tlin  and  White  (1016),  and  Harden 
and  Zilva(a)  (1017)  were  unable  to  confirm  these  observations. 

The  active  preparations  and  crystalline  fractions  hitheilo  obtained 
by  various  workers  are  probably  mixtures  of  active  material  and  im- 
puritie^s,  and  the  passing  over  of  the  active  substance  into  certain  fractions 
is  explained  by  Drummond(a)  (1917)  by  the  assumption  that  this  vitamin 
is  easily  carried  down  by  bulky  precipitates.  The  antineuritic  vitamin  is 
adsorlx^d  by  charcoal  (Chamberlain  and  Vedder(a)(&),  1011),  b^-  fullers' 
eai-th  (Seidell,  1016),  by  mastic  emulsion  or  basic  ferric  phosphate  (Voegt- 
lin  and  Myers (fZ),  1020),  and  by  colloidal  ferric  hydroxid  (Harden  and 
Zilva(c),  1918).  Of  these  absorbing  agents,  fullers'  earth  appears  to  be 
the  most  suitable  one  for  the  purpose  of  preparing  a  quite  stable  concen- 
trate from  aqueous  solutions  containing  this  vitamin.  The  activated 
fullers'  earth  can  be  made  use  of  as  a  source  of  this  vitamin  in  feeding 
experiments  (Eddy,  1016).     Adsorbing  agents  have  so  far  not  been  of 


THE  ]\[ETABOLIS^r  OF  VITAMIXS  345 

assistance  in  the  clieniical  isolation  of  tliis  vitainin,  probably  on  account  of 
the  fact  that  otlicr  material,  especially  organic  bases,  are  also  carried  along 
with  the  activ'c  substance.  In  any  attempt  at  the  isolation  of  this  vitamin, 
proper  consideration  shouhl  be  given  to  the  possible  injurious  effect  of 
alkali  and  heat. 

Fat-soluble  Vitamin  (Fat-soluble  A). — This  dietary  factor  was  first 
discovered  in  butter  (^[cCollum  and  Davis  (a),  1013 ;  Osbonie  and  ^lendel 
(r),  1013),  and  is  usually  found  in  association  with  certain  food  fats  in 
which  it  is  very  readily  soluble.  It  can  be  extracted  from  dried  spinach  or 
clover  by  ether  (Osborne  and  Mendel (r),  1920).  In  water  it  is  only  solu- 
ble to  a  very  limited  degi'ee.  McCollum  (1917)  has  estimated,  for  in- 
stance, that  in  milk  one-half  of  the  substance  present  is  dissolved  in  the  milk 
fat,  which  indicates  that  the  solubility  in  fat  is  approximately  30  times 
gi-eater  than  that  in  water.  Osborne  and  'Mendel {h  }(q)  (1915,  1920) 
obsei-ved  that  butter  fat  treated  with  live  steam  for  21  o  hours  had  not  lost 
any  of  its  fat-soluble  vitamin.  More  recently  Steenbock,  Boutwell  and 
Kent  (1918)  claimed,  however,  that  the  substance  is  slowly  destroyed  at 
40°  to  60°  G.,  and  that  complete  destruction  takes  place  after  4  hours' 
exposure  to  100°  C.  These  observations  were  confirmed  by  Drummond 
(e)  (1919),  who  w^orked  with  butter  and  whale  oil.  The  fat-soluble  vita- 
min in  plant  tissues  is  not  destroyed  by  autoclaving  for  three  hours  at  15 
pounds  pressure  (Steenbock  and  Gross(6),  1920).  The  destructive  process 
is  evidently  a  reaction  of  slow  velocity,  but  of  sufficient  magnitude  to  be 
considered  from  the  practical  point  of  view  of  the  deterioration  of  this 
factor  in  food. 

Saponification  of  butter  fat  with  alcoholic  sodium  hydroxid  does  not 
destroy  the  fat-soluble  vitamin  (McCollum  and  Davi3(cj,  1914),  whereas 
saponification  in  the  presence  of  water  leads  to  complete  destiiiction 
(Dnimmond(/),  1919).  In  the  commercial  "hardening^^  of  certain  oils  by 
means  of  hydrogen,  the  physiological  activity  originally  present  in  the 
oil  is  lost,  this  being  principally  due  to  the  high  temperature  used  in 
this  process  (Drummond,  1919).  This  vitamin  is  also  desti*ojed  when 
butter  is  exposed  for  8  hours  to  ultraviolet  rays  (Zilva.  1019).  Tliere  is  a 
complete  lack  of  know^ledge  regarding  the  chemical  composition  of  this 
substance,  although  recently  Steenbock  (1919,  1920)  has  called  attention 
to  the  possible  identity  of  this  substance  with  a  yellow  pigment,  carotin,  a 
view  which,  how^ever,  is  not  shared  by  Palmer  (1919). 

Antiscorbutic  Vitamin  (C  Factor). — This  vitamin  is  soluble  in  water 
and  alcohol  (Harden  and  Zilva(6),  1918;  Hess  and  Unger(&),  1918)  and 
is  easily  dialysable  through  parchment  (Hoist  and  Frohlich(6),  1912)  and 
porcelain  filters  (Harden  and  Zilva((f),  1918).  The  substance  loses  its 
physiological  activity  on  drying,  sometimes  even  at  low  temperature,  and 
more  readily  at  100°  C.  (Givens  and  Cohen,  1918;  Givens  and  McClug- 
gage(&),  1919).   From  the  experiments  of  Delf  (1918)  it  appears  that  the 


34G  CARL  VOEGTLTlSr 

rate  of  dostruction  of  the  antiscorbutic  vitamin  contained  in  fresh  cabbage 
is  accelerated  about  threefold  when  the  temperature  is  raised  from  G0°  to 
100°  C.  Tlic  destructive  action  of  heat  is  more  pronounced  when  the 
sid>staiice  is  heated  in  an  alkaline  medium  (Ifolst  and  Frohlich(6),  1912; 
Hess  and  Unger(f/),  1910),  whereas  an  acid  or  neutral  reaction  seems  to 
stabilize  it  somewhat  (Harden  and  Zilva,  1018).  The  effect  of  canning 
on  the  antiscorbutic  factor  of  vegetables  was  studied  by  Campbell  and 
Chick  (1010).  ^NTothing  is  known  concerning  the  chemical  composition 
of  the  antiscorbutic  vitamin. 

The  principal  feature  brought  out  by  this  brief  discussion  of  the 
physical  properties  of  vitamins  is  the  fact  that  these  substances  must  be 
considered  as  relatively  unstable,  because  various  influences  tend  to  destroy 
their  physiological  properties.  It  is  readily  seen  that  this  lack  of  stability 
has  an  important  bearing  upon  human  nutrition  and  a  proper  appreciation 
of  this  fact,  combined  with  further  work  on  this  subject,  will  ultimately 
lead  to  more  rational  methods  of  manufacture  and  cooking  of  foods. 


Distribution  of  Vitamins  in   Food 

From  the  standpoint  of  practical  dietetics,  it  is  of  gi*eat  importance 
to  determine  the  vitamin  content  of  the  more  commonly  used  foodstuffs. 
The  available  data  bearing  on  this  point  were  obtained  by  means  of  feeding 
experiments  on  rats,  gaiinea-pigs,  pigeons  and  chickens.  To  a  basal  diet, 
complete  in  every  resjxjct  but  lacking  the  vitamin  under  consideration, 
there  were  added  the  foodstuffs  to  be  investigated  in  such  amounts  as  to 
just  maintain  normal  nutrition  or  gTOwtli  (Chick  and  Hume(<i),  1919). 
The  results,  which  of  course  are  not  absolutely  accurate,  may  be  brie%  sum- 
marized as  follows:  The  principal  sources  of  the  antineuritic  vitamin  are 
the  seeds  of  plants,  eggs,  animal  tissues,  with  exception  of  adipose  tissue, 
the  gTeen  parts  of  plants,  pulses,  and  to  a  more  limited  extent,  milk,  fruits, 
and  tubers.  Brewers'  yeast  is  very  rich  in  this  factor.  In  the  case  of 
cereals,  this  vitamin  is  principally,  if  not  exclusively,  located  within  or 
close  to,  the  embryo,  which  accounts  for  the  deficiency  of  the  highly  milled 
products  in  this  factor,  as  the  milling  process  removes  the  embryo  and 
superficial  layers  of  the  seed. 

The  fai-soluhle  vitamin  is  largely  found  associated  with  certain  animal 
fats,  and  also  occurs  in  the  gi-een  parts  of  plants,  and  to  a  lesser  extent  in 
the  germ  of  cereals.  Butter,  cream,  fish  oils,  and  eg^  yolk  are  rich  in  this 
factor,  whereas  lard,  and  the  vegetable  oils  do  not  contain  it  in  appreciable 
quantities.  No  explanation  is  available  for  the  paradoxical  fact  that  beef 
fat  contains  the  fat-soluble  vitamin  and  that  the  latter  is  not  present 
in  lard. 

The   main    sources   of  the   antiscorhutic   vitamin   are   fresh,    green 


THE  iMETxVBOLISM  OF  VITAMINS  347 

vegetables,  certain  fniits,  and,  to  a  more  limited  extent,  fresh  meat,  tubers 
and  fresh  milk.  In  general,  dried  milk  powders  (Barnes  and  Hume, 
1019),  condensed  and  pasteurized  milk  (Hess(c),  1916)  are  deficient  in 
this  factor.  It  is  interesting  to  note  that  the  germination  of  cereals  leads 
to  the  fonnation  of  the  antiscorbutic  vitamin,  as  shown  by  the  action  of 
sprouted  grains  in  the  treatment  and  prevention  of  scurvy  in  guinea-pigs 
(Fiirst,  1912;  Weill,  Mouriquand  and  Peronnet,  1918;  McClendon,  Cole, 
Engestrand,  1919). 

An  important  relationship  between  the  dietary  value  of  the  natural 
foods  was  brought  out  by  the  systematic  investigation  of  !McCollum  and 
his  coworkers  (1917),  who  were  able  to  show  that  the  addition  of  the 
green  parts  of  plants  to  a  diet  restricted  to  the  seeds  of  plants  has  a 
marked  tendency  to  render  the  diet  more  complete  not  only  w^ith  respect 
to  the  inorganic  salts  but  also  the  fat-soluble  vitamin;  and  previous  work 
had  shown  that  green  vegetables  supply  furthermore  the  antiscorbutic 
vitamin  which  is  absent  in  cereals.  The  conclusion  is  therefore  justified 
that  a  proper  mixture  of  the  green  parts  of  plants  and  the  seeds  does 
possess  a  higher  dietary  value  than  either  of  these  foodstuffs  alone.  A 
mixed  diet  containing,  in  addition  to  cereals  and  gi-een  vegetables,  also 
some  milk  and  fresh  meat  is  the  best  safeguard  against  the  possibility  of  a 
vitamin  deficiency  and  furthermore  insures  an  adequate  supply  of  in- 
organic salts  and  protein  of  proper  biologic  value. 

The  table  on  pages  352-355  includes  the  principal  data  regarding  the 
distribution  of  the  three  vitamins  in  the  common  foodstuffs.  The  informa'- 
tion  contained  therein  may  be  of  sufficient  practical  value  until  more 
accurate  methods  are  worked  out  for  the  quantitative  estimation  of  vita- 
mins in  foods.  The  relative  quantity  of  these  substances  is  indicated  by 
the  number  of  plus  signs.  A  zero  sign  signifies  total  absence  or  insig- 
nificant traces. 

Digestion  and  Absorption  of  Vitamins. — In  view  of  the  relatively 
unstable  character  of  vitamins  it  is  a  matter  of  importance  to  know 
whether  these  substances  are  partly  destroyed  during  digestion.  Quan- 
titative information  on  this  jwint  is  completely  lacking.  However,  it  may 
be  safely  assumed  that  the  utilization  of  the  vitamins  contained  in  certain 
foods  (yeast,  butter,  lemon  juice)  is  fairly  efficient,  as  very  small  quan- 
tities of  the  latter  are  required  to  supply  the  animaFs  needs  in  vitamins. 
Whether  vitamins  are  absorbed  by  the  stomach  or  the  upper  intestines  or 
by  both  of  these  organs  remains  to  be  determined. 

Intermediary  Metabolism  and  Physiological  Action 

After  absorption  from  the  gastrointestinal  canal,  the  vitamins  are  car- 
ried, presumably  by  way  of  the  portal  circulation,  or  possibly  also  the 
hmphatics,  to  the  tissues  of  the  body,  where  tliey  are  stored  up.     It  is 


348  CARL  VOEGTLI]^ 

interesting  to  note  that  different  organs  vary  considerably  in  their  vitamin 
content.  Thus  Cooper (6)  (1913)  has  shown  that  the  antineuritic  vitamin 
content  is  largest  in  ox  liver,  less  in  ox  heart,  and  still  less  in  ox  brain  and 
skeletal  muscle,  the  latter  containing  only  relatively  small  amounts  of  this 
substance  (see  also  Osborne  and  Mendel(;)  (A:),  11)17,  lUlS).  The  pres- 
ence of  this  vitamin  was  also  demonstrated  in  the  spinal  cord  (Voegtlin 
and  Towles,  1913 ),  the  pancreas  (Eddy.  1->10),  the  kidney  (Osborne  and 
Mendel (;■)(*•),  1->1^,  191S),  and  testicle  { Schaumann,  1910)  ;  whereas  it 
seems  to  be  absent  from  adipose  tissue  generally.  These  observations  are 
rather  significant,  as  they  suggest  that  the  antineuritic  vitamin  is  needed  in 
all  tissues,  more  or  less  in  proportion  to  the  magnitude  of  their  metabolism, 
but  not  in  tissues  which  function  as  a  depot  for  reserve  energy.  This  inter- 
pretation is  also  supported  by  the  fact  that  the  yolk  of  eggs  are  rich  in  this 
substance,  whereas  it  seems  to  be  absent  in  e^^g  white.  A  similar  deduction 
may  be  drawn  from  the  distribution  of  this  substance  in  plant  tissues,  as  it 
was  shown  that  it  is  concentrated  within  or  in  the  immediate  neighborhood 
of  the  embryo  or  germ  of  the  corn  and  wheat  kernel  and  that  it  is  absent  in 
the  superficial  layers  and  endosperm  (Voegtlin  and  Myers (6),  1919). 
More  recent  work  has  also  shown  that  the  green  parts  of  plants  contain 
3onsiderable  quantities  of  antineuritic  vitamin,  when  due  allowance  is  made 
for  the  high  water  content  of  these  foods  (Osborne  and  Mendel (n),  1919). 

A  somewhat  different  situation  is  met  with  in  the  distribution  in  the 
body  of  the  fat-soluble  vitamin,  which  is  found  not  only  in  glandular 
organs,  but  also  in  certain  adipose  tissue  (beef  fat).  Strange  to  say,  it  is 
absent  from  lard,  and  skeletal  muscle  appears  to  contain  only  traces. 
Again,  the  liver  is  relatively  rich  in  this  substance,  as  shown  by  the 
high  activity  of  cod  liver  oil. 

Almost  no  data  are  available  concerning  the  localization  of  the  anti- 
scorbutic vitamin  in  the  various  organs  of  the  body,  with  exception  of  the 
well  established  fact  that  fresh  lean  meat  contains  this  factor. 

The  numerous  feeding  experiments  with  deficient  diets  permit  us  to 
conclude  that  the  animal  body,  under  normal  conditions,  contains  a 
considerable  reserve  of  fat-soluble  vitamin,  but  not  of  antineuritic  and 
antiscorbutic  vitamin.  Thus  susceptible  animals  survive  a  much  longer 
period  when  supplied  with  a  diet  lacking  in  the  former,  than  on  a  diet 
deficient  in  the  latter  two  vitamins. 

As  regards  the  role  played  by  vitamin-  in  metabolism,  we  are  still 
more  or  less  limite<:l  to  hypothetical  considerations  supported  to  some 
extent  by  suggestive  observations.  One  of  the  most  perplexing  questions 
is  the  fact  that  different  species  of  animals  have  different  vitamin  require- 
ments. For  instance,  it  is  wtII  proven  that  a  diet  complete  in  every  respect 
but  completely  lacking  the  antiscorbutic  vitamin  will  support  normal 
metabolism,  gi-owth  and  maintenance  of  health  in  rats,  mice,  pigeons  and 
chickens  for  considerable  periods,  whereas  this  same  diet  will  cause  scurvy 


THE  METABOLIS:\r  OF  VITAMIXS  349 

within  a  few  weeks  in  man,  giiinea-pigs,  monkeys  and  dogs.  On  the  other 
hand,  it  has  heen  conclusively  showai  that  all  of  the  liigher  animals  need  a 
certain  amount  of  fat-soluble  and  antineuritic  vitamin  for  proper 
nutrition,  maintenance  of  normal  growth,  reproduction  and  life.  It  has 
been  suggested  by  various  students  of  this  subject  that  the  antineuritic 
vitamin  is  somehow  concerned  with  the  maintenance  of  the  proper  function 
of  the  nei-vous  system,  an  assumption  which  is  supported  by  the  occurrence 
of  severe-  paralytic  symptoms  and  degenerative  changes  in  the  nervous 
system  of  animals  fed  on  a  diet  deficient  in  tliis  vitamin.  More  recently, 
^IcGarrison  has  shown,  however,  that  the  nervous  system  is  by  no  meaiis 
the  only  organ  affected  by  this  particular  vitamin  deficiency.-  A  few 
workers  have  made  the  attempt  to  prove  that  the  antineuritic  vitamin 
has  a  stimulating  action  upon  various  digestive  glands,  this  resulting  in 
an  increased  production  of  secretion.  Bickel(e)  (1917),  for  instance, 
showed  that  a  crude  extract  of  spinach  contains  a  principle  with  a  phaiina- 
cological  action  similar  to  that  of  pilocarpin,  Uhlmann(a)(?>)  (1918) 
studied  the  eifect  of  the  residue  of  an  alcoholic  extract  from  rice  polishings 
on  various  digestive  glands  and  the  sweat  glands.  He  obtained  a  marked 
increase  in  secretion,  following  the  parenteral  injection  of  the  extract.  He 
was  furthermore  able  to  show  that  the  same  extract  caused  contraction  of 
intestinal  muscle  and  a  fall  in  blood  pressure.  The  latter  eifect  he  attrib- 
utes to  a  direct  depressing  effect  on  the  heart  muscle  and  to  vasodilatation. 
Shortly  after  this  paper  had  appeared,  Voegtlin  and  Myers (c)  (1919) 
published  their  findings,  which  were  carried  out  without  a  knowledge  of 
Uhlmann's  work.  They  showed  that  the  intravenous  injection  of  a  highly 
purified  extract  from  yeast  produced  an  abundant  flow  of  pancreatic  and 
biliary  secretion,  resend^ling  in  every  respect  the  effect  produced  by  an 
extract  of  the  duodenal  mucosa  purified  in  the  same  manner  as  the  yeast 
extract.  Alcoholic  extracts  from  liver  produced  the  same  effect,  and  all 
three  extracts  were  shown  to  be  rich  in  antineuritic  vitamin,  when  tested 
as  to  their  therai>eutic  action  on  polyneuritic  pigeons.  As  suggestive  and 
interesting  as  these  findings  may  be,  it  should  be  emphasized  that  the 
pliysiological  effect  noted  by  all  these  observers  may  have  been  due  to  some 
highly  active  impurity  and  not  the  vitamin  per  se. 

Dutcher  (1918)  has  recently  suggested  some  relation  between  the 
antineuritic  vitamin  and  oxidative  piocesses,  as  he  observed  that  the  tissiies 
of  poh-neuritic  birds  showed  a  marked  reduction  in  catalase  and  that  the 
catalaso  activity  was  again  restored  to  normal  after  the  administration  of 
this  vitamin.  He  believes  that  this  substance  increases  the  production 
of  catalasa 

Funk  (1919),  Braddon  and  Cooper  (1914)  claim  that  the  antineuritic 
vitamin  is  essential  for  the  metabolism  of  carbohydrates,  a  view  which  is 
not  shared  by  Vedder  (1918). 

'  For  further  details  see  chapter  on  beriberi. 


350  CAPtL  VOEGTLIjS^ 

l)riimmond(r/)  (IJ)l(S)  stiidiod  the  mctabolisrii  of  rats  fed  on  an  artifi- 
cial diot  deficient  in  antineuritic  vitamin  and  noted  the  presence  of  creatin- 
iiria,  acconipanie^l  hy  decrease  in  food  consumption.  I'he  addition  of  the 
vitamin  to  rhe  diet  was  followed  bv  an  increased  food  intake. 

Incidentallv,  reference  is  made  to  the  work  of  .Mellanhy(c)  (d)  (IIJIO), 
wdio  chiims  to  have  produced  experimental  rickets  in  dogs  by  nieans  of  a 
diet  deficient  in  fat-soluble  vitamin,  which  would  indicate  that  the  sub- 
stance is  concerned  in  the  metabolism  of  calcium.  It  is  impossible  to  ac- 
cept this  view  without  considerable  modification,  as  Hess  and  Unger(7) 
(11)20)  have  shown  conclusively  that  infants  develop  rickets  while  receiv- 
ing "a  fnll  amuunt  of  this  principle,  and  that  they  do  not  manifest  signs, 
although  deprived  of  this  vitamin  for  many  months,  at  the  most  vulnerable 
period  of  their  life.''  McCollnm  and  Simnionds  (1920)  have  also  pre- 
sented evidence  which  is  not  in  agi-eement  witli  Mellanby's  views. 

A  lack  of  fat-soluble  vitamin  in  the  diet  leads  to  the  appearance  of 
xerophthalmia  in  rats  (McCollum)  ;  a  condition  which  had  previously  been 
observed  by  Mori  (lOOi)  in  young  children  whose  diet  was  lacking  in 
certain  fats,  which  are  now  known  to  be  rich  in  fat-soluble  vitamin. 

The  antiscorbutic  vitamin  is  probably  concerned  in  the  growth  of  some 
species,  but  not  of  all,  as  Hess((?)  (1916)  observed  the  appearance  of  scnrvy 
in  infants  in  spite  of  a  preceding  period  of  normal  growth.  Hoist  and 
Frohlicli  have  described  great  fragility  of  the  bones  in  guinea-pigs  suffer- 
ing with  scurvy  which  on  histological  examination  was  shown  to  be  due 
to  lack  of  proper  calcification.  It  would  thus  appear  that  the  antiscorbutic 
vitamin  has  some  relation,  either  direct  or  indirect,  to  calcification. 

To  sum  up.  very  little  indisputable  knowledge  is  available  as  to  the 
part  played  by  vitamins  in  metabolism  beyond  the  fact  that  the  antineu- 
ritic and  fat-soluble  vitamin  are  needed  for  growth  and  that  all  three 
vitamins  are  essential  for  proper  nutrition  of  man  and  some  of  the  higher 
animals.  Taking  into  consideration  that  apparently  very  small  amounts 
fulfil  the  physiological  requirements,  it  is  quite  possible  that  vitamins  act 
as  catalysts  of  some  metabolic  reactions.  They  may  also  possess  an  indirect 
elfect  upon  nutrition  by  stimulating  the  digestive  organs  in  the  way 
indicated  above. 

End  Metabolism  of  Vitamins 

The  available  evidence  regarding  the  ultimate  fate  of  vitamins  in  the 
animal  body  does  not  permit  many  positive  conclusions.  The  only  data 
with  a  bearing  on  this  point  are  a  few  observations  on  the  vitamin  content 
of  the  various  secretions  and  excreta.  IMuckenfuss  (1918)  treated  saliva, 
ox  bile  and  human  urine  with  fullers'  earth  and  fed  these  samples  of 
fullers'  earth  to  pigeons  showing  acute  symptoms,  as  a  result  of  a  polished 
rice  diet.     Improvement  was  noted  when  the  preparation  was  given  in 


THE  :^^ETABOLISM  OF  VITAMI^^S  3r,i 

amounts  corresponding  to  050  to  3,250  c.c.  of  ox  bile,  400  to  1,325  c.c. 
fresh  saliva  or  4,150  to  (3,000  c.c.  of  urine;  from  which  the  author  cori- 
chides  that  this  vitamin  is  probably  present  in  comparatively  small 
amounts  in  saliva,  bile  and  only  in  traces  in  urine.  Some  unpublished 
experiments  by  Yoegtlin  and  ]Myers  also  indicate  that  human  urine 
obtained  from  sul)jects  on  a  mixed  diet  is  very  }x)or  in  antineuritic  vita- 
min, as  "activated''  fullers'  earth  corresponding  to  over  a  liter  of  fre.-h. 
urine,  when  fed  daily  to  pigeons  on  a  pjlished  rice  diet,  was  not  capable 
of  delaying  the  onset  of  polyneuritis. 

Cooper (c)  (1014)  showed  that  alcoholic  extracts  of  feces  of  rice-fed 
hens  and  bread  and  cabbage-fed  rabbits  relieved  the  symptoms  of  polyneur- 
itic pigeons.  This  would  indicate  that  at  least  part  of  this  vitamin  is 
excreted  with  the  feces.     (See  also  Portier  and  Eandoin,  1920.) 

That  the  mammary  gland  secretes  all  three  vitamins  is  well  established, 
as  feeding  experiments  with  fresh  unheated  milk  has  shown  that  this 
food  belongs  to  the  richest  sources  of  fat-soluble  vitamin  and  that  it  con- 
tains also  some  antiscorbutic  and  antineuritic  vitamin,  although  the  last 
two  factors  seem  to  be  present  in  relatively  small  amounts. 

The  evidence  thus  far  points  to  the  destruction  of  vitamins  Avithin  the 
body,  which  renders  it  necessary  to  constantly  replenish  the  supply  throuirh 
a  proper  diet.  The  ultimate  source  of  this  sujiply  is  the  plant,  as  the 
animal  tissues  are  unable  to  produce  vitamins. 

Special  Features  of  Vitamin  Metabolism 

A  discussion  of  the  metabolism  of  vitamins  would  not  be  complete  with- 
out a  brief  reference  to  the  factors  which  safeguard  an  adequate  supply 
of  vitamins  to  the  young  animal  during  the  period  of  its  life  when  it 
is  entirely  dependent  upon  the  milk  of  its  mother.  On  the  basis  of  some 
work  on  rats,  McCollum  and  Simmonds  (1018)  conclude  that  milk  varies 
in  nutritive  value  according  to  the  composition  of  the  food  fed  the  lactat- 
ing  animal.  The  mammary  gland  has  no  power  of  synthesising  vitamins 
(^IcCollum,  Simmonds  and  Pitz,  1016).  An  inadequate  supply  of  fat- 
soluble  and  antineuritic  vitamin  in  the  diet  leads  to  a  corresponding 
diminution  of  these  substances  in  the  milk.  Similar  observations  were 
made  more  recently  by  Hart,  Stcenbock  and  Ellis  (1920)  with  regard  to 
the  antiscorbutic  vitamin  content  of  milk.  They  have  found  that  summer 
pasteur  milk  is  much  richer  in  this  factor  than  dry  feed  or  winter-produced 
milk.  (See  also  Barnes  and  Hume,  1019.)  Osborne  and  Mendel (g) 
(1020)  have  found  little  if  any  difference  in  the  antineuritic  vitamin 
content  of  cows'  milk  during  the  various  seasons,  an  observation  wdiich  is 
easily  explained  by  the  fact  that  the  diving  of  feed  does  not  destroy  this 
vitamin.  Further  evidence  along  this  line  will  Ix?  found  in  the  chapter 
on  beriberi. 


352 


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THE  IIETAEOLTSM  OF  VITAMIXS 


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THE  METABOLIS]\r  OF  VITAMINS 


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356  CARL  VOEGTLIX 

Recent  work  indicates  tliat  the  growth  of  unicellular  organisms,  such 
as  yeast  and  certain  bacteria,  is  dependent  upon  a  supply  of  vitamin. 
As  a  result  of  Bachmann's  observations  (1910),  AVilliams  (a)  (fe)  (1919, 
1920)  has  elaborated  a  promising  method  for  the  quantitative  estimation 
of  the  antineuritic  vitamin,  based  upon  the  observation  that  the  growth  of 
yeast  is  proportional  to  the  vitamin  content  of  the  medium.  The  relia- 
bility of  this  method  shoidd,  however,  be  fairly  established  before  its 
general  adoption  for  work  of  this  kind. 

Drummond(&)  (1917)  has  made  observations  on  the  influence  of  a  de- 
ficiency of  fat-soluble  or  antineuritic  vitamin  in  the  diet  on  the  growth  of 
tumors.  Ke  comes  to  the  conclusion  that  a  lack  of  the  fat-soluble  vitamin 
has  no  effect,  whereas  the  absence  of  the  antineuritic  vitamin  causes  a 
certain  amount  of  inhibition. 

As  a  concluding  remark  it  may  be  said  that  the  work  of  this  last  decade 
has  resulted  in  numerous  discoveries  regarding  the  physiological  and 
pathological  significance  of  vitamins.  Although  some  facts  have  been 
pretty  firmly  established,  this  docs  not  hold  for  all  obsei-vations  made  in 
this  field.  As  a  matter  of  fact,  the  study  of  vitamins  is  still  in  its  infancy 
and  sweeping  generalizations,  as  so  often  made  in  scientific  literature,  do 
not  serve  a  good  purpose.  We  are  fairly  well  informed  as  to  the  distribu- 
tion of  the  three  vitamins  in  the  more  important  foodstuffs.  Further 
progress  will  largely  depend  on  the  chemical  isolation  of  these  substances,  a 
phase  which  so  far  has  attracted  the  attention  of  a  relatively  small  number 
of  investigators. 


SECTION  II 


A  Normal   Diet c  , Isidor  Greenwald 

Introduction — The  Diet  of  Primitive  Peoples — Food  and  Civilization — Crop 
Failures  and  Famine — Criteria  of  Adequacy  of  Diet — Relative  Impotence 
of  Certain  Foods — Dietary  Studies — Manner  of  Conducting  Studies  and 
of  Calculating  Results — Studies  of  Entire  Countries  and  Cities — Studies 
upon  Individuals  and  Groups  on  Fully  Chosen  Diets — Influence  of  Cli- 
mate and  Season  upon  Food  Consumption — Influence  of  Work — Amount 
of  Protein — Amount  of  Fat — Ash  Constituents— Changes  in  Food  Habits 
within  Recent  Times — Vegetarian — Protein  Minimum  and  Optimum — 
Neumann's  Experiments — Chittenden's  Experiments — Fisher — McCay — 
Fat  ^[inimiim — Carbohydrate  Minimum — Minimum  of  x\sh  Constituents 
— Undernutrition — Conclusion. 

\ 


A  Normal  Diet 

ISIDOR  GREEXWALD 

KEW  YORK 

{ntrodudion 

the  Diet  of  Primitive  Peoples. — From  as  early  a  time  as  we 
can  discern  anything  of  the  life  of  man  we  find  that  this  has 
heen  an  almost  unceasing  struggle  for  food,  for  enough  to  enable 
him  to  satisfy  his  wants.  So  far  as  we  can  judge  from  the  re- 
mains, from  the  habits  of  the  animals  most  closely  resembling  man,  and 
from  those  of  backward  or  imdeveloped  peoples,  the  diet  of  primitive  man 
consisted  of  whatever  that  was  edible  that  he  could  secure.  The  Min- 
copies,  or  inhabitants  of  the  Andaman  Islands,  regarded  as  among  the  most 
primitive,  or  lowest  in  scale  of  civilization,  of  the  human  race,  live  chiefly 
on  mangoes  and  other  fruit,  shellfish  and  an  occasional  smaO  wild  pig. 
The  Fuegians,  another  primitive  people,  subsist  almost  entirely  on  shell- 
fish. Heaps  of  shells,  supposed  to  be  the  remnants  of  the  middens  of 
primitive  main,  are  found  in  different  parts  of  the  world  (Avebury,  Tyler). 
Scott-Elliott  believes  the  food  of  Pleistocene  man  to  liave  consisted  of 
nuts,  fleshy  fruits,  small  birds'  eggs,  honey,  insects  and  shellfish.  There 
is  no  evidence  that  man,  except  under  the  influence  of  a  religious  or 
pseudo-scientific  inhibition,  dating  from  very  recent  times,  ever  voluntarily 
restricted  himself  to  a  purely  vegetarian  diet.  On  the  contrary,  amongst 
such  peoples  as  the  Fuegians,  and  in  the  nomadic  and  pastoral  stages 
of  civilization,  his  diet  was  almost  exclusively  of  animal  origin.  The 
relative  importance  of  vegetable  and  animal  foods  varied  with  their  rela- 
tive availability.  Both  kinds  were  frequently  eaten  raw  but  the  earliest 
evidences  and  the  descriptions  of  the  life  of  the  most  primitive  of  peoples 
indicate  that,  from  a  very  early  stage,  man  has  cooked  some  of  Fiis  food,  at 
least  occasionally  and  as  opjwrtunity  offered.  Man  has,  indeed,  been 
called  ^'the  cooking  animal." 

Food  and  Civilization. — The  development  of  civilization  depended 
very  largely  upon  the  kind  of  food  man  was  able  to  secure.  Semple  states: 
"In  Australia,  the  lack  of  a  single  indigenous  mammal  fit  for  domestica- 
tion and  of  all  cereals  blocked  from  the  start  the  pastoral  and  agricul- 
tural development  of  the  native."  The  American  continents  were  more 
fortunate  for.  with  beans,  maize  and  pumpkins,  it  was  possible  for  a 

359 


3G0     "  ISIDOR  GEEEXWALD 

limited  a^'iculture  to  develop.  It  is,  perliap^,  in  North  America  that  one 
can  see  most  clearly  how  the  nature  of  the  available  supply  afl'ected  the 
food  habits  of  the  natives.  The  Indinns  of  the  plains  were  essentially 
hunters  and  lived  largely  on  the  results  of  the  chase.  In  the  east,  agi-icul- 
ture  was  fairly  well  established,  amon<r  some  tribes  at  least,  and  maize, 
beans,  pumpkins  and  other  plants  constituted  a  very  considerable  part 
of  the  diet.  But; it  was  in  what  is  now  the  southwestern  part  of  the  United 
States  and  in  ^Mexico  that  the  greatest  progress  in  agriculture  occurred 
and  it  was  there  that  the  highest  civilization  developed.  In  contrast  with 
the  tribes  of  these  sections,  all  of  whom  were  fairly  well  fed,  we  find 
the  stunted  and  emaciated  Indians  of  the  northern  Rocky  iNEountains, 
der.ied  both  the  chase  of  the  buffalo  and  the  cultivation  of  maize. 

It  w^as  in  the  Old  World  that  animals  susceptible  of  domestication,  es- 
pecially those  suited  for  a  nomadic  life,  were  most  numerous  and  it  was 
there  that  pastoral  civilization  reached  its  fullest  development.  Cereals 
and  legumes  were  also  abundant  and  furnished  the  basis  for  a  more 
settled  life.  It  was  no  longer  necessary  for  so  nmch  time  to  be  given 
to  the  obtaining  of  food ;  more  could  be  devoted  to  other  wants,  the  satis- 
faction of  which  is  the  characteristic  of  civilization. 

Crop  Failures  and  Famine. — All  through  the  ages,  such  margin  as 
separated  man  from  an  actual  food  shortage  has  been  very  narrow.  Famine 
has  always  been  a  very  present  menace,  as  the  liturgies  of  the  churches 
abundantly  testify.  The  yield  of  the  staple  foods,  from  year  to  year, 
is  very  uncertain  even  at  this  time.  With  a  population  dependent  upon 
closely  neighboring  sources  of  supply,  any  failure  of  the  accustomed  yield 
means  scarcity  and  even  starvation.  It  was  only,  with  the  development 
of  transportation,  particularly  in  the  latter  part  of  the  nineteenth  cen- 
tury, that  a  fairly  re«nilar  food  supply  could  be  assured  to  most  of  man- 
kind. Even  then,  famine  was  not  unknown  in  Russia,  China  and  India. 
With  the  breakdown  of  commerce  and  transportation  and  the  withdrawal 
of  large  areas  of  land  and  of  millions  of  men  from  food  production  as  a 
result  of  the  world  war,  famine  has  reappeared  in  regions  from  which  we 
had  once  believed  it  banished. 

Even  in  so  large  and  fertile  country  as  our  own  and  one  so  well  pro- 
vided with  railroads  and  other  means  of  communication,  the  failure  of  a 
staple  crop  may  involve,  if  not  deprivation  of  sufficient  food  energy,  a  fail- 
ure to  secure  sufficient  of  the  less  well-recognized  dietary  constituents.  To 
quote  from  liess(e)  (1020)  :  "It  is  important  for  us  to  realize  that  we  are 
still  dependent  on  the  annual  crops  for  our  protection  from  scurv;^';  in 
other  words,  the  world  is  leading  a  hand  to  mouth  existence  in  regard  to 
its  quota  of  antiscorbutic  food.  The  truth  of  this  condition  has  been  real- 
ized for  Ireland,  sadly  illustrated  by  numerous  epidemics,  notably  the  great 
epidemic  of  184 7  reported  by  Curran.  It  was  demonstrated  by  the  out- 
breaks of  scurvy  in  Xorvvay  in  1904  and  1912  and  was  brought  to  the  atten- 


A  XOEMAL  DIET  361 

tion  of  many  in  the  United  States  in  the  spring  of  1916.  In  this  year  our 
potato  crop  fell  far  below  the  normal,  with  the  result  that  scurvy  appeared 
in  various  parts  of  the  United  States,  especially  in  institutions." 

Short  of  actual  famine  and  the?  acute  distress  and  suffering  due  to 
occasional  crop  failures,  the  development  of  man  may  l>e  hampered  by 
chronically  insufficient  or  improper  food.  The  ease  of  the  RockyMountain 
Indians  has  already  been  mentioned.  Ilipley  regards  the  low  stature  and 
poor  physical  condition  of  the  natives  of  the  Aiivergne  plateau  in  southern 
France  as  duo  to  the  inipossibility  of  obtaining  an  adequate  diet  from 
the  soil  of  that  region.  Removed  from  the  district  while  young,  the  chil- 
dren develop  normally.^  The  peasants  of  the  Abruzzi  seem  to  furnish  an- 
other illustration  of  the  damaging  effect  of  an  unsatisfactory  diet  upon  a 
whole  people.  These  peasants  are  amongst  the  shortest  in  Italy  btit  when 
the  young  men  enter  the  army  and  receive  a  more  adequate  diet  they  grow 
rapidly  and  this  gi'owth  is  gieater  than  for  any  others  except  the  men  from 
a  few  districts  in  which  a  similarly  unsatisfactory  diet  is  employed.  (Al- 
bertoni  and  Rossi(6),  1908;  Lichtenfelt,  1912,  page  M.)  The  damaging 
effects  of  malnutrition  in  cities  have  been  much  discussed.  While  these 
are  generally  considered  to  be  occasional,  rather  than  general,  there  is  some 
evidence  that  they  may  affect  a  very  considerahle  proportion  of  the  pojnila- 
tion  and  may,  indeed,  alter  the  physical  characteristics  thereof.  Thus, 
Collis  and  Greenwood  regard  it  as  likely  that  the  short  stature  of  the  cot- 
ton operatives  in  Lancaster  is  due  to  a  deficient  diet.  The  nature  of  some 
of  these  supposedly  unsatisfactory  diets  and  the  criteria  of  their  inadequacy 
will  be  discussed  later. 

Definition  of  "Normal." — It  is  obvious  that  in  any  given  country 
and  at  any  given  period,  the  people  living  there  and  then  must  r^ard 
their  diet  as  the  normal.  It  is  the  "usual,  common  or  ordinary"  as  the 
dictionary  defines  "normal."  But  to  the  physician,  physiologist  or  hy- 
gienist  the  word  "nonual"  relates  to  good  health  and  the  "usual,  common 
or  ordinary"  is  employed  only  as  a  means  of  ascertaining  what  is  to  be 
considered  healthy.  A  normal  diet  must  be  capable  of  maintaining  man 
in  good  health  and  our  conception  of  a  normal  diet  will  become  moro 
definite  with  increasing  knowledge  of  what  is  to  be  considered  good  health 
and  of  the  relation  between  diet  and  health.  It  may,  then,  fairly  be  ques- 
tioned if  the  "usual,  common  or  ordinaiy"  diet,  as  it  obtains  to-day,  even 
amongst  those  most  free  to  chose  is  really  a  "normal"  diet. 

In  this  chapter  an  attempt  will  be  maile  to  discuss  the  subject  from 
both  points  of  view.  The  nature  and  amount  of  the  food  materials  made 
use  of  by  civilized  man  in  different  parts  of  the  world  •\vill  first  be  con- 
sidered. Then  the  results  of  more  detailed  studies  upon  the  diet  of  groups 
and  of  individuals  in  different  climates,  engaged  in  different  occupations 
and  of  different  economic  status  will  be  presented.     An  attempt  will  be 

*  Ripley  gives  Collignon  as  his  ?iuthoriiy.    I  have  not  been  able  to  find  the  original. 


302  ISIDOK  GREENWALD 

made  to  point  out  certain  propoiiics  common  to  all  or  most  of  such  diets, 
to  discuss  the  significance  of  the  differences  and  to  indicate  wherein  the 
evidence  shows  some  of  the  diets  to  be  inadequate.  Finally,  the  question 
of  a  possible  improvement  in  our  dietary  habits  will  he  discussed  and  the 
various  measures  prof>osed  for  this  purpose  will  bo  considered. 

Criteria  of  Adequacy  of  Diet. — It  is  obvious  from  the  preceding  chap- 
ters that  the  adequacy  of  a  diet  may  be  judged  from  many  different 
aspects;  energy  yield,  nature  and  amount  of  protein,  nature  and  content 
of  inorganic  material,  etc.  Probably,  the  most  essential  of  these  is  energy 
yield.  Unless  the  diet  be  restricted  to  a  certain  few  materials,  it  is,  if 
sufficient  in  energy  yield,  sure  to  contain  a  considerable,  even  if  not  en- 
tirely adequate,  amount  of  protein,  inorganic  matter,  etc.  However,  it 
should  be  clearly  recognized  that  this  primacy  of  energy  requirement  may 
be  due  largely  to  the  fact  that  our  means  for  determining  the  energy 


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Chart  I. — Total  food  value  of  the  chief  world  foods  expresj^ed  in  caluries.  Rice, 
wheat  and  siig-ar  are  practically  all  consumed  as  human  food.  Some  of  the  rye  and 
barley  is  distilled  or  used  for  animal  f(>(Kl.  A  considerable  part  of  the  potato  crop 
is  used  for  industrial  purposes.  Data  from  0.  K.  ?Iolmes,  T/if  Meat  Situation  in  the 
United  f>tates,  Dept.  of  Agriculture,  Office  of  the  Secretary,  Report  No.  109.  Figure 
from  G.  B.  Roorbach,  The  World's  Food  :>upply.  Proceedings  of  the  American  Philo- 
sophical Society,  Philadelphia,  1918,  Vol.  57,  pp.  1-33. 

content  of  the  food  and  the  energy  requirements  of  the  body  are  the  better 
developed.  It  may  yet  be  found  that  man^s  desire  for  food  is  directed 
primarily  to  securing,  not  a  sufficient  supply  of  energy,  nor  even  of  pro- 
tein, but  perhaps  of  some  inorganic  constituent  or  of  some  as  yet  unknown 
or  imperfectly  recognized  organic  substance  of  the  kind  variously  known 
as  vitamines,  protective  substances,  food  hormones,  etc.  Thus  Osborne 
suggested  that  the  beneficial  results  of  exercise  may  be  due,  iu  part,  to 
the  ample  suj>jDly  of  these  substances  secured  as  a  consequence  of  the 
hearty  apjx'tite  thus  produced.  But,  for  the  present,  we  will  consider 
food  primarily  as  a  supplier  of  en  erg}',  then  of  protein  and  only  secon- 
darily of  other  constituents. 

Relative  Importance  of  Certain  Foods. — The  amount  of  energy  con- 
tributed annually  to  the  world's  food  by  the  more  important  food  materials 


A  :n"oemal  diet 


363 


has  heen  calculated  by  Ilolincs  to  bo,  in  trillion  calories:  rice,  000;  wheat, 
382;  sugar,  200;  rye,  164;  barley,  110;  potatoes,  08.6  and  meat  62.4. 
The  chart  on  paire  362  was  prepared  by  Koorbacli  from  Holmes'  fi£!,i.ires. 
Unfortunately,  Hohnes  does  not  cite  his  authorities,  and  the  %iire  for 
sugar  appears  remarkably  high.  The  rehitive  importance  of  the  different 
foods  shown  by  these  figures  is,  however,  true  for  no  one  country.  In  some 
parts  of  the  East,  rice  is  even  more  largely  the  predominant  food  and,  on 
the  other  hand,  the  consumption  of  meat  is  concentrated  in  a  very  few 
countries. 

The  figures  in  Table  I  are  taken  from  Holmes  and  show,  in  pounds, 
the  annual  per  capita  consumption  of  meat  and  meat  products.     'No  data 
are  reported  for  China,  India  and  Japan  but  the  consumption  of  mert 
there  is  known  to  be  small.     The  amount  of  meat  used,  per  person 
gi'eatest  in  the  meat-raising  countries,  in  all  of  which  the  density  of  pc 
lation  is  rather  low.      (Chart  II  is  taken  from  lioorbach.) 

TABLE  I.-C0NSUMPTI0N  OF  MEAT  AND  MEAT  PRODUCTS  (BEEF.  MUTTO.V  AND  PORK)  PER  CAPITA 

POPULATION.— £>a/a/rom  Holmei. 


COUNTRT 

Year 

POCN'DS 

COCNTRT 

Ybar 

POCMW 

Argentine 

1899 

140 

Netherlands 

1902 

70 

Austria-Hungary 

1890 

64 

New  Zealand 

1902 

212.5- 

Austtalia 

1902 
1902 

262.6 

Norway 

1902 

62      ' 

Belgium 

70 

Poland  (Russian). 

Portugal 

1899 

62 

Canada 

1900 

109 

1899 

44 

"      

...!         1910 

137 

Russia  (except  Poland) 

Spain 

1899 

50 

Denmark 

...;         1902 

76 

1890 

49 

France 

1892 

77 

Sweden 

1902 

62 

" 

1904 

79 

Switzerland 

United  Kingdom 

1899 

75 

Germany 

1894 

88 

1893      . 

112 

•• 

1904 

112.7 



1906 

119 

" 

1913 

111  8 

United  States 

1900 

182 

Greece 

1899 

68 

.. 

1909 

171 

Italy 

...;          1901 

46.5 

As  the  population  increases,  pasture  land  is  put  under  cultivation, 
the  production  and  consumption  of  meat  fall  and  the  use  of  the  cereals 
and  other  foods  increases.  A  fairly  high  consumption  of  meat  may  be 
maintained,  and  even  increased,  as  in  Germany  and  Great  Bi'itain,  in 
spite  of  an  increasing  population  in  a  manufacturing  and  trading  com- 
munity if  the  level  of  wealth  is  sufficiently  high  to  secure  the  importation 
of  meat  or  of  concentrated  feeding  stuifs  for  animals.  But^  as  a  rule,  the 
importance  of  meat  in  the  diet  diminishes  as  the  population  increases  and 
such  meat  as  is  consumed  falls  chiefly  to  wealthy  and  powerful  classes. 

The  medieval  laws  restricting  the  taking  of  game  seem  to  have  had  their 
origin  not  so  much  in  the  desire  to  secure  sport  to  the  nobility  as  to  secure 
to  them  an  ample  supply  of  meat,  or  of  certain  kinds  of  meat.  (Lich- 
tenfelt(c),  1913.)  The  same  predominating  use  of  meat  bj  the  wealthier 
and  more  powerful  classes  obtains  to-day  in  all  countries  except  those  in 


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A  :NrORMAL  DIET  865 

which  meat-raising  is  one  of  the  chief  industries.  In  1903,  the  per  capita 
consumption  of  meat  in  Great  Britain  was,  among  artisans,  laborers  and 
mechanics,  two  pounds  per  week;  among  the  lower  middle  classes,  paying 
from  $75  to  $1:^5  annual  rental,  2.5  pcmnds:  in  the  middle  classes,  3.5 
pounds,  and  amongst  the  upper  classes  5.75  pounds.     (Lusk(fc),  1018.) 

As  can  be  seen  from  Holmes'  figures,  the  cereals  furnish  most  of 
man's  food.  Certain' few  are  of  particular  importance.  In  the  earliest 
periods,  barley  was  the  predominating  or  only  cereal.  In  Europe,  barley 
was  supplanted  by  oats  and  by  rye  and  these,  in  turn,  were  in  great  part 
displaced  by  w^heat.  In  eastern  and  southern  Asia  the  supplanting  cereal 
was  rice. 

In  order  to  make  them  more  available  as  food,  man  early  learned  to 
break  and  grind  the  gi-ains,  to  soak  the  fragments  in  water  and  to  cook 
this  pon-idge.  Cereals  prepared  in  this  way  are  to  this  day  a  very  im- 
portant and  even  a  major  part  of  the  food  of  the  people  in  many  lands. 
Familiar  examples  are  the  boiled  rice  of  the  East,  the  oatmeal  porridge 
of  Scotland,  the  maize  polenta  of  Italy  and,  in  a  slightly  modified  form, 
the  many  flour  soups  and  cooked  dough  dishes  of  central  Europe.  It  prob- 
ably did  not  take  man  long  to  discover  that  the  uncooked  mixture  of  cereal 
and  water  could  bo  dried  in  the  sun  or  over  the  fire  and  that  this  then 
furnished,  with  or  without  cooking,  a  readily  available,  yet  durable  source 
of  food.  Present  day  examples  are  spaghetti,  etc.,  noodles  of  all  kinds, 
the  oat  and  barley  cakes  of  northern  Europe  and  the  unleavened  bread  of 
much  of  Asia  and  of  other  parts  of  the  world.  The  preparation  of  an 
actual  bread  came  much  later  and  is,  in  fact,  a  matter  of  comparatively 
recent  and  local  development.  For  this  purpose  neither  rice  nor  maize 
can  be  used  alone  and  rye  and  wheat  are  inmiensely  superior  to  barley. 
This  superiority  depends  upon  the  peculiar  properties  of  the  proteins  of 
wheat  and  rye  flour.  These  form  a  sticky,  extremely  tenacious  mass  when 
mixed  with  water.  This  mass  holds  the  starch,  etc.,  fiiinly,  imprisons  the 
carbon  dioxid  fonned  by  fermentation  and  thus  produces  a  light,  firai 
loaf.  This  will  hold  its  shajx;  in  spite  of  considerable  handling  and  can 
be  preserved  with  comparatively  little  change  for  a  considerable  time  and 
even  indefinitely.  It  is  this  superiority  of  wheat  and  rye  for  bread  mak- 
ing that  has  caused  them  to  so  largely  supplant  the  other  cereals  as  sources 
of  human  food.  "Wheat  bread  is  generally  preferred  to  rye  because  of  its 
color  and  texture  and,  by  some,  because  they  find  the  taste  more  agi'eeable. 
But  there  are  many,  chiefly  those  accustomed  to  it  from  early  life,  who 
prefer  the  taste  of  rye  bread.  At  any  rate,  it  is  still  th-e  bread  of  most 
of  eastern  and  central  Europe,  except  in  the  larger  cities.     (See  Table 

III.) 

However,  there  seems  to  have  been,  until  the  outbreak  of  the  war, 
a  gradual  displacement  of  i-A-e  by  wheat.  To  a  considerable  extent,  no 
doubt,  this  was  due  to  the  increasing  proportion  of  the  population  living 


3GC  ISIDOK  GREEXWALD 

in  cities,  whicli  always  lead  in  the  consumption  of  wheat  as  compared 
with  rye,  barley  or  oats.  But  Sherman (^)  (11)18)  has  collected  figures 
showing  that  in  Russia  in  the  period  from  1804  to  1809,  there  were  1.82 
bushels  of  wheat  and  4.76  bushels  of  rye  consumed  per  person  per  annum. 
During  the  following  five  years,  these  figures  were  2.4G  and  4.78,  res|)cc- 
tively,  and  from  1911  to  1913  were  2.80  and  4.47.  The  magnitude  of 
these  changes  in  a  country  with,  relatively,  so  small  an  urban  population 
indicates  that  the  use  of  wheat  was  increasing  in  the  country  as  well  as 
in  the  cities. 

Dietary  Studies 

Manner  of  Conducting  Studies  and  of  Calculating  Results. — The 
amount  and  composition  of  the  food  consumed  per  person  may  be  deter- 
mined in  various  ways.  As  in  the  calculations  of  Sherman  and  of 
Holmes,  the  total  amount  of  food  raised  in  and  imported  into  a  given 
area,  less  that  exported  and  used  otherwise  than  as  human  food,  may  be 
divided  by  the  number  of  people.  The  method  is,  at  best,  only  an 
approximation  but  it  serves  very  well  to  indicate  the  relative  importance 
of  the  different  food  materials.  Next,  studies  may  be  made  of  groups 
such  as  families,  eating  clubs,  public  institutions,  military  and  naval 
organizations,  etc.,  in  which  the  total  amount  of  food  is  weighed  and, 
with  or  without  deduction  for  waste,  is  di\'ided  by  the  total  number  of 
people  participating.  Finally,  the  food  consumed  by  an  individual  majr 
be  weighed. 

The  composition  of  the  food  may  be  calculated  in  different  ways. 
For  such  gross  calculations  as  those  relating  to  the  food  consump- 
tion of  an  entire  city  or  country,  it  is  obvious  that  only  the  average 
of  a  considerable  number  of  analyses  can  be  used.  In  the  other  cases, 
the  same  procedure  may  be  followed  but  it  is  also  possible,  and  prefer- 
able, to  secure  sufficient  of  most  of  the  materials  to  last  through  all, 
or  a  considerable  part,  of  the  experiment  and  to  analyze  representative 
samples  of  these.  Still  greater  accuracy  may  be  obtained  by  taking  to 
the  laboratory  and  analyzing  a  comfx>site  sample  of  the  food  consimied, 
weighed  as  served,  and  mixed  in  exactly  the  same  proportion  as  consumed. 

Assuming  the  trustworthiness  of  the  subjects,  many  factors  influence 
the  accuracy  and  significance  of  the  results.  Studies  made  imder  labora- 
tory conditions  with  accurate  weighing  and  analysis  of  the  food  are  the 
most  accurate  but  are  obviously  expensive  and  difficult  to  make  m  large 
number  for  a  long  period.  Studies  made  in  the  home  can  be  carried  out 
in  larger  number,  can  be  continued  for  a  longer  period  and  come  nearer 
to  "normal'^  conditions  but  the  accuracy  of  the  weighings  and  the  ap- 
plicability of  the  analytical  data  employed  are  more  questionable.  Daily 
and  seasonal  variations  in  food  consumption  must  also  be  considered.    The 


A  NORMAL  DIET  367 

former  are  cronerally  neutralized  in  periwls  of  a  week  or  longer  but  the 
latter  may  be  appreciable,  particularly  in  agricultural  communities  and 
in  others  in  which  transportation  and  storage  facilities  have  not  been 
well  developed. 

The  results  of  observations  upon  adults  of  either  sex  may  be  reported 
directly  as  so  much  per  person,  per  kilo  or  per  square  meter  of  body  sur- 
face. With  groups  including  both  sexes  or  adults  and  children,  it  is  es- 
sential to  have  some  unit  in  which  to  express  the  results.  Omitting  the 
periods  of  pregnancy  and  lactation,  women  have  a  lower  food  requirement 
than  men  because  of  smaller  body  weight,  lower  basal  metabolism  per  kilo, 
and,  as  a  rule,  less  mechanical  work  performed.  Children  may  eat  le^ 
than  adults  but  consume  more  per  kilo  of  body  weight. 

Choice  of  Factor  for  Calculaling  Food  Consumed  **Per  Man," — 
From  time  to  time,  various  methods  have  been  proposed  for  converting 
observations  made  on  groups  including  women  or  children  to  a  ''per  man" 
basis.  The  table  (Table  II)  on  page  368  is  a  compilation  of  the  more  im- 
portant of  these,  the  food  requirement  of  a  man  of  average  weight  (70 
kilos  or  154  pounds)  engaged  in  a  moderate  amount  of  work  being  taken 
as  100.  The  first  six  columns  are  copied  from  the  report  of  the  Eltzbacher 
commission.  This  was  organized  in  1914  to  survey  the  food  resources 
and  requirements  of  the  German  nation.  It  included  in  its  membership 
both  Zuntz  and  Rubner.  For  the  value  of  the  food  energ;s'  requirement 
of  the  German  pieople,  they  used  the  average  of  the  results  calculated  by 
each  of  the  six  series  of  factors.  IMost  other  investigators  and  reporters 
have  used  Atwatei^'s  factors  and  generally  the  earlier  set.  These^are  cer- 
tainly in  error  in  giving  too  low  a  value  to  the  food  requirements  of  grow- 
ing children.  In  fact,  recent  investigations  (Gephart,  Holt  and  Fales) 
indicate  that  all  the  sets  of  factors  used  by  the  Eltzbacher  commission 
and  by  others  are  erroneous  and  that  rapidly  growing  boys  and  girls  re- 
quire more  food  than  adults.  Holt  and  Fales  have  tabulated  the  energy 
requirements  of  children  at  different  ages.  They  regard  that  of  an  adult 
male  as  3265  calories  per  day.  From  their  figures,  the  author  has  calcu- 
lated the  factors  found  in  the  last  column,  which  are,  for  American 
children,  probably  more  accurate  than  any  others  hitherto  used.  There 
must,  of  course,  be  variations  in  the  value  of  the  factors  in  different  parts 
of  the  world  and  among  different  races  due  to  the  vanation  in  the  age  of 
attaining  maturity  and  the  rapidity  of  gTOwth  at  any  given  age. 

The  factor  for  women  is  generally  taken  as  80  (man  =  100)  though  in 
compiling  the  report  of  the  U.  S.  Commissioner  of  Labor  in  1903  it  was 
set  at  90  and  Rubner  (Eltzbacher  commission)  considered  it  to  be  100. 
Two  series  of  Russian  observations,  cited  in  Table  IV,  yield  the  ratios  81.5 
and  88,  respectively.  Slosse  and  Waxweiler  in  a  series  of  6  comparisons 
obtained  values  for  73  to  95,  average  85.  On  the  other  hand,  Sundstroni 
(1908),  in  his  series  of  observations  on  Finnish  men  and  women,  found  it 


368 


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A  NORMAL  DIET  360 

to  be  only  70.  His  factors  for  the  food  consumption  of  growing  children 
were  also  rather  low.  Probably  these  low  values  are  due  to  the  fact 
that  Sundstrom's  adult  male  subjects  were  all  engaged  in  hard  muscular 
work,  rather  more  severe  than  the  standard  "moderate  work"  used  by  others 
whereas  the  women  and  children  were  not  so  unusually  active.  If  this 
reasoning  is  correct,  Sundstrom's  values  should  be  increased  by  from 
10  to  20  per  cent. 

Results  Reported  as  Food  Consumed  Not  that  Supposed  to  he  Absorbed. 
— Some  of  the  observers  whose  results  are  summarized  in  Table  III  and  IV 
have  reported  their  findings  in  terms  of  ^'availaljle"  calories  and  "digest- 
ible" protein,  the  values  being  calculated  with  the  aid  of  factors  obtained  in 
metabolism  experiments  in  which  the  nitrogen  content  and  energy  value  of 
the  feces  have  been  regarded  as  being  due  to  undigested  or  unabsorbed  food. 
This  does  not,  to  the  present  writer,  appear  to  be  justified.  The  perceatage 
of  nitrogen  in  the  feces  is  approximately  the  same  no  matter  what  the 
diet  but  the  amount  of  feces  formed  and,  consequently,  the  amount  of  nitro- 
gen excreted  therein  is  greater  with  vegetable  material  than  with  animal. 
However,  the  relation  of  fecal  nitrogen  to  food  nitrogen  after  the  ingestion 
of  specific  foods  is  not  a  constant  but  depends  a  great  deal  upon  the  indi- 
vidual, upon  the  method  of  preparation  of  the  food  and  the  nature  of  the 
other  constituents  of  the  diet.  Thus,  Albertoni  and  Rossi  (a)  (1908) 
found  that  the  addition  of  meat  to  the  customary  vegetarian  diet  of  Italian 
peasants,  although  increasing  the  total  nitrogen  of  the  food,  diminished  not 
only  the  relative  but  also  the  absolute  amount  of  nitrogen  in  the  feces. 
On  their  customary  diet  containing  75.7  grams  protein,  three  men  ex- 
creted a  daily  average  of  3.21  grams  nitrogen  in  the  feces.  On  diets 
containing  08.7  grams  protein,  of  which  only  21.2  grams  was  meat  pro- 
tein and  the  remainder  was  derived  from  the  customary  food,  the  nitro- 
gen in  the  feces  w^as  2.94  grams;  and  with  111.13  grams  protein,  of  which 
only  40.8  grams  were  derived  from  meat,  the  fecal  nitrogen  was  2.16 
gi'ams.  Similar  results  were  obtained  with  two  women,  the  figures  being 
55.8  grams  protein  intake  without  meat  with  2.71  grams  nitrc^n  in  the 
feces  and  92.6  grams  protein,  of  which  43.3  grams  were  meat,  on  the 
experimental  diet,  wuth  only  1.533  grams  nitrogen  in  the  feces.  A  similar 
though  much  less  marked  effect  of  added  glucose  was  observed  by  Neumann 
{d )  (1019 )  who  found  that  on  a  diet  of  1000  gi*ams  of  whole  rye  bread,  his 
feces  contained  2.52  gi-ams  nitrogen  daily.  Upon  adding  300  grams 
glucose  to  the  diet,  the  fecal  nitrogen  fell  to  2.44  grams  and,  after  in- 
creasing the  glucose  intake  to  500  grams,  to  2.41  grams. 

Again,  Hindhede(c?)  (1914)  found  that  the  addition  of  plums  to  a 
bread  diet  increased  the  nitrogen  of  the  feces  by  an  amount  gi'eater  than  tlie 
total  nitrogen  of  the  plums.  Hindhede  regarded  this  as  evidence  of  inter- 
ference with  protein  absorption  but,  since  there  was  no  such  evidence  of 
interference  w^ith  carbohydrate  or  fat  absorption,  it  seems  possible  that  the 


370 


ISIDOR  CJREEXWALD 


TABLE  III.  — AMOUNT  AND  NATURE  OF 


Countiy 

Authority 

Per  "Mks 

-•'   PER  D.\T 

Scale  used 
to  convert 
population 
into  "man 
equiva- 
lents"^ 

Percentage  Distri 

Date 

Protein 
grams 

Fa: 

grarn^ 

1273 

Carbo- 
hydrates 
grams 

Calorics 

Meat' 

Milk  and 
products 

WK«o»  '  Other 
^'^'^^1  grains 

1912-7 

United  States.. 

Peari 

121 

M2 
433* 

4290 
3424'" 

J 

25.5 

20.4 

28  9 

7.2« 

H43 

1900-13   Great  Britai.i 
1    and  Ireland 

Committee  of 
Royal  Society 

113 

130 

571 

4009 

I 

34  8 

13  7 

34  6  '      3.6 

1894 

Germany 

Lichtenfelt 
(1898) 

123 

(104) 

91 

528 
(504) 

3800* 
(3336)1 

A 

22  9 

13.7 

40  5 

. 

1907 

Germany  (rural) 
(urban) 

Claassen  (a).. 


(146) 

(14  !> 

(679) 

(5193)' 
(3633)' 

66.7% 

06.8) 

(25.0) 

(2.5) 

(31.8>») 
(21.7»«) 

(98) 

(467) 

66.7% 

(35.4) 

(20.6) 

(13.8) 

1912-3     Germany 

Eitzbacher 
Commission 
per  capita. . . 
per  man 

(93) 
(122) 

i 

(106)   i 
(139;   . 

(531) 
(699) 

(3642-0' 
(4777*)' 

average  of 
A-F=76.2% 

(23.5) 

(21.2) 

(16.6) 

(18.1) 

1890-9 

Paris 

Gautier,  per 

capita 

per  man 

107« 
140 

57 
73    , 

314 

2606^ 
3385' 

43  6 

U.I 

28.0" 

408 

77% 

1886 

Italy 

Lichtenfelt  (b) 
(1903) 

151 

(138) 

78    I 
(67>  ' 

550 

3586 

A 

(524) 

(3448)1 

1904 

Russia 

Sherman(1918) 
per  capita. . . 
per  man 

90 

f 

2997 
3880 

... 

3.4 

70.00 

117 

77% 

*  Figures  in  parentheses  represent  "digestible"  nutrients.  'See  Table  II.  'After  deducting  waste  of  5%  protein,  25% 
fat  and  20%  carbohydrate.  *  Includes  254  calories  from  alcohol.  *  Includes  173  calories  per  capita,  or  228  "per  man,"  from 
alcoholic  beverages,  or  112,  and  147,  respectively,  from  alcohol.  "Gautier  gives  total  as  102  but  total  of  individual  entries  is 
107.5  grams.    '  Includes  354_and  460  calories,  respectively,  from  alcohol.    ^  Includes  fish,  poultry  and  eggs.    » 10.5%  from 

plums  stimulated  the  excretion  of  nitrogen  into  the  intestine.  Mosenthal 
(a)  (1911)  found  that  in  dogs  on  a  mixed  diet,  which  would  be  a  high  pro- 
tein diet  for  man,  the  excretion  of  nitrogen  into  the  intestine  was  about  35 
per  cent  of  the  intake  and  that  '2o  per  cent  was  later  reabsorbed.  Hind- 
hede's  results  could  be  explained  by  an  increased  excretion  of  such  nitrogen 
without  compensatory  reabsorption.  It  is  quite  possible  and  even  probable 
that  such  nitrogen  has  not  been  completely  metabolized  and  therefore  repre- 
sents as  real  a  loss  to  the  body  as  if  it  were  unabsorbed  food  nitrogen  but 
the  fact  has  not  yet  been  fully  established.  It  is  just  possible  that  the 
material  excreted  into  the  intestine  is  as  truly  a  waste  product  as  urea 
or  any  other  constituent  of  the  urine.  However  that  may  be,  it  is  evident 
fioni  the  observations  of  Albertoni  and  Rossi  and  of  Xeumann  that  *'fac- 
tors  of  digestibility"  derived  from  certain  expenments  cannot  properly 
be  used  in  calculating  "digestible  protein"  under  different  conditions.  See 
also  Rubner(aa)  (1918).  Therefore,  the  discussion  in  this  chapter,  unless 
the  fecal  or  urinary  nitrogen  has  actually  been  determined  in  the  pai-ticular 
obseiTation  under  discussion,  will,  unless  specifically  otherwise  noted, 
be  based  upon  the  nitrogen  and  energy  content  of  the  food,  the  latter 
being  calculated  by  the  iise  of  Rubner's  factors,  4.1  calories  per  gi-am  of 
protein  or  carbohydrate  and  9.3  per  gram  of  fat. 


A  XOE:\rAL  DIET 

FOOD  CONSUMED  IN  DIFFERENT  COUNTRIES » 


371 


BcnoN  OP  Protein 

Percent.\ge  Distribltion  of  Calories 

Pcv    1  ^^^""^ 

Nuts  and 
fruits 

Other 
foods 

Mf-at* 

xMilkand    Other  |  „:.     . 
produrt.*       fati    j  ^^^"^^ 

Other 
grains 

Po- 
tatoes 

Other 
vegetables 

Nuts  and 
fnjits 

Susara 

Other 
foods 

3  1 

2  7 

2  0 

03 

24  1 

15.3         4  0    j  25.9 

8.S»* 

34 

2.0 

3.1 

13  2 

03 

'     .         I 

8.1 

3.7 

1 
0.7    1     0.6 

19.6 

f 
12.7         IS     1  30.9 

3.9     1  12.5 

19 

2.3 

12.6 

0  1 

6  3 

13. 7» 

0.3 

2.6 

16.2 

11  0     ,              i           43.5 

9.3 

6.3 

08 

3.9 

9.1" 

1 

(!)  4> 

(13. 3») 

(1.2) 

(24,9) 
(25.4) 

(15  t) 
(17.2) 

(2.9)   |(31.4»)  (15.3) 
(15.8)   1(22.4")     (7.4) 

(5.9) 

(2.8) 

(1.8) 
(9.6) 

(4.S) 

(3.5) 

(0.3) 

■ 

(1.4) 

(0.7) 

IS  0) 

(10.4»») 

(1.0) 

(1.2) 

(17.3) 

(13.1)   1  (1.9)     (16.6)    (22.2»)  (11.7) 

(4.3) 

(2  4) 

(5.4) 

(0  1") 

1 

1.2»» 

13.0>« 

0.1 

15.2 

15.1     !    11                37  1" 

3.4»» 

7.9 

0.8 

"L       - 

6  0 

I3.6H 

\                           ! 

! 

90 

_6_311 

0.1 

4.7 

2.2     i     1.9 

75.3 

10.2 

3.1M 

0.6 

22 

j 

legumes,  w  31.7^  from  rve.  "  5.1%  from  legumes.  "21.0^  from  rye.  "5.4%  from  legumea.-  "  Does  not  intlude  rice. 
»*  Includes  rice.  "  8.8%  from  legumea.  "  5.3%  from  legumes.  «  7.0%  from  maize.  »»  6.7%  from  alcohol.  »» 31.2%  from 
r>e.  -1  21.1%  from  rj-e.  «  15.2%  from  rye.  »  4.8%  as  alcoholic  beverages,  3.1%  as  alcohol.  "  13.6%  from  alcohol.  **2.4% 
from  legumes.    »  5.55%  from  maize. 

Studies  of  Entire  Countries  and  Cities 

The  gi-eat  part  played  by  fo<xl,  or  by  the  lack  of  it,  in  the  World  War, 
was  responsible  for  very  careful  studies  of  the  food  statistics  of  some 
of  the  countries  involved.  Perhaps  the  most  complete  of  these  that  has 
been  published  is  that  made  by  Pearl  for  the  United  States.  In  Table  III, 
there  are  presented  figures  taken  or  calculated  from  Pearl,  from  a  report 
of  a  committee  of  the  lloyal  Society  of  London  and  from  the  reix)rt  of 
the  Eltzbacher  commission.  There  are  also  included  figures  obtained 
from  the  reports  of  Lichtenfelt(//  j(7>)  (1808,  1903)  on  food  consumption 
in  Germany  in  1894  and  in  Italy  in  1880,  of  Claassen(a)  for  the  urban 
and  rural  population  of  Germany  in  1909,  of  Sherman (&)  (1918),  for 
Pvussia  in  1913  and  of  Gautier  for  Paris  from  1890  to  1899.  These  last, 
obtained  from  the  records  of  the  octroi,  or  customs  collected  on  the  impor- 
tation of  food  into  Paris  are  almost  certainly  too  low,  probably  due  to  the 
very  considerabk^  amount  of  smuggling  that  ^vas  carried  on. 

The  figures  show  considerable  variation,  even  for  the  same  coun- 
try. Claassen  reported  an  intake  of  99.8  grams  digestible  protein  and 
3033  available  calories  for  the  urban  population  of  Germany  and  146 
grams  and  5193  calories  for  the  rural  population,  whereas  Lichtenfelt  cal- 


tr/2 


ISIDOr.  GREEXWALD 


culated  tlicm  to  be  only  104  and  3336  for  tho  conntry  as  a  whole.  .  Claas- 
sen's  figures  agree  fairly  well  with  those  of  the  Eltzljacher  commission, 
but  the  latter  show  an  increased  consumption  of  wheat  at  the  exjxjnse  of 
rye  and  a  lessened  meat  consumption  in  the  interval  of  five  or  six  years. 

The  total  energy  consumption  is  over  3400  calories  in  all  countries. 
The  average  protein  intake  is  always  more  than  100  grams.  ^leat, 
including  fish,  poultry  and  eggs,  supplies  roughly  20  per  cent  of  the 
calories  and  somewhat  more  than  this  fraction  of  tho  protein ;  milk  and 
its  products,  from  13  to  17  per  cent  of  the  calories  and  14  to  25  per 
cent  of  the  protein  and  the  cereals,  from  35  to  40  per  cent  of  both  calories 
and  protein. 

The  greatest  variation  is  found  in  the  nature  of  the  cereal  used.  In 
Great  Britain  and  in  France,  this  is  almost  exclusively  wheat;  in  this 
country',  maize  plays  a  not  inconsiderable  role;  but  in  Germany,  particu- 
larly among  the  rural  population,  rye  is  used  almost  exclusively.  (See 
also  pages  365,  376,  377.) 

Except  in  the  United  States,  in  Paris  and  in  the  German  cities,  po- 
tatoes furnish  10  or  12  per  cent  of  the  total  energy  content  and  a  some- 

TABLE  IV.  — SYNOPSIS 
Belgium 


Date 

Authority 

Subjects 

Number  of 
Studies 

Number  of 
Individuab 

Scale  for 

Con- 
version * 

"Man 
Equiv- 
alent*" 

Average 

weight  of 

adult  male 

kilos 

Duration 
days 

1S53 

Engel 

Needv  families 

48 

1 

Families,  income  just  ade- 
quate   

51 

1 

Families,  able  to  save 

54 

1 

1891 

Engel 

Workmen's  families: 
Income  less  than  280  marks 

per  man  per  year 

Income  280-350  marks  per 

man  per  year 

44 

282 

A 

193 

30 

49 

315 

A 
A 

21& 

30 

Income  350-420  marks  per 
man  per  year 

47 

294 

205 

30 

Income  over  420  marks  per 
man  per  year 

48 

276 

A 

202 

30 

Average •  ■  ■ 

188 

1167 

A 

818 

190^S 

Slosse  &  Van 

Workmen 

33 

33 

33 

66.4 

6 

der  Weyer 

Of   these,    metal  -  workers 
(hard  work) 

8 

8 

8 

700 
6S.4 

6 

Wood-car%er3,  shoemakers, 
etc.  (moderate  work) 

13 

13 

13 

6 

1910     Slosse  & 

Weavers •  •  • 

156 

C 

14 

Printers 

36 

C 

14 

through 

Miners 

115 

C 

14 

49 

C 

14 

Greenwood 

» See  Table  IL 


A  JS^OKMAL  DIET 


373 


what  smaller  part  of  the  protein.  The  amount  of  protein  contributed  by 
"other  vegetables"  is  slight  in  Great  Britain  and  in  the  United  States,  is 
greater  in  Kussia  and  is  considerable  in  Germany  and  in  Paris,  owing  to 
the  free  use  of  legumes.  The  part  played  by  sugar  is  greatest  in  the 
United  States  and  in  Great  Britain  but  is  considerable  in  all  countries. 
The  consimiption  in  the  fonn  of  beverages  has  generally  been  included  in 
that  of  the  materials  used  for  their  preparation  but  in  the  reports  of 
Lichtenfelt  and  of  the  Eltzbacher  commission  for  Germany  and  of  Gautier 
for  Paris  this  has  been  separately  calculated  and  found  to  amount  to  from 
5  to  14  per  cent.  It  is  not  surprising,  therefoi*e,  that  the  prohibition  of 
the  use  of  alcoholic  beverages  should,  as  is  claimed  for  the  United  States, 
increase  the  consumption  of  sugar  and  other  sweets. 


Studies  upon  Individuals  and  Groups  on  Freely  Chosen 

Diets 

We  now  have  a  general  conception  of  the  character  of  the  diet  in  these 
countries,  considered  as  units.     How  is  it  with  the  individual?     What 


OF  DIETARY  STUDIES 


Belgium 


CoMPosmoN  Of  Food,  per  Man,  per  Day 

Percentage 
Calories  from 

Perckntaoe  DisTRiBtrnoN  op  Proteim 

Calcu- 
latedor 
ana- 
lyzed 

Protein 
grains 

Fat 
grams 

Carbo- 
hydrate 
grams 

Energy 

yield 

calories 

Protein 

Fat 

Meat « 

Milk 

and 

products 

WTieat 

Rye 

Po- 

tatoea 

Others 

Calcd. 

!i2.f? 

17.3' 

469» 

23413 

25923 
27903 

10.93 

6.93 

65.1* 
72. 7» 

29. 2» 
39. 3» 

504» 
519* 

10.13 

10.53 

10.73 

13    13 

„ 

67. 9» 

56.  i« 

26833 

10.43 
10.93 

19.23 

13.0 

5.8 

543 
41.8 
46.7 

7.0 

14.1 

5.9 

.. 

70. 5» 

70. 6» 

29853 

22.03 

17.7 

6.7 

15.5 

11.9 

6.3 

" 

97.2* 

80.6» 

572» 

571» 
5213 

34903 
36463 

11.43 
12    13 

21.53 

18.5 

9.0 

8.4 

10.2 

7.2 

» 

108» 
85. 9» 

93. 1» 

74.93 

23. 7» 

21.83 

22.4 

10.1 

46.8 

2.5 

9.0 

9.2 

31793 

11.13 

Anal. 

lOoS 

100 

393 

2932 
3110 
2815 

J4.7 

31.6 

.. 

n7 

115 

410 

15.4 

34.3 

" 

100 

107 

381 

14.6 

35  4 

Calcd. 

(80.6)*     (86.9)* 
mW  (103M 
(77.2)«  (127)* 

(520)* 

(3336)* 

9.9 

24.2 

** 

(586)* 

(3817)* 
(3604)* 
(4314)* 

10.2 

25.1 

" 

(497)* 

8.8 
8.2 

32.8 

• 

(«&.2)« 

(130)* 

(658)* 

28.0 

'  Includes  fish,  poultry  and  eggs. 

»  AI!  of  the  values  for  food  consumption  reported  by  Engel  are  loo  low  since  not  all,  but  only  the  principal,  foods  were  inchided. 

♦  Figures  in  parentheses  represent  digestible  nutrients. 

*  "pigcstible"  protein  0.91  to  2.02  gm.  per  kilo  per  day,  average  1,375.     The  man  who  bad  only  0.91  gm.  protein  per  kUtr 
lost  3.48  gm.  nitrogen  per  day 


374 


ISIDOR  GREEXWALD 


Denmark 


TABLE  IV.  —  SYNOPSIS  OF 


Authority 

Subjects 

Number  or 

Average 

1  weight 

of  adult 

male 

kilos 

Du- 
ration 
days 

Co3iPO3m0N  OF  Food,  per  Man  per 
Day 

Date 

studies 

indi- 
viduals 

Scale 
ofCon- 
versioo 

Man 
equi- 
valent 

M.7 

Calcu- 
lated or 
ana- 
lyaed 

Pro- 

tein 

grams 

107 
101 
109 
119 
107 

Fat 
grams 

105 
90 

Carbo- 
hydrate 
grams 

Energy 
yield 
calories 

1910 

Heiberg 
and  Jensen 

Laborers'  families 

in  Copenhagen . . 

In  other  towns. . . 

In  i.slands \ 

In  Jutland  . . . .  / 
Avrage 

27 

F(?> 

Calcd. 

493 

464 

3351 

23 

" 

76.6 

" 

3153 

201 
251 

" 

5S9 

•• 

111 

103 

516 

550 

493 

3595 
3701 

1   749 

" 

ia^ 

3450 

1912 

Hindhede. . 

Author's  family... 

1 

10 

7 

" 

76  1     103 

3418 

Finland 


1904 

Sundstrom 

Students 

University 

Agric.  School  men 
"         '*  women 
Families  of  city 
workmen 

14 

160 
157 
226^ 
ISO''* 

139 

200 
119' 

130 

391 
380? 
"685"'" 
496^'* 

4126 

1 

100 
24 
9 

lO*} 

24 

verted 

67.6 
61.8 
66.8 

Calcd: 

3984? 

1 

14 
14 

'* 

4836' 

Not  con 

" 

3508^'» 

12 

40 

C 

30  8 

14 

" 

455 

3643 

1907 

Sundstrom 

Farmers,  etc.,  men 
"            women 

disregard  6  lowest 

17 

17 

67 

7 

Anal. 

136 

83 

580 
36(fi 

3705* 

25 
19 

25 

69 
69 

7 

" 

91* 

61* 

iSZo*-^^ 

19 

7 

H* 

S92* 

2462*'^<> 

1907 

Sundstrom 

Households  of 
farmers,  etc 

80 

559 

H 

393 

7 

Calcd. 

177 

104 

688 

4516»» 

France 


1906 


Gautier  . . 


Family  of  farm  la-  | 
borer  in  south  of  i 
France I      2 


14 

(fn.") 

12 

385 

Calcd. 

149 

79 

830. 

4745 


•  Includes  oleomargarine.  '  Corrected  for  waste.  •  Includes  other  vegetables.  •  Figures  in  italics  refer  to  foodjconsump- 
tion  per  woman,  not  per  man  equivalent,  i"  Sundstrom  gives  other  figures  but  he  used  othe.  factors  for  energy  values  of 
food.    ^^  Gautier  calculated  food  consumption  of  2  women  and  child  of  7  as  equivalent  to  that  of  one  man. 

variation  is  there  among  individuald  and  what  are  the  factors  responsible 
for  such  variation  ? 

There  have  been  many  observations  published  on  the  food  con- 
simiption  of  individuals  and  of  groups  living  on  their  customary  diet, 
which  is  sometimes  called  a  "freely  chosen  diet."  In  reality  there 
is  no  such  thing.  Man's  choice  is  limited  by  his  geographic  and 
economic  situation,  to  say  nothing  of  such  things  as  food  habits  and  prej- 
udices acquired  early  in  life.  Just  as  was  his  primitive  ancestor,  though 
to  a  lesser  degree,  modern  man  is  limited  in  his  choice  by  his  environment. 

Among  the  earliest  reports  that  are  sufficiently  accurate  to  be  of  any 
considerable  value  are  those  of  Liebig  on  the  food  of  Bavarian  woodchop- 
pers.  Similar  studies  were  made  by  Play  fair,  by  Meinert,  by  Moleschott 
and  by  others  but  the  gi*eatest  impetus  to  the  study  of  the  food  habits  of 
the  people  appears  to  ])e  due  to  the  work  of  Voit.  Basing  his  opinion 
ujjon  the  results  of  previous  investigators  and  upon  the  actual  food  con*. 


A  NOKMAL  DIET 

DIETARY  STUDIES— Contmued 

Denmark 


375 


Percbntagb 

CAL0RIE3  FROM 

Percentage  of  Distribution  of  Protein 

PERCENT.A.OE  DiSTRIBtTIOS  0?  CaLORTES 

ftotein 

Fat 

Meat  2    ^^''kand 
Meat      Products 

Cereals 

Po- 

titoes 

Other 

j 

Mil- and    |-»„„|. 
Meat '-  Product.-    ^'^^^ 

Ml 

29.1 
26.6 
28.7 
25.8 

i               i 
1 
I 

I           1 

1 

13.1 

. 

! 

i                   ■ 
1 

j 

12.4 
13.2 

i 

12.7 

28.3 

9.1 

28.0 

5.7 

34.8 

46.2 

12. 7» 

0.5 

1.6    j    31.7*  ^    3§.» 

J2.7              14  1  i  2  7 

15.5 


Finland 

15.9 

45  1 

43.4 

30.9 

19.9 

2  3 

2.5 

i 

21  9    1    39  5 

i 

24.1 

4  3 

10.2 
13  9 

7.4 

1-5  ^  r.3j 

16.2^ 

44.6 
22.9 

43.2 

44  0 

!— 

19.  r 

17.3 

29.6 

5  1 

4.8 

r.i 

13  5 

2S  8 

3  -S 

17.5* 

U.4 

19.0 

38.8 

32.2 

2.9 

13.1 

27   0      : 

43.9 

-  - 

15.7 

33.2 

28.1 

38.0 

28.1 

1.7 

40 

11.0 

39.0    1 

33.7 

■  1 

!     i.T    ■    -.♦ 

15.0 
16.0^ 

21  6\ 

so.a^f 

19.0 

36.0 

37.0 

8.0 

9.0 

2S.0    1 

50.0 

13.0 

/5.7» 

20.0 

' 

16.1 

21.4 

15.0 

35.0 

41.0 

7.0 

2.0 

10.0 

i 
27.0    i 

48.0    j 

11.1 

!  ^ 

France 


12.9 

! 

i 

sumption  of  men  of  average  weight,  70  kilos,  engaged  in  moderate  work 
in  the  city  of  IMunich,  he  concluded  that  a  normal  diet  for  such  a  man 
should  contain  118  grams  of  protein,  5G  grams  of  fat  and  500  gi*ams  of 
carbohydrate.  Substitution  of  as  much  as  150  gi*ams  of  the  carbohydrate 
by  an  isodynamic  amount  of  fat  was  consideretl  desirable.  This  is  known 
as  Voit^s  standard.  As  Dunluce  and  Greenwood  say,  "It  has  enjoyed  a 
vogue  which  is  not  so  mucli  due  to  the  number  or  accuracy  of  the  laboratory 
experiments  carried  out  by  Voit  as  to  this  investigator's  high  and  well- 
deserved  reputation."  However,  the  necessity  of  so  large  an  amount  of 
protein  has  been  vigorously  denied  and  as  vigorously  affirmed.  The  ques- 
tion will  be  considered  later. 

Some  of  the  evidence  is  contained  in  Table  IV,  which  gives  a  sum- 
mary of  some  of  the  results  obtained  in  what  seem  to  be  some  of 
the  more  important  studies  of  people  on  their  accustomed  diets  made 
since  Voit's  time.    Most  of  these  were  made  on  the  poorer  classes  of  the 


376 


isiDOR  geee:n^wald 


TABLE  IV. -SYNOPSIS  OF 


Germaxy 


Authority 

Subjectd 

1 

NCMBER  OF 

Scale 
of 
con- 
version 

Calcd. 
kilos  b 

Man 

,  e<iuiv- 
alent 

! 

.\verage 

CoMlx>8fTtoN  or  Food  per  Man 

MR  DaT 

Date 

studies 
3 

indi- 
viduals 

weight 

of  a.'lult 

male 

kilos 

1   Du- 

.ration 

days 

Calcu- 
lated or 
ana- 
lyzed 

Pro- 

tein 
grams 

Fat 
grams 

Carbo- 
hydrate 
grams 

Eneri^ 
■   j-icld 
calories 

1880- 
1892 

Derauth. . . 

Pensioners,    etc., 
light  work 

City  laborers 

Farm  laborer 

Families  of  above, 
etc. 

3 

to  70 
ody  w't. 

Calcd. 

103 
131 

50 

546 

3130 

2 

1.5 

Calcd.  to  70 
kilos  bo«ly  w't. 
Calcd.  to  70 
kilos  body  w't. 
Calcd.  to  70 
kilos  body  w't. 

.. 

67 

545 

3472 

1 

" 

137 

89 

590 

3811 

20 

78 

99 

57 

597 

3400 

1890 

V.  Rechen-  .  Families  of  hand- 
berg  weavers.very  poor 

28 

i 

571J 

7 

« 

6.5"]     49'»- 

485" 

2703" 

1899 

Ranke 

Ranke 

Phj-sician    fstlf), 
Jan.  and  Ftb — 

1 
1 

73 

30 

.. 

138 

1C2 

351 

3512 

Phj-sician    (self), 
July  and  .\ug... 

1 

135" 

162" 

372" 

3588" 

1902 

Neumann. . 

J 

Laboratory  inves- 
tigator (self  j .... 

I.aboratorv-  inves- 
tigator («elf) .... 

Laboratorj-  inves- 
ticator  (self).... 

67.5 

3a5 

» 

66 

77 

84 

230 

2309 

66 

15 

Anal. 

156 

221 

169 

2659 

72 

321 

Calcd. 

76 

109 

2068 

1895 

Atwater... 

Bavarian  me- 
chanics  

17 

«. 

134 
137 

63 
55 

61 

491 

3150 

"         farmers 

*"         brewery 

laborers 

" 

&(5 

3295 

. 

5 

149 

755 

4275 

1910 

Claassen... 

Peasant  families, 
Rhine  vaUey.... 

30 

(^0 

109 

146. 

669 

4537 

Greexl.\nd 


1857 


Krogh, 
A.&M. 


Esk'unos 


65 


282^ 


2604* 


"  Per  adult  individual.  *'  See  text,  page  339.  "  12.7%  protein  in  beer.  "  1.4%  protsin  in  beer.  "  Legumes  furnished 
4.5%  of  the  protein  and  l.S^c  of  the  calories.  "  It  is  not  evident  just  what  factors  were  used,  but  they  were  apparently 
lower  than  any  of  these  in  Table  IL     *  Not  all  food  included. 

population  and  many  of  them  were  undertaken  to  ascertain  whether  or 
not  a  condition  of  undernutrition  obtained.  For  this  reason,  it  is  probahle 
that  the  values  reported  are  niiniirial  rather  than  optimal.  In  order  to 
facilitate  comparison,  the  results  have  been  gi-ouped  by  countries  and  with- 
in each  group  have  been  arranged  chronologically,  unless  other  consid- 
erations made  some  other  arrangement  appear  preferable.^ 

'There  i.s  much  valuable  material  for  the  student  of  nutrition  in  the  series  of 
family  mono^aphs  published  by  Le  Play  under  the  title  "Les  ouvriers  europeens" 
and  continued  by  the  .Societo  international^  des  etudes  pratiques  d'economie  sooiale  as 
"Ouvriers  des  deux  mondes."  These  are  a  series  of  complete  studies  of  families  in  many 
parts  of  the  world  and  include  the  amount  paid  for  food,  in  money,  kind  or  labor, 
and  the  amount  and  nature  of  tlie  food  secured.  Unfortunately,  the  character  of  the 
food  is  not  always  sutlieiently  well-detined  to  permit  of  accurate  calculation.  A  similar 
criticism  applie-s  to  the  reports  of  the  Board  of  Trade  of  Great  Britain  on  working- 
class  conditions  in  Great  Britain,  Belgium,  France,  Germany  and  the  United  States. 


A  XOEMAL  DIET 

DIETARY  STUDIES  — ron'iVt^rr/ 

Germany 


377 


Perce-n'taoe 
Caloriks  fbom 

Perce.nt.\ge  Distribution  of  Protei.n- 

PerCENTAOE  DlSTRIBCTJON  OF  C*  LORIES 

Protein 

Fat 

Meat* 

1   Milk 
!    and 
•  Prod- 
ucts 

Cereal3 

Po- 
tatoes 

Other 
tawts 

Others 

1 

^   Milk 
:    acts 

Cereals 

Po- 
tatoes 

Other 
vege- 
tabks 

Sugars 

Others 

14.3 

14  7 

1 

155 

17  9 

j 

15.7 

22.7 

i 

12.0 

15.7 

1 

■ 

- 

9.9 

17.0 

1.1  1     12.0 

61.7 

18.4 

16.1 

42.8 

I 

1 

t 

15.4 

41.S 

I 

11.7 

33.6 

35.9 

27.4 

22.5 

1.6 

12. 7»* 

11.8 

54.6 

15.1 

48.9 

47.0 

27.6 

19.2 

1.9 

4.2'i 

! 

1 

17.5 

18.6 

' 

17.0 

15.5 

14.3 

13.3 

11. 1 

30.0 

12.8 

21.7 

41.1 

11.2 

12.6»6 

0.6 

! 

14.8  !    18.8 

42.0 

15.C 

5.0»« 

1.9 

].] 

Greenland 


44 


48 


The  first  column  gives  the  date  of  the  study  if  that  is  available,  if 
not  that  of  the  publication  and  the  next,  the  name  of  the  author  or  other 
authority  for  the  data.  The  succeeding  columns  give,  in  order,  some  idea 
of  the  social  and  economic  status  of  the  subjects,  the  number  of  studies, 
the  total  number  of  individuals,  the  scale  of  conversion  to  "man  equiva- 
lents," the  number  of  these,  the  average  weight  of  an  adult  male  and 
the  average  duration  of  the  studies.  These  fall  into  two  classes,  accord- 
ing as  the  data  for  the  composition  of  the  food  were  obtained  by  actual 

These  include  the  results  of  questionnaires  on  family  budgets.  Some  of  the  additional 
difficultieis  in  drawing  conclusions  from  some  of  the  calculations  that  have  been  made 
from  some  of  the  Board  of  Trade  data  are  discussed  in  footnote  21  to  Table  IV,  p.  378. 
However,  cursory  examination  of  the  French  monographs  and  of  the  reports 
of  the  Board  of  Trade  indicates  that  more  detailed  consideration  would  only  cor- 
roborate the  conclusions  indicated  by  the  data  presented  in  this  chapter. 


378 


ISIDOR  GREENWALD 


TABLE  IV.  — SYNOPSIS  OF 


Great  Britain 


Date 

Authority 

Subjects 

Number  or 

Scale  for 

con- 
:  version 

1 

"Man 
equiva- 
lents" 

Average 

weight  of 

adult  male 

kilos 

Duration 

Studies 

Indi- 
viduals 

days 

1900 

Paton,    Dunlop 
and  Inglis 

Families  in  Edinburgh: 
Income  less  than  203.;  av.  178.,  4d 
Av.  income  22s..  2d 

5 

32 
30 
34 

c 

18 
17.1 

7 

5 
4 

7 

Av.  income  39  8 

" 

21.4 

7 

Typical,  av.  income  25s..  lOd 

9 

50 

34.4 

7 

, 

1901 

Rowntree,  data 
re  calcd.  by 
Dunluce  and 
Greenwood 

Families  in  York: 
Av.  income  IBs.,  1  Id.  (allundw  266.) 

16 

87             I 

58.5 

70 

3 

17             I 
39             I 

12 

19 

Servant  keeping.            .         , 

6 

30 

9 

1904 

Board  of  Trade; 
calcns.  by 
Dunluce    and 
Greenwood 
and  by  Green- 
wald 

Families  of  workmen  in  cities: 
Income  under  253.;  av.  2l3.,  4>id. 

Income  25-30  s.;  av.  263..  ll'id.. . 

Income  30-358.;  av.  3l3.,  lU^d.... 

Income  35-403.;  av.  36s.,  6Kd 

Income  40s.  or  more,  av.  523.,  Md. 

261 

See 
Note  a 

289 
416 

382 

590 

1911 

Cameron 

Edinburgh  students f  — "— 

I  women 

4 

149    i 

149 
24 

7 

1 

30    j      0.8 

7 

1911-12 

Lindsay '  Glasgow  faniilics: 

1      Income  under  209,  average  ISs,  14d 
j      Income  20-253,  average  233.  lOd. . 

5 

29 

c 

18 

7-14 

10 

63 

c 

C 

39.2 
11.2 

7-14 

1 

3 

20 

7-14 

1916 

Ferguson \  Glasgow  families: 

1  Average  income  27.28 

6 

c 

1 

4 

1       C- 

7 

1917 

Ferguson •  Avera<;e  income  28.48 

6 

i     c 

7 

\verai'e  income  50  63  . . .         

4 

■|     c 

7 

1903 

Dunluce  and 
Greenwood 

British  Agricultural  Laborers 

Northern  Counties 

see 

note  " 

Midland  Counties 

Eastern  Counties 

Southern  and  Southeastern  Coun- 
ties  

» Includes  2.2%  from  peas. 
"  Includes  13.6^  from  rjgar. 

**  Figures  underlined  refer  to  distribution  of  calories,  not  protein.  .    ,       t 

n  The  average  number  of  children  in  the  families  in  the  different  groups  was  3.1.  3.3,  3.2.  3.4,  4.4  and  3.6,  respectively.    In 
their  calculations,  Dunluce  and  Greenwood  used  the  value  0.51  to  convert  the  number  of  children  into  "man  equivalents."     But 


A  FORMAL  DIET 


379 


DIETARY  STVDIES  — Continued 


Great  Britain 


Composition  of 

"odd  per  Man  per  Day 

Percentage 
Calories  from 

Perce-vtage  DisTRMimoN  or 

P30TB3LN 

Calcu- 
lated or 
analysed 

Protein 
grams 

Fat 
grams 

CarlK)- 
hydrate 
grams 

Energy 
yield 
grams 

Protein 

Fat 

i                    ' 

Meat*  Milk  ami  Cemb 
products  ^ 

! 

Po- 
tatoes 

Others 

Calcd. 

93 

69 
82 
92 

396 

2607 
3133 

14  6 

23.6 
24.4 
24.3 
25.5 

27.1        10.6       53.2 
34  1           7.0     :  54  7 
31.9        10.0     '  53.0 

9.0 

•' 

103 

480 
529 
479 

13.5 
13  4 

4.1 

5.0 

" 

115 

3531 
3228 

•' 

108 

88 

13  7 

30.3 
16.3" 

10.2     !  53.0 

3.5    1  3  3" 
4.6"  116.3 «9  20 

1 

12  82'     50.2»J 

•• 

82 

88 

450 

3000 
4102 
4052 

11.2 

27.3 

1              ■^V' 

146griX5tDeatan4S5 
grani*  rj^ar  per  day 
227  gr.iZ^  meaz  and 

" 

117 

130 

589 

11.6 

n.3 

29.7 

i 
1 

45  3^* 

88  g^jjrs  fuiar  per 
day  ■:'>.•  zr&ms  meat 

*' 

112 

161 

511 

37.0 

29  7«> 

and  113  graois  :ugar 
per  ihy 

86 

59 

536 

3094 

11.4 

17.6 

i          5  ei.ar. 

101  gnris  meat  and  73 
grair..«  r^^ar  per  day 

" 

92 

71 

565 

3348 

11.2 

19.6 

55  2» 

117gri:L«2;?atand85 
grarii  j  --^.tr  per  day 

" 

99 

82 

588 

3581 

11.3 

21.3 
22.5 

f  55.5»> 

i  

i 

142graE:.«  meat  and  93 
graco  rjzar  per  day 

" 

98 

86 

582 

3589 

11.0 

1  54.0«> 

! 

llfigrar:*  meat  and 98 
graroj  ?j  gar  per  day 

108 

100 

644 

4013 

no 

23.1 

53  32^ 

! 

154  grsns  meat  and 
1 10  graas  s'j^ar  per 
day 

•• 

140 
162 

138 

516 

3976 

14.4 

32.3 
32.4 

! 

•• 

139 

495 

3990 

16.6 

'■' 

.. 

98 

76 

86 
98 

385 
531 

506 

2689 
3457 

3618 

14.9 
13.9 
13.9 

23.1 
26.3 

39.5  I       8  4     !     46.9 

3.8 

1.5 

" 

118 
118 

29.1 
31.4 

9.9    :    51.8 

4  1 

3.6 

" 

10.8     ;     50.2 

3.6 

3.9 

" 

96 
98 

96 

467 

3198 

12.3 
13.4 

27.9 
27.2 

22.8 
24.8 

i     ! 

" 

88 

439 

3017 

i          { 

'• 

93 
112 

72 

462 

~  498 

;940 
3331 

13  0 
13.8 

* 

89 

! 

„ 

88 
~S8- 
_92_ 

96 

113 

M7 

3654 

9.9 

27.8 
24.6 
21.5 

1 

" 

90 

537 
.597 

3698 

10.6 
10.5 

? 

•• 

83 

3598 

•• 

84 

600 

3634 

10.8 

24.6 

1 

i 

in  the  families  with  the  larger  incomes  it  is  probable  that  some  of  the  family  income  came  from  the  earnings  of  some  of  the  chil 
dren.  Th«sc  children  would  be  older  than  the  average  and  would  eat  more.  Even  if  this  effect  be  disregards,  the  families 
with  smaller  income  woild l>*i  likely  to  those  mo.'^t  recently  established,  with  the  youngjer  children,  whose  foo-i  coriSumption 
would  be  lower  than  the  a\erage.  The  effect  of  income  upon  the  amouat  and  character  of  the  food  consumed  is,  therefore, 
probably  exaggerated  in  these  figures. 


380 


ISIDOR  GREENWALT) 

TABLE  tV.  —  SYNOPSIS  OF 
India 


Authority 

Subjects 

NuuBER  or 

Scale  for 
Conversion 

"Man 
equiva- 
lents" 

Average 

weight  of 

adult  male 

kilos 

Date 

Studies 

Individuals 

Dura- 
tion 
days 

1908 

McCay  (1908) 

Bengali  students,  ration  scale. . . . 
Anglo-Indian  and  Eurasian  stu- 

1 

54 

1 

1912 

McCay  (1912) 

Bengalese  cultivators 

middle  classes,  not 
above  indigence 

Approx.  50 

indigence 

Thibeuns,  etc..  rickshaw  men. . 

Italy 


Authority 

Subject* 

NtTHaxJt  OP 

Scale  of 
conversion 

"Man 
equiva- 
lents" 

Average^ 

weight  of 

adult  male 

Date 

Studies 

Individuals 

Duration 
days 

1886 

Lichtenfeltfl903) 

Workers  in  food  industries — 
Textile  workers 

5 

. 

9 

Laborers 

7 

1894 

Memmo 

M3n  at  moderate  work.  Rome, 
ordinar>-  diet 

3 

3 

60.7 

7 

Native  of  chestnut-eating  dis- 
trict,   chwtnut   diet,   easy 
work 

1 

1 

59.1 

7 

Acorn  diet,  very  light  work. . . 

1 

1 

65.5 

1893 

Manfredi 

Poor  men.  Naples,  cobblers — 

"   man.        "     mason 

"       "           "     carper;ter.  . 

2 

2 

51 

5 

1 
1 

1 

55 

5 

1 

62 

7 

1906 

Albertoni   and 
Rossi 

Peasants  of  the  Abruzzi,  men 

7 

7 
5 

60.4 

5 

**       "       "         "    women 

5 

Not 
converted 

50.S» 

S 

Java 


1892 

Eijkman 
(1&93) 

Mala>-s,  Laboratory  servants. . . . 

medical  student 

Europeans  in  Java,  physicians, 
etc                    

4 

4 

47.5 

4.5 

1 

1 

58.1 

5 

11 

7 

65.4 

4 

•  Figures  in  italics  refer  to  food  consumption  per  woman,  not  per  "man  equivalent." 


A  NORMAL  DIET 

DIETARY  STUDIES  — Continued 

India 


381 


C!oMpo8iTioN  or  Food  pbr  Man  per  Dat 

Percentage 
Cawbies  rROM 

— — — ■ — 

FSRCENTAOB-DlSTRIBirnON  07  Pbotein 

Calcu- 
Iat<'fJ  or 
analyzed 

Protfin 
grama 

Fat 
grams 

Carbo-       Energy 
hydrate        yield 
grams        calories 

Protein 

Fat 

Meat  2 

Milk  and 
products 

Rice 

Other 
cer«ala 

T^     (  Other 

Calcd. 

67 

72 

549 

319«J 

8.6 

20.8 

13.9 

30.5 

19.9 

269         87 

" 

95 

56 

467 

2S22 

13.8 

18.5 

41.6 

4.4 

13.4 

26.8 

12.9 

2.1 

•• 

52 

25 

475 

2390 

8.9 

9.8 

9.7 

87.3 

5  7 

22 

.. 

50 

50 

400 

2310 

8.9 

20.5 

10.1 

7.5 

72.5 

69 

23 

» 

70 

175-200 

90 

300 

23.50 
6300  + 

12 

36 

14.4  + 

10.7 

19.4 

41.2 

4  3 

1.6 

" 

125-130 

3750^000a 

» Includes  16  oz.  milk  and  4  oz.  meat  per  day. 


Italy 


CoMPf>smox  OF  Food  per  Man  per  Dat 

Percentage  Calories 

FROM 

Calculated 

or 
analyzed 

Protein 
grams 

Fat 
grams 

Carbo- 
hj-drate 
grams 

calories 

ftotein 

Fat 

••"  ■            '  - 

Calculated 

143 

31 

713 

3808 

15.4 

7.6 

" 

128 

29 

662 

3470 

15.1 

7.8 

" 

168 

48 

909 

4866 

14.2 

9.2 

" 

227 

62 

932 

5326 

17.5 

10.8 

Analyzed 

106 

30 

495 

2745 

15.8 

10  2 

87  grams  digestible  protein  and  2563 

.. 

59 

19 

464             2521 

9.6 

7.0 

available  calories 

44.4  grams  digestible  protera  and  2171 

available  calories 
98  grams  digestible  protetzt  and  1892 
available  calories 

" 

124 

63 

252             2120 

24.0 

27.4 

" 

75 

38 

379 

2208 

13.9 

15  4 

" 

71 

29 
56 

391             2155 

13.4 

12.3 

" 

94 

475       :      2852 

13.5 

18.3 

" 

73 
60» 

63 

450      I      2746 

10.9 

18.1 

52.9  grams  digestible  protein  and  24S0 
available  calories 

46* 

5;a*         ggo4* 

//.«» 

i9.4' 

42.7  grams  digestible  protein  and  2004 
available  calories 

Java 


Anal. 

70 

29 
64 

92 

482 

3254 

8.9 
14 

16 

8.3 

96 

426 

2731 

22 

" 

98 

262 

2553 

34 

m 


ISIDOR  GREENWALD 

TABLE  IV.— SYNOPSIS  OF 
Japan 


Authority 

1        NcKBCK  or 

1 

Scale  for 
conversion 

"Man 
equiva- 
lents" 

Average     _ 

Date 

Subjects 

■  Studies 

Individuab 

weight  of 
adult  male 

uuration 
days 

IwO 

Eiijkmaa 
(through  Oshima) 

Prisoners,  no  work 1 

20+ 

47  6 

light  work 1 

20+ 

48  0 

hard  work 1 

1S>9 

Nagase  (Oshima) 

Military  colonist  in  Formosa  .          1 

1 

1 

59          17 

ISOO  i  Tsuboi  (Oshima) 

Jinrickshaw  man j         1 

1 

r 

62.4      1        4 

1^9 

Inaba 

Fartners,  rice  diet !        7 

barley-rice  diet '         7 

"        average  of  all 14 

idio 

Yukawa 
•• 

CeUbate    monks,  young,   co 
work 8 

8 

445 

Celibate  monks,  light  work. ....        I 

, 

52.1 

Celibate  monks,  old,  no  work .         3 

3 

51.8 

1911 

Hiohede  (1920) 

Diet  list  of  Japanese  pa\ilioa,  : 
Dresden.  1911,  hard  work. .          I 

7 

light  work ...        1 

5 

i919 

Kobu  and 
Soicamoto 

Workmen !        4 

1 

2 

32 

Russia 


Authority 

Subjecti 

JfPMSES  or 

Date 

Studies 

Individuals 

1S89 

Erisraar.n  (1SS9)... 

Factory  worker*                      

50 

1670 

1904 

Smolensky 

Factory  workers,  ordinary  diet 

3 

"             "      far:  days 

3 

Peasants,  Goveni:2eat  Moscow,  poor 

"      well-to-do 

Laborers,  Cronsta^i:  docks,  ordinary  diet 

"     fastdays 

Laborers  and  mechacics.  Cronstadt,  wages  18-24  rubles 
per  month,  5  sp-r.-^:  for  food 

Ditto,  24-28  nib:^.  7.5  spent  for  food 

Ditto,  30-48  rabies.  1.3.5  spent  for  food 

Fishers  at  mouth  of  Volga,  men 

women 

Peasants,  2  distrirts,  men 

. 

"         2      *'         !  same),  women 

Average  of  all  reported  by  Smolensky 

94 

*  Figures  in  italics  refer  to  food  consumption  of  wo!i>en  not  "man  equivalents.' 


A  NOKMAL  DIET 
DIETARY  STVDIES— Continued 


383 


Japan 

CoMPOSinoN  or  Food  per  Man  per  Dat  |     ^"loST "^ 

Peucentaoe  op  Distribctio.v  or 
Protein 

Calcu- 
lated or 
analyzed 

Pro- 
tein 
grams 

48 
57 
75 

Fat 

grams 

Carbo- 
hydrate 
grams 

£nerg>- 
yield 
calories 

17S2 

As 

I'rottin 

1 

As 
fat 

Meat* 

Cereals 

Anal. 

6.8 

372 
458 

11  0 

8.6 

! 

" 

7  6 
9.8 

2175  ;     11  7 

3  2 

^ 

•• 

630 

2y75  ;     10.3 

2.9 

.•    i 

" 

59 

7.7       594     i     27.52  i      8.9  \      2,3 

Calcd. 

158 

25. C  i  1031 

5113  j     12.7 

4  7 

" 

78 

16.9 
31.6 
24.3 

530 

2676 
3529 

11.9 

5.9 
8.3 

!            i 

" 

126 

663 
597 

14.6 

!            I 

"       [     102 

?Ml  !     13.5 

7.2 

■  i            I 

Anal. 

57 

14.6 

'345 

1S04 

12.9 

7.5 

i 

38  grams  digestible  protein 

.. 

87 

21.2 

531 

2719 

13.1 

7.3 

1 

and  1651  available  calorie* 
63  grams  digestible  protein 

and  2547  available  calories 
41  grams  digestible  protein 

and  1872  available  calories 

" 

60 

12  3 

347 

2020 

12.3 

5.7 

Calcd. 

120 

31  5 

3536 

14.6 

83 

5 
7.5 

63 

32    ! 

" 

81 

18.6  1 

2770 

12.0 

6.2 

76              7    j    9.5 

" 

96 

18.9 

766 

3766 

10.4 

4.7 

Russia 


Composition  op  Food  per  Man  per  Dat 

Percentagk  Calories  from 

Calculated 

Protein  grama 

Fat  grams 

Carbohydrate 
grams 

Energy  yield 
calories 

Protein 

Fat 

Calculated 

132 

80 

583 

3676 

14.7 

20.2 

133             j 

565 

3507 

15.5 

18.8 

121             1              71 

603 

3706 

13.4 

20.0 

109             1             80 

542 

2935 

15.2 

92 

146             1             29 

669 

3784 

15.8 

11.8 

2?0 

48 

931 

5603 

16.1 

15.7 

216 

95 

1(340 

6033 

147 

14.6 

123                           43 

563 

3207 

15.7 

12.3 

122                           52 

419 

2704 

18.5 

18.0 

146                         140 

460 

3785 

15.8 

34.4 

303                           71 

462 

3797 

32  5 

17.3 

S19*                         43» 

463» 

S194* 

gs.i* 

li.S» 

138                           39 

560 

3223 

17.5 

11.2 

12-2*                         Sl^ 

625» 

fs;^» 

17.6» 

lO.tfi 

149                          57 

4040 

15.1 

13.1 

$H 


ISIDOR  GREENWALD 


TABLE  IV.— SYNOPSIS  OF 


Sweden 


Authority 

Subjects 

Number  or 

Average 

!  weight 

;of  adult 

male 

kilos 

Du- 
ration 
days 

CoMPOsmoN  Of  Food  per  Ma v  per  Dat 

Date 

Stu- 
dies 

Indi- 
vidual 

Calcu- 
lated or 
analyzed 

Protein 
grams 

Fat 
grams 

Carbo- 
hydrate 
grams 

Energy 
yield 
calories 

1887 

Hultgren  and 
Landergren 
(1889) 

Hultgren  and 
landergren 
(1889) 

University  students  — 
University  professor 

5 

1 

68 

10.4 

Calcd. 

128 

115 

300 

3034 

1887 

96 

8 

.. 

137 

113 

345 

3205 

1887-8 

Hultgren  and 
Landergren 
(1891) 

Workingmen 

11 

9          67 

7.3 

.. 

159 

91 

610 

4023 

1893-8 

England  (Tiger- 
stedt.  1000) 

Lumbermen  in    north  of 

Sweden: 

"Rivermcn" 

Choppers,  etc 

Of  these  tatter 

Lumbermen,  etc.,  groups 

Of  these  a  group  of  2 

'96~ 

17 
96 

64.4 
67.3 

22 

<e 

124 

214 

284 

424 

4239 

63 

*' 

140 

732 

6214 

1 

72 

68 

36 

•• 

181 

415 

1145 

9292 

119 

•• 

130 

271 

696 

5905 

2 

69 

„ 

152 

523 

720 

8439 

s 


Switzerland 


1912      Gigoa 


Workmen 


8         68.9         7       Anal 


107 


93       402       3181 


"Beer. 


Legumes. 


analysis  of  samples  of  the  material  used  in  these  studies  or  were  obtained 
by  calculation  from  published  analyses  of  similar  food  materials,  with 
or  without  occasional  supplementary  analyses  by  the  author.  The  figures 
in  the  following  columns  represent  the  daily  intake  per  man  (if  in  italics, 
per  woman)  of  protein,  fat,  and  carbohydrate.  Then  follow  tho  total 
energy  intake,  the  fractions  of  this  contributed  by  protein  and  by  fat, 
the  contributions  to  total  protein  and  total  energy  content  made  by  the 
different  classes  of  food  materials  and  other  data  that  appeared  to  be 
of  interest. 

Some  of  the  figures  have  been  taken  from  the  original  publications, 
some  have  been  obtained  through  other  authors,  as  indicated,  and  some 
have  been  calculated  by  the  writer.  Many  of  the  publications  cited  contain 
data  that  permit  of  calculations  to  fill  many  of  the  vacant  spaces  in  the 
table  but  the  labor  of  such  calculations  is  onerous,  and  seems  to  be  out  of 
proportion  to  the  value  of  tlie  results  to  be  expected. 

From  the  material  presented  in  previous  chapters,  it  is  evident  that  the 
food  consumed  must  suj)ply  energy  for  the  following  demands:  1.  the 
basal  metabolism,  2.  the  increase  in  metabolism  due  to  the  ingestion  of 
food,  3.  the  increase  in  metabolism  due  to  muscular  work,  4,  the  mainte- 


A  NORMAL  DIET 


SB5 


DIETARY  STVDIES-Continucd 


Sweden 


CawkiesVbom  •             Percent.voe  DiSTHiBunoN  or  Protein 

Percentage  Disthiblttox  of  Caloriks 

Protein 

Fat 

Mtat* 

! 

Milk  and 
Products 

Cereals 

Po- 
tatoes 

Other 
vege- 
tables 

Others 

Meat* 

Milk  and 
products 

c— '^|.^ 

Other 
vcKe- 
tablea 

Otbets 

17.3 

35.3 
32  8 

47.7 

16.8 

15.3 

17.5 

52.6 

10.6 

20.6 

16.2 

21.6 

28.1 

21.4 

37.8 

5.9 

4.6 

3.1» 

1 
14.7       18  8 

1 

1 

46.9  !     10.4 

4.2 

2.S» 

12.0 

47.0 
42.4 

31.4 

28.2 
26.2 

23.5 

42.8 

0.1  Ma 

2  9«» 
4.5»» 

9.3 

2.9 

60.3 

5.2 

8.0 

41.5 

58.2 

11.1 

9.7 

42.6 

8.0 

41.5       45.4 

54.6 

Switzerland 


13.8  I    27.2 


nance  of  body  temperature.  Variations  in  the  amounts  of  energy  required 
for  these  purposes  mean  variations  in  the  amount  of  food  required  and, 
presumably,  in  the  amount  consumed.     This  we  shall  find  to  be  the  ease. 

The  many  variables  involved  make  direct  comparison  of  the  tabulated 
figures  difficult  but  by  considering  only  one  at  a  time,  fairly  regular  rela- 
tions appear. 

Influence  of  Climate  and  Season  upon  Food  Consumption.-— It  is 
a  generally  accoi>ted  belief  that  less  food  is  required  in  summer  than 
in  winter  and  less  in  the  tropics  than  in  temperate  climates.  But  there 
are  very  few  accurate  observations  and  such  as  there  are  do  not  support 
this  belief. 

In  a  study  of  the  rations  consumed  by  a  battalion  of  French  soldiers, 
Perrier  found  an  apparently  regular  change  with  the  season.  (Table  V.) 
But  these  soldiers  were  fresh  recruits  in  October  and  Perrier  ascribed  the 
large  consumption  of  food  in  October  and  Xovember  to  this  fact.  The 
peak  came  in  N'ovember,  the  consumption  of  food  being  then  100  calories 
greater  than  in  the  following  January  and  February.  When  the  men  were 
at  camp,  June  22  to  July  11,  the  new  mode  of  life  and,  probably,  the  in- 


w 


38& 


ISIDOE  GREEXWALD 


TABLE  IV.—SYNOPSIS  OF 


Ux 

TED 

St.ates 

Authority 

Subjects 

NCMBgR  OF 

Scale                   age 
for      "Man  i weight 

Du- 
ration 

Composition  of  Food  per  Mas 

PER  DaT 

Date 

1       i    a'^ 

con- 
ver- 
sion 

equiva- 
lents'* 

01 

adult 
male 
kik)a 

days 

Calcu- 
lated 

or  ana- 
lysed 

Calcd. 

Pro- 

teih 

grams 

Fat 
grams 

Carbo- 
hydrate 
grams 

Enenry 
yield 
ca  Jo- 
nes 

1920 

Pearl 

Selected  studies  in 
American  families, 
with  average  an- 
nual    income     of 
each  group 
Mother  wage  earner 

S640 

Garm'tmakers  S724 

Laborers $1497 

Retired $1647 

1 

1 

! 
'    s 

105 

65 

472 

'J95 

2895 

7       ; 

*• 

109 
94 

81 
102 

3145 

,     6    ! 

" 

479 

3210 

5 

" 

81 

121 

420 

3095 

Clerks  (office)$193l      11 

J         2252* 

" 

92 
97 

120 

419 

312.5 

Mechanics...  $2133       8 

Teachers 82150     32 

Profess!  men  $220S;     17 

2.59*« 
620!» 

" 

113 
125 
148 

460 

3245 

" 

88 
99 

430 

438 

395 

319.5 

43j>»< 

9:« 

" 

3480 

Engineers    (profes- 
sional)  $2253 

Salesmen....  $2527 
Fanners 

5 

.. 

85 

128 

3070 

5 

~r 

121" 
3^" 

" 

90 
102 

111 
131 
113 

405 
506 
447 

29S0 

12 

" 

3W0 

Average |  116 

J 

" 

95 

31S.5 

1903 

Atwater 
(1903) 

Farmers 

Athletes 

14     i 

G 

Calcd. 

108 
181 

136 
194 

493 

3767 

23 

G 
G 

" 

506 
451 

4617 

Business  men,  stu-| 
dents •    41 

" 

124 

142 

367S 

190i 

Woods  and 

Mansfield 

Maine  lumbermen. 
"Chopping    and 

yarding" 

Average  of  all  op- 
erations  

2 

47  or  77 

i 

75.8 

11 

Calcd. 

206 

387 

563 

8140 

5 

174  or 
200 

73.1 

9.4 

" 

182 

337 

812 

6995 

1917-8 

Murlin... 

U.  S.   soldiers   in 
training      camps 
(suppaed)M2'... 

Consumed 

427 

- 

7 

Calcd. 

131 

134 

516 

3S99 

427  : 

7 

♦• 

122 

123 
136 

485 

36^?3 

Confjumed   p  1  u  s  j 
canteen  purchases     427 

7 

.. 

127 

545 

399S 

Of  these 

(consumed)" 

213 

7 

7 

" 

138 

183 
121 

527 
496 

3963 

1       .__ 

. 

•• 

129 

36S7 

1917 

Benedict, 
Miles  and 
Ileth 

Students 12           12 

1 

66.0 

3 

Anal.        97 

3097 

1S9G-7 

Atwater 

and 

Bryant 

B 

Workmen's   fami- 
lies.   New   York 
City,  children  of 
normal  weip:ht. . . 

No.  of 
children 
in  family 
10  :      3.7 

C 
C 

10 

Cakd. 

101 
92 

124 

382 

3175 

Children     below 
normal  weight, . . 

11  !      4.3 

10 

» 

95 

349 

2693 

1901-4 

Wait 

Families,     eastern 
Tennessee     chil- 
dren   of   normal 
weight 

28         2.8 

c 
c 

14 

77 

smi 

Children    below 
normal  weight. . .        10 

2.6 

14 

" 

75 

3304 

m 


**  "Man  equivalents"  multiplied  by  number  of  days. 

^  .Vrmy  rations  are  not  generally  considered  a  freely  chosen  diet  b'jt  under  the  system  in  use  at  the  training  camps  du.'ing 
the  period  of  these  studies,  the  rations  were,  within  the  limits  imposed  by  geographic  and  economic  considerations,  practically 
the  "free  choice"  of  the  mess  sergeants.  They  were  supplemented  by  individual  purchases  at  the  regimental  orchange.  Both 
sources  of  food  were  included  in  these  studies. 

"  Supplied  and  consumed  at  army  mess.    Canteen  purchases  not  included. 

"  See  page  416. 


A  KOEMAL  DIET 

DIET.UIY  ST  LADIES— Continued 

United  States 


387 


C^SmT^inOM    '  PERCKNTACBDlSTRmUTIONOrPROTTI?* 


Percentage  Distribltion  of  Calories 


Protein 

i 
1 

Fat 

1  Meat» 

i 
1 

1  Milk  am 
product 

I  Cereals 

Vegetables 

Fruit 

Meat* 

'.Milk  and 
products 

Cereals 

1 
\egetables   Sugars  ;  Fruit 

i 

15 

21 
24 

i 

14 

12 

30 
37 
36 

11 

12 

12 

32 

11 

36 

12 

40 

11 

39 
34 

12 

11 

33 

12 

33 

{ 

11 

34 
39 

i 

i 

15 

13 

37 

10 

44 

44.8 

0.3 

26.3 

27. 8» 

0.6 

43.1 

4.2 

24. 3» 

13. 8» 

11.1 

11 

45 

3.5 

u 

32 

-28T 

30.3 

14 

32 

13 

31 

14 

31 
32 

14 

46  9 

4.0 

26.4 

4.4 

5  3 

12.3 

3.0 

5  7 

2.9 

12.3  i  16.5 

13 

1 

[ 

13 

36 

47  2 

11.4 
8.3 

31.8 

tabIS 
8.3 

Fruit  ; 
1.2  ; 

■  i 

0.2  1 

27.9 

13.6 
13.6 

39.6 

tables 

7.7 

Fruit  : 
O.S     10.3 

14 

32 

46.6 

34.3 

10.8 

25.8 

38.2 

9.6 

M  !  ll-fi 

8.8 

11.7 

7.3 

71.4 

8.4 

0,3 

21.1 

6.2 

60.4 

6.6 

1 

1.3;    4  5 

9.3 

12.7 

6.8 

64.6 

14.6 

0.2 

19.7 

5.9 

57.4 

7.2 

6.9 

1.8 

»*  Chieiy  beans 


creased  exercisCj  led  to  a  consumption  of  4065  calories,  which  far  exceed- 
ed tho  maximnm  of  the  previous  winter.  During  the  year,  the  men  gained 
an  average  of  742  grams  in  weight.     It  is  probable  that  most  of  this  gain 


ISIDOE  GREENWALD 


occurred  in  tho  first  few  months  and  thus  accounts  for  the  large  food  con- 
sumption at  that  time. 

TABLE  V.—FOOD  CONSUMPTION  OF  SOLDIERS  IN  DIFFERENT  MONTHS  OF  THE  YEAR 


Month 
Subjects 

Battalion     French    recruita 
190S-1909 

Oct. 

3 
3606 

Nov. 

3789 

19 
3706 

Dec.  I  Jan. 

3765   3681 

36       37 

3819    3827 

i 

Feb. 
3695 

Mar. 
3670 

Apr. 
3648 

May 
3599 

.^.35* 

20 
3517 

July 

4065* 

13 
3609 

Aug. 

3458« 

14 
3658 

Sept. 

8 
3487 

oc. 

13 

3727 

Nor 

7 
3918 

Dec. 

Men  in  U.  S.  training  campa 
1917-1918  No.  of  studies.. 

Food  consumption 

30 
3864 

42 

3894 

77 
3545 

30 
3514 

5 
4145 

»  October  10  to  31. 

'June  1  to  17. 

•  This  period  at  camp,  June  22  to  July  11. 

♦July  12to.\ug.  12. 


During  1917  and  191 S,  a  series  of  nutritional  surveys  were  made 
in  the  training  camps  of  the  United  States  Army.  (See  Table  IV.) 
Although  they  were  not  made  upon  the  same  men  throughout  the  year,  the 
observations  were  so  numerous  and  each  made  with  so  large  a  number  of 
men,  probably  over  200,  as  to  furnish  useful  averages  for  the  present  pur- 
pose. When  the  energy  content,  in  calories,  of  the  food  consumed  per 
man  per  day  is  calculated  for  the  different  months  of  the  year,  as  in  Table 
V,  certain  seasonal  changes  become  evident.  Beginning  in  October,  1917, 
the  figures  showed  a  gradual  increase  in  food  consumption  until  it  reached 
3894  calories  in  March,  falling  to  3545  in  April.  This  level  was  con- 
tinued in  May,  June  and  July.  In  August,  there  was  a  slight  rise  but 
in  September  there  was  a  return  to  the  summer  level,  after  which  there 
was  a  rise  to  December,  1918,  at  which  time  the  observations  endecL 
The  peak  of  the  previous  years  was  passed  in  ^N^ovember  and  the 
food  consumption  in  October,  IN'ovember  and  December  was,  respectively, 
121,  212  and  326  calories  gi-eater  than  in  the  corresponding  months  of 
the  previous  year.  Attempts  to  correlate  the  cui*ve  of  food  consimiption 
with  variations  in  local  temperature,  wind  velocity,  humidity,  etc.,  were 
not  successful.  It  would  seem  more  likely  that  the  higher  consumption  of 
food  in  the  winter  was  due  to  the  gi*eater  muscular  activity  of  the  men. 
There  is,  moreover,  another  factor  of  possibly  even  greater  importance; 
Practically  all  the  men  in  training  gained  weight.  If  this  gain  did  not 
occur  in  summer  or  was  then  much  smaller  than  in  winter,  this  differ- 
ence alone  would  account  for  the  differences  in  food  consumption.  The 
effect  of  the  armistice  in  modifying  the  attitude  of  the  men  in  regard  to 
the  conservation  of  food  may  help  to  account  for  the  larger  food  consump- 
tion during  the  last  two  months. 

According  to  Eijkman(&)  (1897),  the  basal  metabolism  of  Europeans 
in  Java  was  not  lower  than  in  Europe  and  Dutch  physicians  there  ato 


A  XOEMAL  DIET  389 

as  much  food  as  men  of  similar  occupation  in  Holland.  Similarly,  Eanke, 
in  ^lunicli,  found  that  he  required  as  much  food  to  maintain  hi^  body 
weifjht  in  summer  as  he  did  in  winter. 

The  explanation  of  this  uniformity  of  food  consumption  over  a  wide 
range  of  external  temperature?  appears  quite  obvious.  Except  under  very 
unusual  circumstances,  man  selects  his  clothing  so  as  to  keep  the  tempera- 
ture of  most  of  the  body  surface  at  about  30"  C.  If  the  customary  activ- 
ities of  the  individual  involve  a  heat  production  w^hich  is  too  great  to  be 
dissipated  with  maintenance  of  surface  temperature  at  30°,  the  individual 
may,  and  generally  does,  diminish  his  food  consumption  but  only  at  the 
cost  of  loss  of  body  substance  or  ability  to  do  work.  Thus  Ranke,  in 
the  experiment  above  referred  to,  found  that,  of  free  choice,  he 
would  have  consumed  400  calories  less  per  day  during  the  summer  but 
that  he  then  lost  weight  which,  for  the  purpose  of  the  experiment,  was  to 
be  kept  constant.  He  accordingly  ate  enough  to  maintain  his  body  weight 
but  experienced  increasing  discomfort  until,  at  the  end  of  the  month, 
there  was  a  definite  gastro-intestinal  disturbance  and,  apparently,  an 
increased  susceptibility  to  infection.  It  is  important  to  remember,  in  this 
connection,  that  the  average  temperature  of  the  room  in  w^hich  Ranke  spent 
most  of  his  time  was  21.0°  C.  in  summer  and  18,0^  C.  in  winter.  The 
humidity  is  not  stated  but  was  probably  lower  in  w^inter  than  in  summer, 
so  that  the  cooling  effect  of  the  air  was  greater  in  winter  than  in  summer. 
Moreover,  when  indoors,  Ranke  wore  the  same  clothing  in  summer  as  in 
winter,  so  that  it  seems  quite  likely  that  the  dissipation  of  heat  was  inter- 
fered with  and  that  this  led  to  the  disturbances  he  noted. 

If  external  conditions,  such  as  temperature  and  humidity,  do  not 
permit  the  removal  of  the  heat  produced  in  ordinary  metabolism,  the 
temperature  of  the  body  is  raised,  the  basal  metabolism  is  raised  and  may 
thus  be  even  greater  in  w^arm  weather  than  in  moderate  (Young). 

It  is  quite  possible  that  the  inability  to  maintain  a  high  metabolism 
in  warm  weather  and  in  the  tropics  is  responsible  for  the  indolence  and 
lack  of  energy  displayed  by  man  under  those  conditions. 

With  very  low  external  temperatures,  on  the  otlier  hand,  the  heat  pro- 
duced in  metabolism  may  not  be  sufficient  to  cover  the  heat  loss,  even 
though  this  be  reduced  to  a  minimum  by  means  of  much  clothing.  The 
feeling  of  cold  is  experienced  and  muscular  activity  is  increased  (shiver- 
ing), with  consequent  increase  in  the  production  of  heat.  With  short 
periods  of  exposure,  shivering  may  not  appear  and,  in  such  cases,  as 
found  by  Eijkman(c?)  (1897),  metabolism  is  the  same  at  from  6°  to  12° 
C.  as  at  24.5°  C.  though  the  clothing  be  light  and  the  subjects  complain 
of  cold  at  the  lower  temperature.  There  may  be  some  direct  stimulating 
effect  of  cold  upon  metabolism  (see  discussion  in  Tigerstedt(^),  1919,  Vol. 
I,  page  168),  but  such  action  must,  ordinarily,  play  a  very  inconsiderable 
part. 


390  ISIDOE  GREEjS'WALD 

The  effects  of  season  and  of  climate  upon  the  energy  content  of  the 
food  may  therefore  be  neglected  except  as  they  may  affect  the  body  weight 
or  conduce  to,  or  be  unfavorable  to,  muscular  activity. 

Relation  of  Body  Weight  to  Food  Consumption. — The  basal  metabol- 
ism is  roughly  proportional  to  the  body  weight  (Harris  and  Benedict) 
and,  consequently,  so  is  the  energy  content  of  the  quota  of  food  needed  to 
satisfy  this  requirement. 

The  increase  in  metabolism  due  to  the  ingestion  of  food  depends  upon 
the  amount  and  nature  of  the  food  consumed,  the  nature  of  the  individual 
and  upon  other  factors  which  seem  to  make  it  vary  from  time  to  time  in 
the  same  individual  with  the  same  kind  of  foo<l  (Benedict  and  Carpenter). 
But  this  constitutes  only  a  small  part  of  the  total  metabolism  and  may 
therefore  also  be  considered  as  proportional  to  the  body  weight. 

The  same  relation  holds  for  the  amount  of  energy  required  to  move 
the  body  about.  That  required  to  supply  energy  for  external  work  varies 
wdth  the  nature  and  amount  of  the  work  to  be  perfonned  and  with  the 
muscular  efficiency  of  the  individual.  But  it  is  probable  that,  as  a  rule, 
in  occupations  involving  much  muscular  work,  the  individual  weighing 
considerably  less  than  70  kilos  (154  pounds)  will  do  less  than  one  of  that, 
or  slightly  greater,  weight 

Except  in  the  case  of  individuals  of  unusual  body  form,  the  total 
metabolism  and,  consequently,  the  food  requirements  of  adults  leading 
about  the  same  kind  of  life  may,  therefore,  be  expected  to  be  propor- 
tional to  the  body,  weight.  With  much  greater  body  weights,  the  propor- 
tionality can  no  longer  be  expected  to  hold  for  an  ever  increasing  part  of 
the  weight  is  contributed  by  the  comparatively  inactive  adipose  tissue. 
And  this,  in  truth,  is  usually  found  to  be  the  case.  Selecting  from  Table 
IV,  groups  within  wdiich  other  factors  may  be  considered  to  be  relatively 
constant  and  consulting  the  original  publications  for  the  data,  we  obtain 
the  following  figures  for  the  food  consumption  in  calories  per  kilo  of  body 
weight: 

Demuth,  3  pensioners,  light  work,  47,  46,  41  Average  45 

Yukawa,    Japanese   celibate    monks,    young,    no 

work,  36.5,  50.0,  41.6,  39.0,  36.3,  40.1,  23.9, 

34.1, 

old,  no  work,  37.9,  35.6,  35.0 
Eijkman   (1893),  European  physicians,  etc.,  in 

Java,  32.2,  38.7,  32.0,  44.9,  36.6,  30.5,  31.5, 

33.3 
Eijkman,  Malay  laboratory  servants,  49.6,  41.7, 

55.4,  55.8 
Hultgren  and  LandergTen,  Swedish  students,  40.9, 

48.4,  44.2,  38.1,  46.8 


<( 

37.7 

« 

36.2 

a 

35.0 

u 

50.6 

a 

43.7 

A  NOKMAL  DIET  391: 

Within  any  one  group,  the  energy  content  of  the  food  consumed  is 
almost  as  proportional  to  the  body  weight  as  the  basal  metabolism  is  found 
to  be  (Harris  and  Benedict).  The  factors,  such  as  varying  body  form, 
differences  in  activity  of  endocrin  glands,  that  account  for  the  latter  will, 
probably,  also  exphiin  the  latter.  The  effect  of  variations  in  body  weight 
in  the  same  individiuil  upon  the  amount  of  food  required  to  maintain  a 
particular  body  weight  will  be  considered  later.     (Page  414.) 

Influence  of  Work. — lieference  has  been  made  to  the  variations  in 
energy  requirement  with  differences  in  the  amount  of  muscular  work 
performed.  The  amount  of  energy  expended  in  a  given  task  or  occupation 
by  different  individuals  has  been  measured  in  several  instances  but  the 
results  are  rather  conflicting.  Much  depends  upon  the  previous  training 
and  experience  of  the  individual,  but  even  with  individuals  of  similar  his- 
tory, the  amount  of  energy  expended  in  the  same  occupation  varies  tremen- 
dously (Becker  and  Hamiilainen,  Lusk(/i),  1917,  Sherman (c),  1918,  Ben- 
edict audCathcart  andWallerand  associates(a)  (b)  (c) ).  To  a  considerable 
extent,  this  variation  is  probably  due  to  differences  in  the  amount  of  work 
accomplished,  but  other  factors  may  also  play  a  part.  ^Nevertheless,  it  still 
remains  true  that  typesetters  and  cobblers  do  less  work  than  machin- 
ists and  that  business  and  professional  men  do  not  use  their  muscles  as 
much  as  farmers  or  laborers.  And,  consequently,  men  whose  occu- 
pations involve  muscular  exercise  do  not  usually  eat  so  much  as  do 
those  who  do  much  physical  work.  In  some  of  the  obsei-vations  con- 
solidated in  Table  IV,  this  fact  may  be  obscured  by  three  other  factors. 
Of  these,  the  influence  of  body  weight  has  already  been  discussed.  Of 
possibly  equal  significance  is  the  fact  that  the  reports  are  not  only  for 
individuals  but  for  groups  and  families.  The  very  large  food  consump- 
tion of  a  laborer  doing  hard  work  may  no  longer  be  so  apparent  when  the 
only  report  is  that  for  the  food  consumption  of  the  family.  It  may  be  that 
the  family  of  a  man  who  is  engaged  in  hard  work  will  be  similarly  more 
active  but  it  certainly  is  not  always  the  case.  (See  also  discussion  of  Sund- 
strom^s  results,  pages  367-3G9.) 

The  influence  of  mental  work  upon  food  intake  may  be  neglected. 
There  is  no  evidence  that  mental  work,  even  of  the  most  fatiguing  nature, 
appreciably  aft'ects  the  amount  of  metabolism.  Starling(5)  (1919)  has 
suggested  that  mental  work,  while  not  requiring  much  energy,  may  require 
that  to  be  supplied  at  a  high  pressure.  This  would  justify  a  liberal  pro- 
tein and  energy  allowance  in  the  food  of  brain  workers. 

Influeyue  of  Eco7iomic  Status. — Last,  but  not  least,  is  the  economic 
factor.  Beginning  with  Engel's  figures  and  proceeding  down  the  table, 
one  can  see  that  in  every  instance  in  which  infonnation  as  to  income  is 
included,  except  for  one  or  two  in  the  summary  by  Pearl,  food  con- 
sumption increases  with  increase  in  income.     It  is  important  to  remembe: 


302  ISIDOE  GREEXWALD 

this  and  to  note  that  evoii  in  the  neediest  families  studied,  tho  energy 
content  of  tlio  food  does  not  fall  below  al)OUt  2500  calorics  per  man  per 
day,  except  in  the  case  of  those  of  low  body  weight,  such  as  the  Italians 
studied  by  Manf  redi  or  the  Japanese  and  Malays  studied  by  others. 

Amount  of  Protein. — The  character  of  the  food  and,  consequently,  the 
relative  importance  of  protein,  fat  and  carbohydrate  in  making  up  the  total 
energy  content  of  the  diet  varies  considerably  with  different  peoples  and 
different  circumstances.  But  there  are  some  quite  evident  uniformities 
and  comparisons.  Except  in  the  most  needy  families,  the  protein  content 
of  the  food  anywhere  in  the  world  does  not  fall  appreciably  below  one  gram 
per  kilo  or  70  gTams  for  the  man  of  average  weight  in  northern  Europe  and 
in  the  United  States  and  it  is  generally  as  much  as  1.3  to  1.5  grams  per 
kilo,  or  100  grams  per  man.  The  fraction  of  the  total  energy  contributed 
by  protein  vaiies  from  8.5  per  cent  in  some  Oriental  diets  and  in  those 
of  some  of  the  poorer  classes  in  Europe  to  as  much  as  18  or  19  per  cent 
in  some  of  the  Swedish  and  Finnish  diets  and  even  to  32  per  cent  in  the 
case  of  the  fishers  at  the  mouth  of  the  Volga  who  probably  subsist  largely 
upon  fish  and  to  44  per  cent  among  the  Esquimaux  (Krogh).  But  except 
for  people  under  such  unusual  circumstances,  the  protein  rarely  contributes 
over  18  per  cent  and  generally  only  from  12  to  15  per  cent  of  tlie  total 
energy.     This  comparatively  narrow  range  is  worthy  of  note. 

ijjfect  of  Wo7*h. — ^len  at  hard  work  eat  more  protein  than  do  those  not 
so  engaged,  but,  apparently,  this  is  due  entirely  to  the  greater  consumption 
of  food  and  not  to  a  specific  demand  for  protein  or  foods  rich  in  protein. 
The  fraction  of  the  energy  contributed  by  protein  to  the  diet  of  men  at  hard 
work  is  frequently  less  than  in  the  case  of  others  of  similar  economic  status 
and  engaged  at  lighter  work.  This  is  most  strikingly  illustrated  in  the  case 
of  the  diet  of  the  Maine  lumbermen  in  w^iich  the  protein  contributed  only 
10.5  per  cent  of  the  calories,  a  smaller  proportion  than  was  reported  for 
any  other  group  in  the  United  States,  except  for  some  from  the  southern 
states.  Similarly,  the  diet  of  lumbermen  in  the  north  of  Sweden  con- 
tained less  than  10  per  cent  of  the  calories  in  the  form  of  protein  (only 
8  per  cent  in  the  case  of  the  man  whose  total  was  9292,  and  7.4  per 
cent  for  the  two  men  wdiose  average  was  8439),  whereas  Hultgren  and 
Landergren  reported  16  per  cent  for  Swedish  working  men  and  Sundstrom 
15  to  IC  per  cent  for  the-Finni-rh  ain'icultural  population. 

Effect  of  Economic  Status. — The  amount  of  protein  consumed  is  gen- 
erally lowest  with  those  of  smallest  income  and  grows  larger  with  increas- 
m^  income.  But  this  increase  is  not  indefinite  and  probably  the  total 
rarely  goes  above  160  gi-ams  or  2.3  gTams  per  kilo.  The  relative  impor- 
tance of  pioteiu  as  a  contributor  of  energy  may,  however,  be  slightly  gi-eater 
among  the  poor  than  among  those  of  slightly  greater  inccme.  A  gi-eater 
share  of  the  necessary  economy  in  food  is  attained  at  the  expense  of  the 
fat.     At  the  other  end  of  the  range  of  incomes,  the  proportion  of  enc7"g}' 


A  ]\^OEMAL  DIET  3^5 

contributed  by  protein  is  apt  to  be  sliglitly  lowered  by  tbe  increasing  con- 
sumption of  sugars  and  fats. 

Amount  of  Fat. — The  amount  of  fat  consumed  varies  with  the  coimtry, 
economic  status,  occupation  and  tbe  time.  Japanese  diets  seem  to  contain 
the  least  fat  of  any  that  have  been  studied,  the  maximum  in  the  really 
native  diets  being  about  30  grams,  which  is,  or  was,  the  recent  European 
minimum.  The  fat  consumption  is  also  much  k)wer  in  Italy,  particularly 
among  the  laboring  classes,  than  in  northern  Europe.  Probably,  this  low 
fat  consumption  is,  in  both  Italy  and  Japan,  due  to  the  general  operation 
of  the  next  factor  to  be  considered,  the  economic. 

In  every  series  in  which  data  are  available  beginning  w^ith  Eng-el's  of 
1853,  the  amount  of  fat  eaten  increases  regularly  with  the  income.  There 
are  a  few  slight  deviations  from  this  rule  in  the  series  reported  by  Pearl 
and  in  the  Scotch  families  of  Lindsay  but  the  number  of  observations  in- 
cluded in  these  exceptional  cases  is  rather  small.  In  Pearl's  series  fat 
constitutes  37  per  cent  of  the  caloi'ies  in  the  diets  of  the  professional  men. 
There  is  one  group  (salesmen)  of  higher  income  ($300  or  14  per  cent 
more)  in  which  fat  contributed  only  34  per  cent  of  the  calories  but  there 
are  only  five  studies  included  in  this  gi*oup.  In  Lindsay's  series,  fat 
plays  a  slightly  gTcater  part  in  the  diets  of  the  families  with  income  under 
20s  than  it  does  in  those  of  families  with  an  income  of  from  20  to  25s, 
and  as  great  a  pail;  as  in  the  group  with  an  income  of  from  27  to  31s, 
but  the  number  of  studies  in  these  groups  is  only  5,  10  and  3,  respectively. 

The  largest  amount  of  fat  is  found  in  the  diet  of  American  and 
Swedish  lumbermen,  which,  in  one  case,  contained  as  much  as  523  gi'ams 
fat,  furnishing  58  per  cent  of  the  calories.  American  athletes  and  Fin-, 
nish  students  come  next  with  194  and  191  grams,  furnishing  39  and  45 
per  cent  of  the  total  calories.  In  general,  the  amount  and  relative  im- 
portance of  fat  in  the  diet  increases  with  the  total  food  intake,  though 
in  the  diets  of  sedentary  jxjrsons  with  ample  income,  the  effect  of  the  in- 
come may  outweigh  that  of  the  energy  intake  as  is  illustrated  in  Eanke's 
and  Xeumann's  observations  on  themselves  (42  per  cent  and  from  34  to 
66  percent,  respectively). 

During  the  fifty  years  immediately  preceding  the  World  War,  there 
seems  to  have  been  a  general  increase  in  the  amount  of  fat  consumed,  at 
least  in  several  countries.  Thus,  Engel  estimated  the  fat  consumption  in 
families  wdiose  income  permitted  saving  to  be  30  grams  i>er  man  per  day  in 
1853*,  but  in  1899  found  it  to  be  not  less  than  5G  grams  in  any  group 
studied.  The  averages  for  all  families  were  2S.5  grams  in  1853  and  74.9 
in  1801.  In  1008,  Slosse  and  van  der  Weyer  found  74  grams  to  be  the 
minimum  in  33  studies  of  the  diet  of  Belgian  workinginen  and  Slosse  and 
Waxweiler  found  that  in  only  ten  out  of  1065  Belgiaii  workingmen's  fam- 
ilies was  it  less  than  35  grams  and  in  only  132  was  it  less  than  60  gi-ams. 
Similarly,  Lichtenfelt  estimated  the  fat  cousum]>tion  in  Germany  in  1894 


394  ISIDOK  GREEI^WALD 

to  be  94  grams  per  man  per  day,  whereas  Claassen,  in  1 907,  estimated  it  as 
141  grams  (digestible)  for  tiie  urban  and  195  grams  for  the  rural  popula- 
tion. The  Eltzbacher  commission  phiced  it  at  139  grams  for  the  popula- 
tion as  a  whole  in  1912-1913.  The  series  of  reports  from  English  cities 
confi nn  this  tendency,  thouirh  the  number  of  observations  is  rather  small. 
Thus  in  1900,  Paton,  Dunlop  and  Inglis  found  that  Edinburgh  families 
with  incomes  of  less  than  20s  used  an  average  of  9G  grams  of  fat  per  man 
per  day;  those  with  ample  income  used  92.3  grams.  In  Glasgow  in 
1911-1912,  Lindsay  found  76.3  grams  in  families  with  less  than  203  in- 
come and  98  gi'ams  in  those  with  an  income  of  from  27  to  3l3.  In  1916, 
also  in  Glasgow,  Ferguson  found  it  at  the  same  level,  though  the  wartime 
restrictions  on  the  use  of  fat  might  have  been  expected  to  reduce  the  figure. 
The  high  value,  88  grams,  calculated  by  Dunluce  and  Greenwood  from 
Eowntree's  reports  for  York  families  with  incomes  of  less  than  26s  weekly 
seems  to  be  due  to  some  local  factor.  It  is  greater  than  that  reported  for 
similar  families  in  Edinburgh  or  Glasgow  and  much  greater  than  that 
calculated  by  Dunluce  and  Greenwood  from  the  Board  of  Trade  returns 
for  a  large  number  of  cities  in  Great  Britain.  It  is  interesting  to  note 
that  the  northern  counties  reported  a  higher  fat  consumption  among  the 
agricultural  laborers  than  did  the  other  counties  of  England.  Within 
Rowntree's  series,  the  usual  economic  effect  is  observed. 

The  amount  of  protein  and  of  fat  and  their  contribution  to  the  total 
energy  of  the  diet  having  been  discussed,  little  remains  to  be  said  regarding 
the  carbohydrate,  save  that  it  furnishes  the  remainder  of  the  energ}%  from 
400  to  600  grams  per  man  per  day  being  required.  The  increasing  con- 
sumption of  cane  sugar  is  discussed  on  pages  395  and  397. 

Ash  Constituents. — Comparatively  few  studies  of  normal  or  customary 
diets  have  included  determinations  or  calculations  of  the  amount  of  the 
inorganic  constituents.  Tigerstedt(e)  (1911)  had  the  samples  collected 
by  Sundstrom(?>)  (1908)  in  his  study  of  the  diet  of  the  Finnish  agi'icul- 
tural  population  analyzed  for  some  of  the  ash  constituents  with  results 
sho\\Ti  in  the  first  part  of  Table  TV..  The  figures  following  were 
calculated  to  European  body  weights  from  Japanese  diets  by  Rubner 
(hb)  (1920).  These  are  followed  by  those  obtained  by  Xelson  and 
Williams  in  a  study  of  the  calcium  content  of  the  urine  and  fecea  of 
four  normal  men  (U.  S.)  on  their  accustomed  diets.  Then  come  the 
figures  calculated  by  Sherman(c)  (1918)  for  150  supposedly  typical 
American  dietaries,  and,  finally,  those  calculated  by  Blathervvick  for  32 
studies  in  army  training  camps  and  by  Howe  (reported  by  Blatherwick) 
for  four  others.  The  enoinnous  difference  between  the  calcium  and  phos- 
phorus contents  of  the  Finnish  and  the  American  and  the  Japanese  diet- 
aries is  due  to  the  great  difference  in  the  amount  of  milk  consumed.  (See 
also  page  415,  for  Rubner's  calculation  of  inorganic  food  constituents  in 
Gei-many  before  and  during  the  war.) 


A  NORMAL  DIET  395 

Many  investiprators  have  observed  and  calculated  tlie  contributions 
made  by  animal  and  vegetable  material  to  the  total  food.  Particular  im- 
portance has  been  attached  to  the  content  of  animal  protein,  which  has 
been  regarded  as  far  superior  to  vegetable  protein.  More  recent  investiga- 
tion has  indicated  diat  this  distinction  is  not  altogether  justified.  It  is 
true  that  animal  proteins  are,  as  a  class,  rather  more  etr'f-ctive  as  builders 
of  body  protein  than  are  vegetable  proteins  but  there  are  marked  excep- 
tions. Thus  gelatin  is  the  classic  example  of  an  incomplete  protein  where- 
as the  protein  of  the  jxjtato  is  one  of  the  most  efficient  (Iliudhede(c)  1013, 
Eosc  and  Cooper).  Isolated  plant  proteins  such  as  gliadine  or  zein  may  be 
very  inadequate  but  the  mixed  proteins  of  wheat  or  of  maize,  as  found 
in  flour  or  meal,  will  maintain  nitrogen  equilibrium  at  a  fairly  low  level, 
particularly  if  the  whole  gi^ain  be  used  or  if  it  be  supplemented  by  a  small 
quantity  of  other  proteins  such  as  those  in  milk.  In  any  mixed  dietary, 
even  if  wholly  of  plant  origin,  the  proteins  are  almost  sure  to  be  suffi- 
ciently varied  to  compensate  for  any  individual  inadequacies  if  only 
the  total  amount  of  protein  be  sufficient.  Therefore,  no  attempt  has  been 
made  to  indicate  in  Table  IV  the  quantity  of  animal  protein  consumed. 
However,  in  many  cases,  that  can  be  calculated  from  the  figures  given  for 
protein  from  meat  and  from  milk  and  its  products. 

But  the  source  of  the  protein,  while  of  itself  of  not  so  gTcat  significance, 
is  important  as  an  indication  of  the  amounts  of  those  little  kno\vn  sub- 
stances, variously  denoted  food  accessories,  food  hormones,  protective  sub- 
stances or  vitamines,  that  may  be  present.  Some  idea  of  the  inorganic  con- 
tent of  the  food  may  also  be  obtained  in  this  manner.  For  this  reason, 
there  have  been  included  in  Table  IV,  where  the  data  were  available  or 
could  readily  be  calculated,  the  contributions  made  to  total  protein  and,  in 
some  cases,  to  total  energy  also,  by  each  of  the  classes  of  food  materials,  as 
was  done  in  Table  III.  The  same  differences  that  were  evident  in  Tables 
II  and  III  also  appear  in  Table  IV.  In  addition,  there  are  differences 
due  to  occupation,  economic  status,  etc.,  most  of  which  have  already  been 
discussed. 

In  all  regions  and  at  all  times,  man  seems  to  have  sought  and  found 
some  beverage,  otlier  than  water,  to  use  with  his  meals.  Meat,  ale,  milk, 
(sweet  and  fermented),  wine,  coffee,  tea,  cocoa  and  many  others  have 
been  used.  Particularly  striking  is  the  use  of  four  plants  of  widely  dif- 
ferent botanical  nature  but  all  containing  caffein  or  a  related  substance. 

Changes  in  Food  Habits  within  Recent  Times. — The  introduction 
of  new  foods  as  a  result  of  the  importation  of  new  species,  the  im- 
provement of  old,  or  the  development  of  transportation  may  greatly 
modify  the  food  habits  of  a  people.  Maize  and  potatoes,  unkno^vii 
before  the  discovery  of  America,  are  to-day  two  of  the  staple  crops  of 
Europe  and  are  fundamental  to  the  economy  of  several  countries.  The 
improvement  of  the  sugar  beet  has  helped  to  lower  the  price  of  sugar  and, 


39G 


ISIDOR  GREEXWALD 


TABLE  VI.— .ASH  CONSIITUENTS  OF  ORDINARY  DIETS 


FissiSA  AGRicuLTtJ.x\L  PoPCLATio.v,  WoMs.v.  25  Ofl3ERAATio.v3  o.v  21  Pkrsons,  7  Days  E.vch,  ANALTitED.     (Sundntrom  I90S) 


SrBSTANCE                                            Per  Woman  per  Dat 

Per  3000  Calories 

t    Minimum    \    Maximum 
i      Grams      j      Granu 
"tilcmm '        1.13        j        3.86 

Average 
Grams 
2.28 
0.66 

Minimum 

Grams 

1.50 

Maximum 
Grams 
4.17 

Average 
Grams 
2  79 

Magnesium i        0.21                 1.14 

0.50 

1.11 
4.54 

0  84 

Phosphorus 1  69                4  25 

2.76 

2.52 

3.34 

Rest ;      15.44              43.48 

1 

27.75 

Finnish  AoRiccLTfR.\L  Po?i:u\TioN-.  Me.v.  14  Observations  ox  H  Persons,  7  Days  Each,  Analyzed.    {Sundsinm  1908) 


Substance 

Per  Man  per  Day 

Per  3000  Calories 

Calcium 

Minimum    j   Maximum 

Grams            Grams 

1.92                9  85 

Average 
Grams 
3.79 

Minimum 

Grams 

1.68 

Maximum 
Grams 
5.13 

Average 
Grams 
3  06 

Magnesium 

0.73                1.39 

1.09 

0.69 

1.02 

085 

Phosphorus 

2.79        1        6.00 

4.32 

2.05 

4.21 

3  37 

Rest 

2S92 

62.79 

42.26 

Japanese  Diets,  Calcclated  to  Ecropean  Body  Weights  by  Rcbner  (1920) 


Substance 

Minimum 
Grams 

Maximum 
Grams 

Average 
Grams 

Calcium 

0.281 

Magnesium 

0.414 

Rjosphorus 

2.12 

Potassium 

2.81 

Four  American  Men.  Six  Studies  of  Fm:  Days  Each,  Analyzed.     {NeUon  and  WUlUnnt) 


Substance 

Minimum 
Grams 

Maximum 
Grams 

Average 
Grams 

0.676 

1.016 

0.852 

ly)  .AiiERiCAN  Dietaries,  Calculated.    (Sherman,  1918-B) 


SUBSTANCR 

Per  Man  per  Day 

Per  3000  Calories 

Calcium 

Minimum 
Grams 
0.24 

Maximum 

Grams 

1.87 

Average 
Grams 
0.73 

Minimum 
Grams 
0.35 

Maximum 

Grama 

1.47 

Average 
Grams 
0  73 

Magnesium 

0.14 

0.67 

0.34 

0.17 

0.53 

0.34 

Potasfflum 

1.43        1        6.34 

3.39 

1.63 

5.27 
4.83 

340 

Sodium* 

0.19 

4.61 

1.94 

0.22 

1.95 

Phosphorus 

0.60 

2.79 

1.58 

0.72 

2.30 

1.59 

Chlorin* 

0.88 

5  83 

2.83 

0.83 

7.26 

2.88 

Sulfur 

0.51 

2.82 

12.8 

0.80 

2.35 

1.30 

Iron . .              

0.0080 

0.0307 

0.0173 

0.0090 

0.0234 

0.0174 

Does  not  include  salt  added  to  food.    Consequently  is  much  too  low. 


A  XOILMAL  DIET 


SO* 


T.UJLE  n.-ASH  CONSTITUENTS  OF  ORDINARY  DIETS 


32  Akmt  Organizations  is 

Tkaixinq  Camfs,  Cautcuvted. 

(Blathertdek) 

SCBSTAXCE 

Minimum 

1   Maximum 

Average     i 

1 

Calcium 

0.374 
1  510 

1.060 

0.711 

Phosphorus 

2.S^t5 

2  171 

0.020.] 

0  0494 

■ 

FOIR  IXFAXTRY  Co.MPAMES  OF  SaME   ReGIMEXT  AT  CaMP  CoDT  DCRIXQ  SaME  PeKIOD  OP  7  DaT5 

Calcclated  by  Howe.  Published  by  Buatherwick 

Substance  , 

Minimum 
Grams 

Maximum 
Grams 

Average 
Grama 

Calciuin 

0.416 

0542 

0.493 

Phosphorus 

1.662 
0.0210 

!        1.801 

1.731 

Iron         .       .                     .       

0.0221 

0.0216 

• 

in  that  way,  has  helped  make  what  was  formerly  a  luxury,  a  relatively 
cheap  and  common  food.  The  consumptiou  of  sugar  within  the  last 
century  increased  tremendously  throughout  tlie  western  world,  though 
some  countries  consumed  more  than  othei*s.  The  United  States  appears  to 
lead  the  world  in  the  per  capita  consumption  of  sugar,  with  Great  Britain 
a  close  second.  Whether  or  not  this  large  consumption  of  sugar  is  de- 
sirable or  not  is  still  a  moot  question. 

As  one  result  of  freeing  populations  from  dependence  upon  local 
sources  of  supply,  the  development  of  transportation  and  refrigeration 
lias  helped  to  change  the  character  of  the  food,  particularly  in  making 
fresh  foods  available  throughout  the  year  and  in  giving  the  rest  of  the 
world  access  to  the  products  of  tropical  and  semi-tropical  countries. 

But  these  beneficial  effects  have  been  very  largely  confined  to  the  cities 
and  towns.  In  rural  regions,  the  same  causes  seem  to  have  led  to  less  de- 
sirable changes.  Instead  of  diversified  farming,  the  tendency  has  been  to- 
wards a  "one  crop"  or  *^cash  cro])"  agTiculture.  Fnder  such  a  system  the 
farmer  no  longer  raises  much  of  his  own  food  but  has  only  one  crop  which 
lie  sells  for  cash,  with  which  he  buys  his  food.  He  buys  the  purified,  staple 
and  stable  foodstuffs  and  loses  many  valuable  food  constituents.  The  de- 
velopment of  transportation  and  industry  has  not  yet  made  it  possible  fcwr 
him  to  buy,  in  addition  to  the  staple  foods,  the  fresh  vegetables,  etc.,  that 
ho  also  needs- ,  Souietimes,  too,  ignorant  of  the  true  values  of  foods,  he  may 
sell  his  own  product  to  copy,  through  the  village  store;  the  habits  of  the 
city.  To  quote  from  Rubnerf  7)  (1913)  :  "I  have  noticed  a  very  unfavor- 
able influence  of  urban  food  requirements  on  the  milk-producing  districts  of 
some  regions  of  Switzerland,  Gei'inany,  which  is  so  characteristic  that  it 
deserves  consideration.  The  milk-producing  regions  of  the  Bavarian 
highlands  and  of  Switzerland  had  formerly  an  extremely,  healthy,  strong 


398  ISIDOR  GREENWALD 

and  temperate  population.  Milk  was  largely  used  as  a  food,  and  the  ex- 
cess of  production  was  placed  on  the  market.  In  the  course  of  years  the 
communities  gradually  established  central  creameries  in  which  the  fat  is 
withdrawn  from  the  milk  by  means  of  centrifugal  machines  to  produce 
cream  and  Initter.  The  impoverished  milk  is  partly  returned  to  the  farm- 
ers. The  milk  producers  are  paid  in  cash  for  their  product,  but  a  poor 
and  insufficient  food  now  takes  the  place  of  a  former  healthy  one.  The 
money  now  goes  to  the  saloons.  The  potato  conquers  a  new  territory.  In- 
stead of  the  butter  which  was  formerly  used,  cheap  fats  are  now  bought; 
in  short,  the  change  in  diet  is  exactly  such  as  we  find  with  the  poorer 
working  jKipnlation  in  the  cities.  The  eflfects  are  exactly  the  same.  Physi- 
cal deterioration  in  such  districts  becomes  more  and  more  pronounced, 
reaching  finally  a  low  level.  This  is  a  very  serious  condition,  which  at- 
tracts attention  and  which  must  be  combated  by  all  possible  means." 

A  similar  effect  seems  to  have  been  produced,  in  a  rather  different 
manner,  in  our  own  southern  states.  Formerly  the  corn  was  ground  in 
small  mills  and  all  of  it  was  used.  'Now  much  of  it  is  sold  for  cash  and 
•^new  process"  or  degerminated  meal  is  purchased.  It  is  quite  possible  that 
the  present  high  freight  rates  will  have  one  good  result  in  encouraging 
diversified  farming  and  the  home  pi'oduction  of  more  of  the  necessary 
food. 

Indirectly,  the  improvement  of  transportation  and  the  development 
of  industiy  as  a  whole  have  helped  to  change  food  habits  because  of  the 
improvement  in  economic  condition.  It  is  to  this  that  we  must  ascribe 
the  increased  consumption  of  meat  and  fat  in  Germany  and  Belgium,  and 
the  gradual  change  from  rye  to  wheat  bread.  The  tendency  to  copy  the 
diet  of  the  wealthier  classes  is  everywhere  marked.  The  nature  of  this 
diet  is  determined  largely  by  taste  and  fashion.  The  wealthier  can,  and 
do,  secure  for  themselves  the  foods  which  have  the  more  agreeable  taste, 
and  others,  as  soon  as  they  can  afford  them,  also  wish  to  secure  these 
foods  for  themselves.  But  taste  will  not  alone  explain  the  relative  order 
of  esteem  in  which  foods  are  held.  At  one  time  shad,  oysters  and  lobsters 
were  so  plentiful  along  the  eastern  coast  of  the  United  States  as  to  be 
despised.  To-day,  they  are  delicacies.  Diminishing  supply  may  be  re- 
sponsible for  this  but  not  for  all  similar  instances.  !N"ot  all  rare  edible 
articles  are  highly  esteemed  fo'xls.  Nightingale  tongues  and  peacock 
breast  are  no  longer  prized  as  they  were  in  imperial  Rome.  Again,  it  is 
not  so  many  years  ago  since  calf  thvinus  glands  could  bq  had  at  New 
York  slaughter  houses  for  the  asking.  To-day  they  are  the  expensive 
sweetbreads.  That  complex  of  varying  influences  that  we  call  fashion  has 
helped  detemiine  man's  food  habits  as  it  has  his  other  social  practices. 
(See  also  Fairchild.) 

Canned  foods,  w^hile  adding  tremendously  to  the  variety  of  foods  avail- 
able, have,  to  the  extent  that  they  have  replaced  fresh  food,  tended  to  re- 


A  NOEMAL  DIET  399 

duce  tlio  narrow  margin  of  intake  over  requirement  of  protective  sub- 
stances or  vitaniines. 

A  factor  of  considerable  importance  is  the  eifect  of  advertising  in  ac- 
celerating and  initiating  changes  in  the  character  of  the  foods  employed. 
The  sales  of  s|KXMfic  articles  of  food  can  bo  as  greatly  stimulated  as  can 
those  of  any  other  commodity.  Some  of  this  advertising  may  be  of  quire 
a  misleading  character,  even  though  the  specific  statements  be  absolutely 
true.  Thus,  butter  substitutes  are  advertised  as  ^^purely  vegetable'^  or  as 
containing  only  vegetable  fats,  as  if  this  were  an  advantage  when  it  is  ex- 
actly the  opi>osite  for  vegetable  fats  do  not  contain  an  important  substance 
which  is  present  in  most  animal  fats,  particularly  in  butter. 

Due  to  a  combination  of  the  factors  alreadv  considered,  cn'ains  are  no 
longer  ground  at,  or  near,  the  place  of  consumption.  The  appearance  and 
the  keeping  qualities  of  the  product  must  be  carefully  considered.  As  a 
result,  rice  is  polished  and  the  germ  is  carefully  removed  from  wheat 
and  maize.  But  the  diet  that  was  adequate  when  more  than  half  of  it  con- 
sisted of  the  entire  gi*ain  may  no  longer  serve  to  maintain  the  race  in 
health  and  vigor  if  half  the  food  consists  of  only  part  of  the  grain,  for 
the  two  parts  differ  widely  in  composition.  See  Chapter  on  vitamins. 
(For  further  discussion  of  changes  in  food  habits  see  Lichtenfelt(c),  1013, 
Kubner(r),  1913,  Grotjahn,  and  Mendel.) 

We  have  now  considered  the  actual  food  consumption  of  man  in  differ- 
ent parts  of  the  world  as  reported  by  many  observers  and  have  noted 
certain  similarities,  many  differences  and  a  number  of  progi-essive  changes 
of  quite  general  significance.  To  what  extent  are  these  resemblances  to 
be  considered  as  evidences  of  real  physiological  need  ?  Is  man's  appetite 
a  projwr  measure  of  his  food  requirement  ?  Xeed  we  eat  so  much  or  should 
we  eat  more  ?  Which  is  preferable,  the  high  meat  diet  of  the  English  speak- 
ing peoples  and  of  those  of  the  Argentine,  the  bread  and  milk  diet  of  Fin- 
land or  the  comparatively  meat-  and  milk-free  diet  of  Japan  ? 


Vegetarianism 

First  comes  the  question  of  vegetarianism.  Space  does  not  permit 
a  full  presentation  of  the  benefits  claimed  to  follow  the  exclusion  of  meat 
from  the  diet.  There  can,  however,  be  little  doubt  that  vegetarians  have 
performed  many  feats  requiring  much  muscular  energy  and  have,  in  sev- 
eral races  and  other  competitive  sports,  made  a  very  striking  showing.  But 
there  can  also  be  little  doubt  that  vegetarians,  as  a  class,  are  not  distin- 
guished for  good  physique  or  for  exceptional  strength  and  endurance.  Such 
showing  as  they  have  made  seems  to  have  been  due  largely  to  the  rigorous 
training  earnest  advocates  of  the  cult  have  imposed  upon  themselves. 
(Caspari,  Albu,  Ilindhede(a)  (c) C^),  1912,  1913,  1914.) 


400  ISTDOr.  GREEXWALD  ? 

Tho  argument  that  meat  is  not  the  "natural''  fo(xl  of  man  would  seem 
to  1)0  fallacions.  (Pa^^e  .*]"»!>.)  ^Forcover,  any  sncli  objection,  if  valid, 
would  apply  e(iually  well  to  all  cooked  f(K)ds  and,  indeed,  to  all  cultivated 
varieties  of  plants  and  throw  us  back  upon  the  wild  fruits  of  the  forest 
and  unbroken  prairie. 

The  place  of  meat,  as  of  any  other  food  in  the  diet,  is  to  be  decided 
entirely  upon  physiolofrical  and  economic  considerations.  Physiological 
investigations  indicate  no  objection  to  the  use  of  meat  save  in  so  far  as 
the  unduly  large  consumption  of  meat,  in  increasing  the  amount  of 
protein,  may  be  unwise.  The  economic  objection  is  not  so  readily  disposed 
of.  The  animals  whose  tlesh  is  used  for  food  return  in  that  manner  only  a 
small  proportion  of  the  total  energy  they  receive  ( Armsby).  To  a  great  ex- 
tent, it  is  true,  this  is  obtained  from  materials  that  are  unfit  for  human  con- 
sumption but  to  the  extent  that  animals  are  fed  grain,  or  other  pi-oducts 
of  land  that  could  be  used  to  gTOw  grain,  vegetables  or  fruit,  they  do  com- 
pete directly  with  man  for  readily  utilizable  foods.  The  loss  in  the  ani- 
mal in  converting  energy  of  the  vegetable  food  into  potential  energy  in  the 
form  of  muscle  and  fat  is  one  of  the  factors  responsible  for  the  compara- 
tively high  cost  of  meat  in  most  countries.  That  is  the  objection  to  the 
free  use  of  meats.  So  much  of  the  income  available  for  the  purchase  of 
food  is  spent  for  meat,  which  can  be  dispensed  with,  that  not  enough  is 
left  for  milk  and  vegetables  which  are  practically  indispensable. 

Benedict  and  Roth  have  shown  that  the  basal  metabolism  of  vegetarians 
is  not  appreciably  less  than  that  of  meat-eaters.  Unless  the  muscular  sys- 
tems of  vegetarians  are  markedly  more  efficient  than  those  of  their  fel- 
lows, the  metabolism  due  to  muscular  work  must  be  the  same.  Such 
economies  in  food  consumption  as  are  claimed  for  vegetarians  and  whicli 
the  observations  of  Jaffa  seem  to  corroborate  must  therefore  be  due  to  the 
operation  of  some  other  factor,  probably  the  state  of  nutrition  or  level  of 
metabolism.     (Page  414.) 

One  of  the  great  disadvantages  of  a  vegetarian  diet  is  its  bulk.  With 
the  ordinary  vegetarian  diet,  the  work  required  of  the  digestive  apparatus 
is  considerably  greater  than  with  a  mixed  diet.  This  objection  does  not 
apply  to  the  so-called  lacto-vegetarianism,  which  permits  the  use  of  milk 
and  eggs.  Such  a  diet  has  much  to  commend  it.  It  need  not  be  bulky. 
The  milk  and  eggs  furnish  protein  of  exceptionally  good  quality  to  com- 
pensate for  possible  deficiencies  in  those  supplied  by  other  articles  of  the 
diet.  They  contain  much  phosphorus  and  calcium,  the  latter  of  which 
is  apt  to  be  present  in  insufficient  quantity  if  milk  is  not  included  in  the 
diet,  and  furnish  a  considerable,  if  seasonably  varying,  quantity  of  some 
of  the  vitamines  or  protective  substances.  Moreover,  the  cow  and  hen  re- 
turn in  the  form  of  milk  and  eggs  much  more  of  the  energy  they  receive 
than  they  do  if  kept  for  their  meat  (Armsby).    In  spite  of  what  is  often 


A  NORMAL  lJx"T  401 

said  to  be  an  uneconomical  manner  of  distribution,  milk  is,  for  most  people 
in  this  country,  a  comparatively  cheap  food. 


Protein  Minimum  and  Optimum 

% 

The  question  of  the  protein  minimum  anil  optinuim  has  engaged  the 
attention  of  physiologists  for  many  years.  While  the  necessity  of  a  cer- 
tain' amount  of  protein  has  been  recognized  from  the  lieginning,  it  has 
been  believed  that  the  optimum  could  be,  and  was,  readily  exceeded  and 
that  the  excess  was  distinctly  injurious.  This  belief  has  been  due  chiefly 
to  the  fact  that  protein  is  not  completely  oxidized  to  carbon  dioxid  and 
water,  as  are  carbohydrates  and  fats,  but  leaves  a  non-combustible  residue 
which  nuist  be  excreted  by  the  kidneys.  Other  objections  are  the  high 
cost  of  protein  foods,  their  ready  susceptibility  to  putrefaction  in  the  in- 
testine and  the  fact  that  only  a  small  part  of  the  potential  anergy  in  pro- 
tein is  available  for  work,  the  remainder  being  excreted  as  urea,  etc.,  or 
useful  only  as  heat.  Since,  as  a  rule,  the  lattel-  is  produced  in  excess  of 
requirements,  this  part  of  the  protein  energ^y  may  also  be  regarded  as 
lost. 

There  have  been  many  experiments  on  the  so-called  nitrogen  minimum 
— the  minimum  amount  of  nitrogen  in  the  food  required  to  maintain  an 
equilibrium  with  that  of  the  excretions.  Sherman(/j  (1020)  has  collected 
the  results  of  100  experiments  in  25  different  investigations  of  this  nature 
and  has  calculated  the  values  found  to  a  uniform  basis  of  70  kilos  body 
weight.  There  is  no  difference  in  the  per  kilo  requirements  of  men  and 
women.  The  average  of  all  109  experiments  is  44.4  grams.  The  range  of 
values  is  very  considerable,  from  21  to  65  grams,  but  out  of  the  109  values, 
94  fell  between  29  and  56  grams,  with  an  average  of  42.8  grams,  and  76, 
derived  from  19  investigations  and  inchuling  20  men  and  4  women  as  sub- 
jects, fell  between  30  and  50  grams,  with  an  average  of  40.6  grams.  Ex- 
pressed in  tei'ms  per  kilo  body  weight,  these  averages  become  0.635,  0.61 
and  0.58  respectively.  Most  of  these  experiments  were  of  comparatively 
short  duration  and  consequently  the  values  obtained  must  be  regardc-d  as 
absolute  minima  and  not  as  satisfactory  and  altogether  sufficient  amounts. 

The  apparently  low  protein  intake  of  the  Japanese  and  other  Oriental 
peoples  has  long  been  noted  but  the  earliest  observations  of  any  degi'ee 
of  accuracy  seem  to  have  been  those  of  Eijkman  on  the  diet  of  Japanese 
prisoners  and  those  of  Nagase  on  the  diet  of  a  military  colonist  in  Formosa- 
(Both  cited  from  Oshima. )  In  the  latter,  tlie  content  of  protein  was  about 
one  gram  per  kilo  body  weight.  Jt  was  about  the  same  in  the  diets  of 
the  prisoners  doing  no  woi-k  but  was  higher  (1.18  grams)  in  the  diets  of 
those  doing  light  work  and  still  higher  (probably  1.5  grams  oi-  more)  in 
the  diets  of  those  at  hard  work.     These  diets  were  not  *'freelv  chosen" 


402  ISIDOR  GEEENWALD 

but  were  probably  not  greatlj^  different  from  those  to  which  the  men  had 
been  accustomed. 

In  1800  von  Rechenberg  published  the  results  of  his  studies  of  the 
families  of  hand  weavers  in  Zittau,  a  small  town  in  Germany.  The  average 
intakoof  protein  was  1.14  grams  per  kilo,  but  the  condition  of  the  people 
indicated  that  they  were  undernourished.  They  were  very  poor  and  their 
diet  was  not  at  all  what  they  would  have  selected  had  tjiey  enjoyed  l>etter 
conditions. 

Neumann's  Experiments. — Neumann's  studies  on  himself  were  really 
the  first  to  show  that  so  low  a  level  of  protein  metabolism  could  be  obtained 
on  a  mixed  diet  and  maintained  for  a  considerable  period  without  evidence 
of  ill  effect.  The  diets  were  such  as  he  had  been  accustomed  to,  althouirh 
necessarily  restricted  in  variety  during  the  course  of  his  studies,  for  he 
analyzed  many  of  the  foods  himself.  The  first  experiment  included  305 
consecutive  days.  In  the  following  year  there  was  a  second  experiment  of 
120  days.  Three  years  later  (four  years  after  the  first)  a  third  study  was 
begun.  With  tlie  exception  of  November,  December  and  January,  this 
extended  from  May  1000  to  June  1001.  While  reported  as  one  experiment 
of  321  days,  it  really  consisted  of  two  separate  studies  of  approximately 
half  that  length.  The  protein  intake  in  the  first  and  third  studies  was 
approximately  one  gram  per  kilo  and,  in  spite  of  the  rather  low  content 
of  energy,  Keumann  gained  slightly  in  weight.  There  was  no  evidence  of 
any  ill  effect. 

In  the  second  experiment  referred  to,  all  the  foods  used  were  analyzed 
and  the  nitrogen  of  the  urine  and  feces  M'as  also  determined.  Neumann 
found  that  he  lost  nitrogen  and  weight  on  the  food  as  he  then  selected  it 
and  retained  both  only  on  a  rather  higher  level  of  protein  and  energy  in- 
taike  than  in  the  previous  experiment.  The  values  now  obtained  over  a 
suitable  period  of  15  days  were  1.16  grams  protein  and  40  calories  per 
kilo  per  day.  It  seems  probable  that  a  consistent  error  was  responsible  for 
the  much  lower  values  for  energy  content  in  the  other,  not  carefully  ana- 
lyzed, diets. 

Chittenden's  Experiments. — Very  soon  after  the  appearance  of  Neu- 
mann's pajx^r,  Chittenden  published  the  results  of  his  long-continued  ob- 
servations on  himself,  his  friends  and  associates,  on  college  athletes  and  on 
a  group  of  soldieis.  The  experiment  on  himself  was  begun  when  he  was 
47  years  old  and  weighed  G5  kilos.  He  gi*adually  reduced  his  diet  until, 
eight  months  later,  he  weighed  only  58  kilos.  By  that  time  an 
arthritis  had  disappeared,  not  to  return,  and  he  no  longer  suffered  from 
headaches  and  bilious  attacks  which  had  formerly  appeared  periodically. 
He  was  able  to  do  as  much  physical  work  as  formerly  with  less  than 
the  customary  degTce  of  fatigue  and  muscular  soreness.  Observations 
during  the  following  year  showed  that  the  nitrogen  of  the  urine  averaged 
5.60  gi*ams  per  day  and  that  the  intake  with  the  food  was  approximately 


J 


A  XOEMAL  DIET  403 

one  f(ram  more  or  6.69  grams  per  day.  Similar  exporimGnts  on  his  friends 
and  associates  gave  similar  results.  The  body  weight  fell  slightly  and  then 
remained  stationary.  For  long  periods  the  nitrogen  in  the  nrine  remained 
at  a  fairly  constant  low  level,  which  was  not  so  low,  however,  except  with 
Mendel,  as  it  was  with  Chittenden.  The  average  for  all,  including  Chitten- 
den, was  0.117  gram  nitrogen  per  kilo  per  day  or  the  etiuivalent  of  0.74 
gram  metabolized  protein  j)er  kilo  per  day. 

Experiments  in  which  the  nitrogen  of  the  foo<^l.  as  well  as  that  of  the 
urine  and  feces,  was  determined  gave  similar  results.  The  energy  con- 
tent of  the  food  was  not  determined  by  analysis  but  was  calculated  from  the 
results  of  published  analyses.  This  involved  a  considerable  degree  of  eri-or. 
with  such  complex  mixtures  as  were  here  employed. 

In  calculating  the  nitrogen  balance,  the  nitrogen  of  the  perspiration 
was  not  included.  With  men  engaged  in  sedentary  occupations,  the 
amount  of  this  was  probably  not  great  but  it  may  very  well  have  been 
large  enough  in  May  and  June  to  have  wiped  out  the  apparent  positive 
nitrogen  balance  (0.38  and  0.35  gm.,  respectively)  in  the  second  experi- 
ments with  Mendel  and  Beers  and  to  have  increased  the  nitrogen  loss  in 
the  corresponding  experiment  with  Chittenden  and  Underbill.  Moreover, 
the  small  gain  of  nitrogen,  even  if  entirely  real,  is  none  too  large,  when  it 
is  remembered  that  in  other  similar  periods  there  was  a  gi'eater  loss. 
Taking  all  nine  experiments  together  therc  was  an  average  loss  of  0.329 
gram  nitrogen  per  man  per  day,  with  an  intake  of  0.125  gram  nitrogen 
and  32.0  calories  per  kilo  per  day.  Practically  the  same  values,  0.133 
gram  nitrogen  and  32.4  calories,  were  obtained  in  the  four  experiments 
with  positive  nitrogen  balance.  For  a  man  of  70  kilos,  these  values  would 
become  58  grams  protein  and  2338  calories. 

Eight  athletes  were  under  observation  for  five  months  and  during  the 
last  two  months  of  this  period  the  average  daily  nitrogen  excretion  in 
the  urine  was  0.127  gram  per  kilo.  Seven  of  these  subjects  were  used  in 
a  seven  day  metabolism  experiment.  Considering  all  the  results,  there 
was  an  average  daily  loss  of  0.06  gram  nitrogen  (not  including  that  in 
rh('  perspiration)  per  man  npon  an  average  daily  intake  of  0,147  gram 
nitrogen  and  3S.4  calories  per  kilo.  Considering  only  the  four  experi- 
ments in  which  there  was  a  positive  nitrogen  balance,  the  values  were 
0.158  gram  nitrogen  and  41.4  calories  per  kilo.  For  a  man  of  70  kilos, 
these  would  correspond  to  69  gTams  protein  and  2898  calories.  It  is 
interesting  to  note  that  the  ratio  of  nitrogen  :  calories  was  lower  in  the  food 
of  the  athletes  than  it  was  in  that  of  the  teachers.  Notwithstanding  the 
fact  that  these  athletes  had  previously  been  accustomed  to  a  high  protein 
diet,  they  suffered  no  ill  eifect  other  than  a  slight  loss  in  weight  which  may 
even  have  been  advantageous  and  continued  to  increase  their  muscular 
strength,  as  measured  by  appropriate  tests. 

A  detail  of  soldiers  of  the  Medical  Department  of  the  United  States 


404  IS  I  DDK  GEEEXWALD 

Army  was  sent  to  Xow  Haven  as  subjects  fur  (liittcndcn's  expcrinicnts. 
Tlie  obsorvatinus  iipin  them  JiflVMCNl  from  those  upon  the  students  and  of- 
ficers of  the  university  in  thjii  th(?  «liet  was  prescribcil.  After  about  two 
weeks  upon  tlieir  aeeusrcunotl  nifions,  the  food  was  scle(;ted  by  Chittenden 
to  contain  less  prntciii  and  to  fu tnish  a  rather  smaller  amount  of  energy, 
wliile  retainiuii  a[)i>roxiuiat('!y  the  same  bulk  and  furnishing  considerable 
variety.  Per  kil<»  of  body  wei<rht,  the  avera.ae  daily  urinary  nitrogen, 
over  a  period  averaiiinu"  144  days  varied  from  O.IOG  to  0.148  gram,  the 
average  of  all  l»eing  0.128  i>er  kilo  or  7.80  grams  per  individual.  The 
weight  of  the  men  remained  nearly  constant,  some  gained  a  little,  otliera 
lost,  but  the  los.-es  were  advantaiicous  rather  than  otherwise.  The  men  were 
regularly  engai:ed  in  drill  and  other  exercises  and  improved  progressively 
in  muscular  strength  and  general  physical  condition  during  the  whole  of 
their  stay  in  Xew  Haven. 

These  ob.-^ervutions  were  confirmed  by  three  metabolism  experiments, 
In  the  first,  of  six  days'  duration,  each  man's  food  contained  a  daily  aver- 
age  of  from  7.71  to  8.23  grams  nitrogen,  or  from  0.111  to  0.153,  averaging 
0.135  gram,  per  kilo  and  furnished  approximately  2078  calories,  or  33  per 
kilo.  In  all  cases  the  excretion  of  nitrogen  in  the  urine  and  feces  was 
greater  than  the  intake  in  the  food.  Six  weeks  later,  a  second  experi- 
ment of  seven  days  was  begun.  The  food  now  furnished  2509  calories 
or  40.4  per  kilo  and  contained  from  9.27  to  9.64  gi-ams  nitrogen,  or  from 
0.128  to  0.180,  average  0.157,  grams  per  kilo.  Upon  this  diet,  all  the  men 
but  one  gained  nitrogen,  the  average  retention  being  0.591  gram  per  man 
per  day.  A  third  experiment  of  five  days  came  a  month  later.  The 
energy  content  of  the  foiMl  was  approxinuitely  2840  calories  or  45.0  per 
kilo  and  it  continued  from  8.14  to  8.67  grams  nitrogen,  or  from  0.112  to 
0.157,  average  0.139,  gram  jX'r  kilo.  Three  men  retained  nitrogen  and 
eight  men  lost,  the  average  of  all  being  a  daily  loss  of  0.254  gram  per  man 
per  day. 

Since  these  losses  occurred  in  spite  of  the  fact  that  the  diet  furnishetl 
300  calories  per  man.  or  5  per  kilo,  more  than  that  employed  in  the  previ- 
ous experimeitt,  it  would  seem  that  the  nitrogen  of  the  food  had  been  re- 
duced to  t(;o  !.»vv  a  level.  Ilie  afyparent  nitrogen  retention  in  the  sec- 
ond experiuH^nt.  0.501  gram  p<'r  man  per  day,  is  probably  not  much,  if 
at  all,  greater  rluin  wou]«l  be  ace;;unted  for  by  the  perspiration  in  men  en- 
gaged in  as  much  exercise  as  was  taken  by  these  subjects.  We  may  there- 
fore conclude  that  the  least  ade-.fuate  nitrogen  intake  demonstrated  by  those 
experiments  upon  soldiers  to  be  0.5  grams,  equivalent  to  about  GO  gi-ams  of 
protein  per  day.  Calcuiated  to  70  kilos,  it  would  be  69  grams.  Similarly, 
the  energy  content  would  be  2^<M)  calories.  These  values  are  very  nearly 
the  same  as  those  obtained  frnni  the  experiments  upon  athletes. 

Although  some  of  the  food  served  was  not  eaten,  the  entire  detail 
received  practically  the  same  diet.     Xevertheless,  as  Benedict(6)  (1900) 


A  XORMAL  DIET 


405 


pointed  out,  there  was  a  grent  variation  in  tlic  amount  of  nitrogen  in  the 
feces  of  the  different  men,  a  variation  which  does  not  api)ear  to  have  been 
obsencd  in  other  experiments  uj>on  men  receiving  identical  diets.  Dur- 
ing the  first  j>eri{.Ml  the  ratio  of  fecal  nitrogen  to  itnul  nitrogen  varied 
from  '.>.06  to  24.6,  average  1^.0  per  cent;  in  the  se<:-ond,  from  10.7  to  24.4, 
average  17.C,  j>er  cent;  and  in  the  third,  from  18.1)  to  27,  average  24.2^ 
j>er  cent.  It  varied  in  the  same  man  in  the  different  exjK'riments.  Bene- 
dict regarded  these  variations  as  evidences  of  a  possible  disturbance  of 
the  mechanism  of  absorption.  But  the  variations 'in  the  case  of  the  sol- 
diers were  greater  than  were  observed  with  the  professional  men  (from 
10.0  to  10.0,  average  15.1  pet  cent)  or  witli  the  athletes  (13.3  to  21.4, 
average  16.2  per  cent)  although  the  diets  within  these  gToups  were  not  uni- 
form. It  seems  to  the  writer  that  the  irregular,  and  high,  values  for  the 
nitrogen  in  the  feces  of  the  soldiers  may  have  been  due  to  the  ingestion  of 
additional  food.  That  the  men  should  sometimes  have  ^'broken  diet"  seems 
quite  likely.  If  they  did,  they  would  have  been  likely  to  attempt  to  conceal 
their  action  by  failing  to  collect  all  the  urine  or  feces.  At  any  rate,  varia- 
tions in  the  excretion  of  nitrogen  in  the  urine  such  as  were  recorded  in 
many  instances  and  some  of  which  are  included  in  the  following  summary 
of  the  urinary  nitrogen  excretion  on  the  last  four  days  of  the  second  balance 
experiment  appear  inexplicable  except  as  a  result  of  intentional,  or  acci- 
dental, failure  to  collect  all  the  urine. 


Nitrogen  Excreted 

IX   THE   URI.VE  of 

=   1 

i 

5 

t£  '-i       ' 

s 

S 

A 

■i 

s 

t». 

s 

g 

In 

1 

3 

1 

1 

.5 

8.750  ; 

G.S5 

7.37 » 

6.55 

7.18 

8.10' 

7.83 

lost 

7.56 

7.78" 

6.18 

7.05 

10.427    i 

7.95 

8.22 

4.99 

7.93 

hM^ 

7.35 

5.5d* 

7.51 

7.49     . 

7.68 

lost 

10.483   i 

6.10 

8.09 

b.S^ 

7.67 

8.69* 

-).29  • 

0.55 

7.08 

7.54  " 

5,5Q 

8.71 

10.2t>5 

7.96 

8.20 

7.01 

7.95 

8.20  = 

8.07' 

6.77  • 

6.81 

8.23 

7.69 

.4.78 

Intake  the  same  for  each  man,  except  as  follows:    1.  8.555;   2.   9.30;    3.   11.107; 
4.  10.024;  5.  10.392;  6.  10.654;  7.  10,880;  8.    10.215;    9.    8.164:    10.    8.1G4;    11..  10.475. 


However,  in  spite  of  all  the  objections  to  some  of  the  details,  there  can 
be  no  question  but  that  Chittenden's  results  did  show  that  it  w^as  possible 
for  men  to  maintain  themselves  in  good  health  and  with  a  gain,  rather 
than  any  demonstrable  loss,  in  physical  and  mental  vigor  for  a  considerable 
perirxl  of  time  on  diets  containing  less  protein  than  had  previously  been 
considered  necessary. 

Fisher. — Chittenden's  observations  were  extended  by  Fisher  in  his 
studies  of  the  effect  of  diet  upon  endurance.  It  was  found  that  students  on 
a  low^  protein  diet,  yielding  only  a  moderate  supply  of  energy,  less  than 
these  students  had  been  in  the  habit  of  obtaining,  regularly  increased  in 


400  ISIDOK  GREEXWALD 

their  fK)wer  of  endurance  in  a  nnnibcr  of  physical  tests.  The  experi- 
ments were  not  well  controlled  but  thev  showed  that  healthy  yonng  men 
could  live  in  an  apparently  i>erfectlj  healthy  condition  for  at  least  two 
nioiitlis  on  a  diet  containinu;-  only  ().*.)T  i^rani  protein  |>er  kilo  pen-  day. 

McCay. — The  advocacy  of  a  h)W  protein  dietary  was  severely  attacke<l 
hy  ^IcCay,  wlio  based  his  criticisms  chiefly  up<m  the  results  of  his  escperi- 
ence  in  India.  McCay  found  that  Bengalis,  as  their  incomes  increased, 
partook  to  a  larger  and  larger  extent  of  protein  food.  The  poorer  classes, 
who  were  also  in  poorer  health,  subsisted  chiefly  on  rice,  with  only  small 
additions  of  meat,  fish,  milk  or  eggs.  Some  of  his  data  and  othei-s  calcu- 
lated from  them  are  included  in  Table  IV.  McCay  emphasized  the  poor 
physical  condition  of  those  whose  diets  contained  little  protein  as  compared 
with  that  of  those  who,  like  the  wealthier  Bengalis,  the  Sikhs  and  others, 
ate  more  protein. 

Perhaps  the  most  striking  of  all  McCay's  studies  is  one  upon  Bengali 
and  Anglo-Indian  and  Eurasian  students  at  the  same  college.  The  for- 
mer received  a  diet  furnishing  3100  calories  but  only  67  grams  protein, 
the  latter,  only  2S22  calories  but  05  grams  pi-otein.  The  average  weight 
of  the  Bengali  students  was  54  kilos  and  they  gained  very  little  (less  than 
one  kilo)  during  their  stay  at  the  school,  in  spite  of  a  gain  of  1.5  to  2.5 
inches  in  height.  There  was  no  increase  in  the  girth  of  the  chest.  The 
xlnglo-Iudian  and  Eurasian  students,  however,  gained  an  average  of  8.2 
kilos  during  the  three  years  and  their  chest  girths  Avere  increased  b}^  an 
average  of  one  inch.  While  racial  peculiarities  may  have  had  something 
to  do  with  the  result,  it  seems  probable  the  difference  in  food  played  an 
important  part. 

However,  since  ^IcCay^s  work  was  published,  there  has  been  an  in- 
creasing recognition  of  the  importance  of,  not  qnly  the  amount  of  protein, 
but  its  kind,  the  nature  of  the  constituent  ainino-acids,  and  of  the  signifi- 
cance of  other  dietary  constituents.  The  diet  of  the  Bengali  (students  and 
others)  may  well  be  criticized  as  containing  not  too  little  protein  but  pos- 
sibly not  enough  of  certain  amino-acids,  or  even  more  likely,  as  being  de- 
ficient in  certain  vitamines,  or  protective  substances,  or  in  one  or  more 
inorganic  constituents. 

Hindhede.  — In  a  series  of  experiments  designed  to  detennine  the  mini- 
mum nitrogen  intake  required  to  maintain  equilibrium,  Hindhede  (c)(^) 
(1013,  1014)  succeeded  in  maintaining  two  men  for  considerable  periods 
on  diets  containing  rather  less  protein  than  those  employed  by  Chittenden. 
The  foods  he  used  consisted  of  potatoes,  or  bread,  with  butter  or  margarin, 
with  or  without  the  addition  of  onions,  plums,  rhubarb  or  strawberries. 
The  onions  helped  to  make  the  large  quantities  of  potatoes  more  palatable. 
The  other  additions  acted  as  vehicles  for  sugar,  thus  permitting  a  reduction 
in  the  amount  of  bread.  The  nitrogen  they  contair^d  did  not  appear  in 
the  urine  but  in  the  feces.     Sometimes,  indeed,  the  addition  of  plums. 


A  XORMAL  DIET  407 

rhubarb  or  straw1)erries  to  the  food  led  to  an  increase  in  the  fecal  nitro- 
gen gToater  than  the  total  nitrogen  of  the  added  food.  In  this  manner, 
the:5e  additions  served  to  reduce  the  amount  of  what  Ilindhede  regarded 
as  "digestible  protein,'-  which  he  calculated  from  the  difference  between 
the  nitrogen  of  the  food  and  that  of  the  iecea.  In  this  manner  Ilindhede 
was  able  to  arrive  at  extraordinarily  low  figures  for  protein  metabolism. 
But  as  pointed  out  on  page  3()9,  this  procedure  may  not  be  justified  and 
in  the  present  discussion  of  Ilindhede's  results,  the  nitrogen  of  the  food 
will  be  considered. 

The  lowest  value  for  nitrogen  intake,  with  maintenance  of  equilib- 
rium, was  obtained  on  the  potato  diet  with  T.5D  gi*ams  nitrogen  or  about 
47  gi*ams  of  protein  for  a  man  of  70.7  kilos,  (The  slightly  lower  value, 
6.98  gTams  nitrogen  or  -i-t  gi-ams  protein,  obtained  in  period  E,  was  prob- 
ably accompanied  by  a  loss  of  nitrogen  for  the  apparent  gain  of  0.2  gram 
nitrogen  per  day  was  scarcely  sufficient  to  account  for  the  loss  in  perspira- 
tion in  the  case  of  a  man  engaged  in  the  hard  work  Fr.  Madsen  was  then 
perfomiing.)  This  appears  to  be  the  lowest  protein  intake,  accompanied 
by  a  ix)sitive  nitrogen  balance,  that  has  been  recorded. 

The  analytical  results  reported  by  Ilindhede  cover  a  very  consider- 
able period,  two  years  in  the  case  of  Fr.  Madsen.  It  is  difficult  to  ex- 
tend quantitative  obsenations  over  even  so  long  a  time  as  that  and  any 
of  longer  duration  are  almost  impossible.  But  it  should  be  remembered 
that  Hindhede's  subjects,  paiticulai'ly  the  two  Madsens,  were  accustomed 
to  a  very  low  level  of  protein  metabolism  and  were,  nevertheless,  healthy, 
vigorous  men,  well  above  the  average  in  muscular  development  and  en- 
durance. Ilindhede's  own  customary  diet  contained  only  10.34-  gi-ams 
nitrogen  or  64.6  grams  protein  ]:>er  day  and  that  of  his  family,  which 
included  children,  only  75.7  gi-ams  per  man. 

The  energy  content  of  the  food  consumed  by  Ilindhede's  subjects 
appears  to  be  rather  high.  It  is  possible  that  this  low  level  of  protein  me- 
tabolism could  be  attained  only  at  the  cost  of  a  large  carbohydrate  metabol- 
ism. However  that  may  be,  it  is  noteworthy  that  the  very  low  protein  me- 
tabolism observed  in  the  case  of  the  ^ladsens  neeessitate<l  a  very  monotonous 
and  limited  dietary.  Ilindliode  himself  called  attention  to  the  difficulty  of 
making  a  potato  diet  palatable  or  even  endurable  for  any  considerable 
period.  It  required  the  gi'catest  care  in  the  selection  and  pi*eparation  of 
the  potatoes.  On  the  bread  diets,  large  quantities  of  sugar  were  required 
in  order  to  maintain  the  energy  yield  of  the  food  while  keeping  the  pro- 
tein content  ]o\v. 

As  a  matter  of  fact,  unless  unusual  reliance  be  placed  upon  more  or 
less  purified  foods  such  as  starch,  sugars  and  fats,  it  is  nearly  impossible 
to  obtain  3000  calories  without  securing  at  the  same  time  about  70  gi-ams 
of  protein  or  one  gTam  per  kilo.  Tveference  to  Table  IV  shows  that  this 
level  is  reached  by  all  the  dietaries  reported,  if  only  the  energy  content 


408  ISIDOIl  GKEEXWALD 

is  high  enough.  From  Sherman's  compilation  (page  401)  it  is  evident 
that  this  is  75  per  cent  or  more  above  the  minimum  requirement.  The 
danger  of  falling  below  the  minimum  protein  requirement  is,  therefore, 
slight.  As  Bayliss  said,  ^'Take  care  of  the  calories  and  the  protein  will 
take  care  of  itj?elf.''  That  is  certainly  true  of  the  minimum  for  mainte- 
nanco  hut  it  is  not  quite  so  evident  that  the  optimum  will  be  thus  attained. 

Liberal  Protein  Intake  a  Possible  *' Factor  of  Safety"  (:Mcltzer). — In  a 
memorable  lecture  delivered  in  1000,  ^leltzer  called  attention  to  "The 
Factors  of  Safety  in  Animal  Structure  and  Animal  Economy''  and  sug- 
gested that  the  tendency  of  mankind  to  seek  a  level  of  protein  metabolism 
al)ove  the  minimum  might  be  such  a  factor  of  safety.  Just  as  we  are  pro- 
vided with  kidney,  liver  and  lung  tissue  in  excess  of  the  apparent  minimum 
requirement,  so,  too,  the  excess  of  protein  above  the  minimum  determined 
by  experiment  might  sene  as  a  factor  of  safety  to  cover  emergencies  and 
insufficiencies  some  of  which  we  may  not  at  present  be  able  to  recognize. 

Aside  from  its  value  as  a  factor  of  safety,  there  are  not  wanting  evi- 
dences of  the  desirability  of  a  rather  liberal  supply  of  protein.  Not  only 
do  the  more  vigorous  and  prosperous  individuals  consume  a  liberal  al- 
lowance of  protein  but  so  also  do  the  more  vigorous  nations.  This  may  be 
effect  rather  than  cause  and,  undoubtedly,  is  so  in  many  cases  with  in- 
dividuals. Meat  and  other  protein  foods  are  prized  for  a  number  of  reasons 
including  their  agreeable  taste,  stimulating  action,  etc.  This  has  led  to 
a  comparison  of  the  desire  for  a  liberal  allowance  of  pi'otein  with  the 
desire  for  alcohol.  This  seems  to  be  based  upon  entirely  too  superficial 
resemblances.  We  now  have  a  fairly  good  conception  of  how  and  why  al- 
coholic beverages  came  to  be  so  regularly  employed  by  man.  We  know 
fairly  well  how  they  act  to  secure  the  effect  desired.  W^e  know  what  are 
the  consequences  of  excessive  indulgence  and  even  of  the  regular  use  of 
small  quantities.  We  also  know  that  not  only  scattered  individuals  for  a  few 
months  or  years  but  entire  peoples  for  generations  have  maintained  them- 
selves in  full  health  and  vigor  without  the  use  of  alcohol.  There  is  to- 
day no  such  body  of  evidence  in  respect  to  the  advantages  of  a  low-protein 
diet.  f>ome  protein  is  needed.  A  slight,  or  even  moderately  gi*eat  exces-:^ 
can  scarcely  be  so  very  disadvantageous.  When  overindulgence  in  protein 
shall  have  lx?en  shown  to  be  followed  by  ill  effects  at  all  comparable  to 
those  following  the  excessive  use  of  alcohol,  comparison  will  be  in  order 
but  hardly  until  then. 

Change  of  diet  of  whatever  character  has  too  often  led  to  improvement 
in  clinical  condition  for  one  to  lay  much  stress  upon  the  fact  that  Demuth 
observed  such  improvement  on  increasing  the  pi-otein  content  of  the  diet  of 
some  of  his  patients.  But  such  results  as  those  repin-ted  by  Moullnier  with 
some  72  Indo-Chinese  taken  from  Aiuiam  to  the  Yangtso  valley  as  laborers 
are  not  so  readilv  dismissed.    The  men  first  fed  themselves  as  they  had  been 


A  NOEMAL  DIET  400 

aceiLstomed  to  at  home,  chiefly  on  rice.  After  sevx'ral  months,  with  tlie  ap- 
proach of  cold  weather,  they  tired  easily  and  did  very  little  work.  They 
were  then  rationed  and  received  100  «^rams  biseiiify  800  grams  rice,  300 
L'^rams  meat,  15  lirams  fat  and  10  grams  salt,  vielding,  in  all,  3000  calories 
daily.  Their  capacity  for  work  promptly  uicrease<l  and,  when  the  meat 
ration  was  later  diminished,  the  Annamese  bouglit  jjork  and  poultry  out  of 
their  own  funds. 

The  following  account  of  a  similar  instance  is  copied  from  Starlinsr(6) 
(1010).  ''Thus  Major  Ewing  relates  how  on  a  railway  job  in  Canada, 
the  Italian  workmen  were  found  to  become  inefficient  at  about  11  oVlock 
in  the  morning.  These  workmen  were  spending  only  seven  to  eight  dollars 
for  food  at  the  canteen  as  against  fifteen  dollars  expended  by  the  Canadian 
workmen.  The  chief  difference  in  the  diet  conditioned  by  this  economy  was 
in  the  meat.  The  company  then  insisted  on  the  Italians  spending  fifteen 
dollars  a  month.  With  the  extra  money,  they  bought  fat  beef  and  it  was 
then  found  that  their  w'ork  was  entirely  satisfactory."  It  may  be  objected 
that  the  favorable  results  in  both  these  instances  were  due  to  the  increased 
amount  of  food  and  not  to  the  increased  amount  of  protein.  But,  if  the 
total  amount  of  food  had  originally  been  insufficient,  the  men  would,  in  all 
probability,  have  been  hungry  and  would  have  eaten  more. 

Starling  believes  that  the  food  of  the  Italians  was  originally  too  poor 
in  fat  and  that  the  men  felt  the  lack  of  this  and  responded  to  the  addition 
of  fat  in  the  form  of  fat  beef.  But,  while  it  is  true  that  people  accustomed 
to  a  liberal  amount  of  fat  suffer  from  lack  of  it,  there  is  little  reason  to 
believe  that  its  lack  should  inconvenience  those,  who  like  these  Italians, 
pi'obably  never  had  any  considerable  amount  of  fat  in  their  food. 

A  similar  effect  of  meat  feeding  upon  the  laboi*ers  eng-aged  in  the  con- 
stniction  of  another  railroad  is  mentioned  by  Collis  and  Gi^eenwood  (page 
254). 

Complete  data  are  lacking  but  it  seems  to  the  writer  that  in  all 
these  cases  the  improvement  was  due  to  the  increased  protein  content  of  the 
food.  The  original  diets,  while  selected  in  accordance  with  previous  habits, 
were  possibly  of  not  so  higli  a  protein  content  as  in  their  native  country. 
A  change  from  unpolished  rice  to  polished  jrice  in  the  cases  of  the  Anna- 
mese or  from  one  kind  of  flour  (as  such  or  as  bread  or  macaroni,  etc.)  to  an- 
other with  the  Italians  would  have  been  quite  sufficient  to  have  produced 
an  apjpreciable  change  in  the  protein  content  of  the  food. 

It  is  curious  that  pliysiological  literature  should  be  so  plentiful  in 
arguments  for  a  low  protein  diet  based  on  the  fact  that  protein  is  not  com- 
pletely oxidized  but  leaves  a  residue  to  be  excreted  by  the  kidneys.  Why 
there  should  be  so  much  solicitude  for  the  kidneys  rather  than  for  other 
parts  of  the  apparatus  of  metabolism  is  not  entirely  clear.  Whatever  may 
be  the  case  in  disease,  it  is  yet  to  be  demonstrated  that  the  healthy  kidney 
is  in  any  way  injured  by  being  required  to  excrete  15,  or  even  20,  rather 


410  ISIDOR  GREEXWALD 

than  7  grams  of  nitrogen  per  day.  A.  and  31.  Krogh  found  no  evidence  of 
the  prevalence  of  kidncT  disease,  etc.,  among  the  Eskimos.  There  is 
rather  more  reason  to  he  sparing  in  our  use  of  the  simpler  carholivd rates, 
for  it  has  now  heen  demonstrated  that  a  considerable  number  of  individuals 
who  would  ordinarily  be  considered  nonnal  have  rather  a  limited  tolerance 
for  sugars  and  that  this  tolerance  can  probably  be  impaireil  by  continuously 
exceeding,  or  approaching,  this  limit.  Apparently  the  factor  of  safety 
in  the  metabolism  of  glucose  is  less  than  it  is  for  protein  metabolism. 

Fat  Minimum.  — During  the  war,  and  after,  the  importance  of  fat  in  the 
diet  was  gTcatly  emphasized.  The  lack  of  fats  was  most  severely  felt  by  the 
people  of  central  Europe  and  there  were  not  a  few  who  ascribed  to  their  lack 
of  fats  the  widespread  occurrence  of  nutritional  disorders,  particularly  *^war 
edema."  The  Inter-Allied  Food  Commission  adopted  2  oz  (57  grams)  of 
fat  per  man  per  day  as  the  minimum  upon  which  the  peoples  of  the  allied 
countries  were  to  be  asked  to  subsist.  The  absolute  need  of  even  so  little 
is  questionable.  Experiments  by  Hindhede  showed  that  his  subjects  could 
maintain  themselves  with  much  less  fat.  Fr.  Madsen's  diet  included  an 
average  of  10.8  gi-ams  fat  for  107  days.  After  a  vacation  of  21  days,  dur- 
ing which  he.confined  himself  to  a  fat-poor  diet,  there  was  another  period  of 
120  days  during  which  the  average  fat  content  of  the  food  was  13.9  gi-ams. 
Then  came  another  vacation  of  21  days,  then  a  period  of  140  days  with  an 
average  fat  ration  of  12.8  grams  and  then  another  vacation  of  38  days.  Dur- 
ing both  of  these  vacations,  Madsen  kept  on  a  fat  poor  diet.  Finally  there 
was  a  period  of  106  days  with  a  diet  containing  an  average  of  14.2  grama 
fat.  In  all,  he  lived  for  over  18  months  on  a  diet  containing  less  than  15 
grams  of  fat  per  day.  Similarly,  Holger  Madsen  ate  food  containing  an 
average  of  6.G  gi-ams  of  fat  per  day  for  117  days  and,  after  a  three  weeks 
vacation,  7.0  grams  fat  for  180  days.  After  a  two  months  vacation,  there 
w^as  another  period  of  106  days  with  an  average  of  7.5  gi-ams  of  fat  per  day. 
The  vacation  diets  were  also  poor  in  fat. 

These  results  were  not  obtained  in  connection  with  the  low  protein  diets 
previously  discussed.  Except  for  30  days,  Fr.  Madsen^s  fat-poor  diet  regu- 
larly contained  over  100  gi'ams  of  protein  and,  during  the  period  in  which 
it  fell  below  this  level,  Madsen  lost  weight.  But  whether  this  was  due 
to  the  lack  of  protein  and  of  fat  or  merely  to  the  deficiency  in  energy  con- 
tent, which  was  at  its  lowest  in  this  period,  it  is  difficult  to  determine.  Hol- 
ger Madsen  did  not  maintain  his  weight  of  70  to  72  kilos  on  a  fat-)X)or 
diet  containing  less  than  90  grams  of  protein  but,  after  his  weight  had  fallen 
to  65  kilos,  he  maintained  himself  at  this  level  and  even  gained  a  little  on 
a  diet  containing  60  to  70  gi-ams  of  protein,  6  to  7  grams  of  fat  and  furnish- 
ing 3000  calories. 

Experiments  by  Osborne  and  Mendel  on  rats  support  the^e  obsei*vations 
as  do  the  observed  dietary  habits  of  Japanese  and  other  Oriental  peoples 
as  well  as  those  of  the  poorer  classes  in  Europe.  However,  it  seems  probable 


A  NOKMAL  DIET  411 

that,  wLen  the  diet  'is  deficient  in  fats,  particularly  in  those  of  animal 
origin,  it  must  contain  considerable  quantities  of  the  green  leafy  vegetables 
as  these  and  the  animal  fats  appear  to  be  the  only  sources  of  the  fat-soluble 
vitamin  <>r  vitamins. 

But  if  fat  is  not  absolutely  necessarA-,  it  is  certainly  very  useful,  for  our 
whole  accustomed  cookery  is  dependent  upon  the  use  of  fat.  \Yithout  it, 
the  housewife  of  western  Europe  and  of  the  Unitwl  States  does  not  know 
how  to  prepare  food  nor  does  her  husband  relish  it  when  it  is  prepared. 
Food  prepared  without  fat  leaves  the  stomach  rapidly — it  does  not  "stay 
with  one.''  For  those  who  require  a  large  supply  of  energ}',  the  use  of  fat 
is  advantageous  in  that  it  supplies  energy  in  a  very  concentrated  form,  nine 
calories  per  gram  and  all  of  it  food,  instead  of  four  calories  per  gi*am,  as 
with  protein  and  carbohydrate,  with  each  gram  accompanied  by  from  0.5 
to  9  grams  water. 

Carbohydrate  Minimum. — Carbohydrates  furnish  more  than  fifty  per 
cent  of  the  energy  content  of 'most  diets.  If  greatly  reduced  in  amount, 
signs  of  defective  fat  metabolism  may  appear.  However,  the  inhabitants, 
of  the  arctic  regions  appear  to  maintain  good  health  on  diets  containin^j 
very  little  carbohydrate.  The  possible  ill  effects  of  an  excess  of  carbohy- 
drate, particidarly  of  the  simple  sugars,  have  already  been  mentioned 
(page  410)  and  are  discussed  more  fully  in  the  chapter  on  diabetes. 
.  Minimum  of  Ash  Constituents. — The  requirements  of  the  body  for  in- 
organic constituents  have  been,  as  yet,  only  scantily  investigated  and  the 
demands  for  phosphorus  and  calcium  have  received  the  gi'eater  part  of  the 
attention  that  has  been  given  to  the  subject. 

Sherman (c?)  (e)  (1020)  has  compiled  the  available  data  for  these 
elements  in  a  manner  similar  to  that  used  in  the  detennination  of  the  pro- 
tein requirement,  to  which  reference  has  already  been  made.  In  95  exj)ei'i- 
ments  included  in  17  investigations  (12  of  which  were  by  Shennan  and  his 
collaborators),  the  daily  requirement  of  phosphorus  varied  from  0.52  to 
1.20,  with  an  average  of  0.88  gram  per  TO  kilos  body  weight.  Sherman 
states  that  *^in  a  detailed  study  of  the  food  supplies  of  224  families  or  other 
groups  of  people  selected  as  typical  of  the  population  of  the  United  States 
only  eight  showed  less  than  0.88  gram  of  phosphorus  per  man  per  day  and 
in  all  but  two  of  these  cases  the  phosphorus  content  would  have  reached  this 
figure  if  the  food  consumed  (without  changing  its  character)  had  been  in- 
creased in  amount  to  a  level  of  3000  calories  per  man  per  day.  The  two 
cases  which  apparently  contained  less  than  the  average  actual  requirement 
of  phosphorus  and  would  still  have  been  thus  deficient  if  the  food  had  been 
sufficient  in  amount  to  cover  the  energy  requireinent  amply  were  both  re- 
ported from  the  southern  states,  .  .  .  Outside  of  the  southern  regions  where 
the  food  consists  too  largely  of  patent  flour  and  new  process  (degenninated) 
cornnieal,  the  danger  that  a  freely  chosen  American  dietary  will  be  deficient 
in  either  protein  or  phosphorus  does  not  appear  serious,  in  the  light  of  our 


412  ISIDOK  GKEENWALD  ' 

present  evidence,  so  far  as  the  requirement  of  maintenance  is  concerned." 

The  compilation  of  the  objei-vations  on  calcium  showed  that  in  07  ex- 
periments belonging  to  14  investigations  (10  of  them  hy  Sherman  and  bis 
collaborators),  the  indicated  daily  requirement  varied  from  0.27  to  0.82, 
average  O.4."),  gram  per  70  kilos.  Sherman  jxvinted  out  that,  whereas  only 
one  out  of  224  supposedly  typical  American  dietaries  fell  below  the  indicat- 
ed protein  requirement,  one  in  six  was  deficient  in  calcium.  If  all  that  fell 
below  3000  calories  were  increased  to  this  level,  none  would  be  deficient 
in  protein,  but  one  in  seven  would  still  be  deficient  in  calcium.  It  is  inter- 
esting to  observe,  in  this  connection,  that  only  one  of  Blatherwick^s  32 
army  dietaries  fell  below  0.4.5  gram  of  calcium. 

The  possible  occurrence  of  a  calcium  deficiency  and  consequent  advis- 
ability of  "liming  the  nation'^  seems  recently  to  have  attracted  considerable 
attention  in  Germany.  Rubner  (1020)  has  considered  the  question  and  has 
concluded  that  with  such  foods  as  are  used  in  Germany  and  are  now  avail- 
able, there  is  no  danger  of  a  calcium  deficiency  for  adults,  so  long  as  they 
get  enough  food  to  satisfy  their  energy  requirements. 

Rubner  also  calculatetl  the  values  for  the  inorganic  content  of  some 
Japanese  diets  to  European  body  weights  with  the  results  shown  in  Table 
VI.  The  calcium  content  is  much  below  Sherman's  indicated  requirement 
and  is  certainly  considerably  below  that  which  was  customarily  consumed  in 
Gerin,any  (page  415)  but,  if  the  analytical  figures  chosen  by  Rubner  are 
correct,  is  certainly  adequate  icith  Japanese  dietaries.  It  may  not  be  with 
European  food  materials. 

It  is  suggested  by  Rubner  that  the  low  fat  content  of  Japanese  diets  may 
be  related  to  their  low  calcium  content.  If  they  ate  more  fat  (vegetable 
oils,  etc.),  the  Japanese  would  not  eat  so  much  of  their  customary  foods 
and  would  thus  obtain  even  less  calcium  than  they  do  now-  and  might  then 
suffer  from  a  deficiency. 

A  certain  absolute  minimum  of  calciuni  and  of  other  inorganic  ele- 
ments is  im questionably  needed,  but  there  are  obsei*vations  that  indicate 
that  this  minimum  may  vary  considerably  under  the  influence  of  dilferent 
factors.  The  first  and  most  obvious  of  these  is  the  texture  of  the  fowl  and 
the  ease  of  digestion  of  the  protein  and  carbohydrate  contained  therein. 
Hart,  Steenbock  and  Hopjx'rt  found  that  cows  and  goats  lost  much  less 
calcium  on  rations  otherwise  identical  if  they  received  fresh  grass  rather 
than  hay.  McCluggage  and  Mendel  found  that  the  calcium  and  magnesium 
of  carrots  and  of  spinach  were  poorly  utilized  by  the  dog.  While  it  is 
true  that  Rose  found  that  the  calcium  of  carrots  was  as  well  utilized  by 
women  as  that  of  milk,  it,  nevertheless,  seems  possible  that  in  some  other 
foods,  less  readily  digested,  some  inorganic  constituents  are  not  made 
fully  available  for  absorption. 

The  nature  of  the  chemical  combination  in  which  the  element  appears 


A  XOPv:MAL  diet  413 

may  play  an  im|x>rtarit  2>art.  Oriiaiiic  iron  is  generally  considered  to  ho 
more  valuable  than  inorganic,  altliough  the  evidence  is  still  conflicting. 
Also,  althrmgh  the  requirement  of  the  ])ody  f(>r  pho.s{>horu;  may  he  met  en- 
tirely hy  inorganic  i>hosphate,  it  is  p«jssihle  that  a  larger  amount  is  required 
than  if  some  is  present  in  organic  comhination. 

lielaiion  of  Ash  Const ttuenfs  hf  One  Anoflier. — The  existence  of  factors 
of  quite  (litlerent  kind  is  indicaTe<l  lyy  tlie  results  of  Buntre  who  found  that 
the  ingestion  of  potassium  increased  the  excretion  of  so<lium  and  by  those 
of  Hart  and  Steenbock  who  observed  a  simihir  effect,  in  swine,  of  the  inges- 
tion of  magnesium  upon  the  excreti«»n  of  calcium.  It  is  jwssible  that  some 
such  action  was  responsible  for  the  increase  of  O.IG  gram  in  the  excretion  of 
calcium  in  one  of  Sherman's  experiments,  following  tlie  addition  of  lean 
beef,  containing  0.01  gi-am  calcium,  to  the  basal  diet.  The  relation  of  the 
inorganic  constituents  of  the  fuod  to  one  another  is  evidently  of  consider- 
able importance. 

Of  all  such  relations,  one  of  the  most  obvious,  though  not  necessarily 
one  of  the  greatest  physiological  significance,  is  the  relation  between  acid- 
and  base-forming  elements.  Sherman  and  Gettler  first  called  attention  to 
this.  Bhitherwick(a)  (1914)  showed  that  with  some  foods  such  as  prunes 
and  cranberries  which  contain  considei-able  quantities  of  benzoic  acid, 
which  is  not  oxidized  in  the  body  but  conjugated  with  glycine  and  excreted 
as  hippuric  acid,  this  may  play  a  considerable  role  in  the  determination  of 
the  acid-base  equilibrium  of  the  body.  Meats  and  cereals  contain  an  ex- 
cess of  acid-forming  elements,  most  fruits  and  vegetabltrs  an  excess  of  al- 
kaline, milk  a  slight  excess  of  alkaline,  and  an  ordinary  mixed  diet  a  slight 
excess  of  acid,  elements.  In  his  study  of  32  anny  dietaries.  Blatherwick(i[>) 
(1910)  found  a  variation  from  an  excess  of  acid  equivalent  to  39  c.c.  nor- 
mal acid  to  an  excess  of  alkali  equivalent  to  2.4  c.c.  normal  alkali  per  man 
per  day.    The  average  of  all  was  2.2  c.c.  normal  acid. 

Medical  literature  is  rich  in  references  to  the  supposed  ill  effects  of  an 
acid  diet  but  most  of  these  will  not  stand  a  careful  examination.  The  fact 
that  most  organic  acids  are  oxidized  to  carbon  dioxid  and  water  has  gen- 
erally been  disregarded.  Moreover,  most  of  the  evidence  indicates  that  the 
body  is  able  to  neutralize  the  excess  of  acid  that  may  be  formed  by  neutral- 
izing it  with  ammonia,  at  the  expense  of  the  urea  of  the  urine. 

Rose  and  Berg  have  reported  that  an  acid-forming  diet  increases  the 
need  for  protein.  Their  preliminary  report  is  very  interesting  but  accep- 
tance of  their  views  must  await  publication  of  their  detailed  results  and 
confii'mation  thereof.  Such  confirmation  would  appear  not  to  be  forthcom- 
ing for  Jansen  (1919)  and  Fulige  have  denied  any  such  influence. 

So  little  is  known  of  the  nature  of  the  vitamins  or  protective  substances 
that  it  is  impossible  to  state  with  any  degree  of  definiteness  just  what  are 
the  requirements  for  human  nutrition.  There  seem  to  be  at  least  three  of 
these  substances  that  must  be  supplied  but  there  may  be  more.    To  what 


414  ISIDOE,  GREEIs^WALD 

amounts  these  are  required  we  do  not  know.  It  is  ix>ssible  that  these 
amounts  will  he  found  to  vary  considerahly  with  the  nature  and  amount 
of  other  constituents  of  the  diet.  Sonic  evidence  that  this  is  so  is  already 
available.  For  a  further  discussion,  the  reader  is  referred  to  the  chapter 
on  vitamins. 

Undernutrition 

For  years  it  has  been  known  that  fasting  reduces  basal  mctalx>lism  but 
the  significance  of  this  fact  as  indicating  a  means  of  lowering  the  level 
of  metabolism  does  not  appear  to  have  been  fully  appreciated  until  after 
the  outbreak  of  the  war.  Then  it  was  noted,  particularly  in  Gennany,  that 
large  numbers  of  people  maintained  themselves  in  good  health  and  remained 
capable  of  performing  their  accustomed  tasks  while  eating  much  less  food 
than  they  had  previously.  They  lost  w^eight  but  not  continuously  and  the 
loss  was  slight  in  comparison  vrith  the  saving  in  food  effected.  The  energy 
content  of  the  food  of  the  city  population  was  probably  abjut  2500  calories 
per  man  per  day,  but  was  increased  by  means  of  extra  rations  for  those 
working  in  factories,  mines,  etc.  (though  still  remaining  below  the  accus- 
tomed quantity)  and  by  extra  foods  purchased  openly  or  surreptitiously  by 
those  whose  means  permitted  them  to  do  so. 

Loewy  and  Zuntz  showed  that  this  maintenance  at  a  lower  level  was 
duo  to  lowered  basal  metabolism  and  not  merely  to  the  reduction  in  the 
protein  of  the  food. 

The  success  of  the  German  people  in  maintaining  health  and  vigor  on 
such  low  diets  appeared  so  striking  that  it  seemed  almost  a  foregone  con- 
clusion that  their  previous  food  intake  had  been  greatly  excessive. 

In  this  coimtry,  Benedict,  Miles,  Roth  and  Smith,  in  a  series  of  experi- 
ments, found  that  a  gi-oup  of  twelve  young  men  wdiose  usual  requirement 
of  food  w^as  3090  calories  per  day  lost  weight  when  placed  upon  a  diet  fur- 
nishing only  from  1600  to  1800  calories,  until  after  five  weeks  they  had 
lost  10.5  per  cent  of  their  body  weight.  Thereafter,  without  changing 
the  character  of  the  food  from  that  to  which  they  were  accustomed,  they 
w^ro  furnished  an  average  of  106 7  calories,  upon  which  the  body  weight  re- 
mained stationary  for  a  period  of  several  months.  Examination,  by  McCol- 
lum,  of  the  diet  furnished  these  men  showed  that  it  was  not  deficient  in  any- 
known  dictaiy  constituent  but  only  in  total  energy  content.  At  first  it 
seemed  as  if  this  economy  in  food  was  accomplished  without  any  imtoward 
effect  but  as  the  experiment  continued  it  became  evident  that  the  men  were 
not  capable  of  the  physical  exei-tion  that  had  previously  been  readily  dis- 
played. They  lacked  spirit  and  were  easily  tired.  To  use  a  colloquialism 
Avhich  many  of  them  used  to  describe  their  condition,  they  lacked  "pep." 
There  w^as  no  clear  e^'idence  of  lack  of  mental  power  but  there  was  a  very 
decided  lessening  of  sexual  desire. 


A  NORMAL  DIET  415 

Coincidentally,  reports  from  Germany  showed  that  similar  effects,  but 
greatly  intensified,  were  appearing  there.  The  early  favorable  results  of  a 
reduced  dicta ly  were  found  to  be  illusory  and  a  very  real  failure  to  accom- 
plish the  usual  amount  of  work  was  evident  on  all  sides. 

War  Edema.— -Outbreaks  of  what  came  to  be  known  as  "war  edema"  or 
"hunger  edema"  appeared  in  1017  and  became  more  and  more  frequent  as 
time  went  on.  The  mortality  figiu-es  soon  showed  an  increase,  particularly 
in  the  number  of  deaths  from  tuberculosis.  A  very  good  review  of  the  sup- 
posed etFects  of  the  war  diet  on  the  incidence  of  disease  was  published  by 
Determann. 

Manj^  factors  have  been  held  responsible  for  the  api>earance  of  "war 
edema."  It  is  easy  to  point  out  some  of  these,  such  as  the  lack  of  protein 
and  of  fat  (page  -110),  but  there  seem  to  be  natural  and  experimental  diet- 
aries that  share  these  deficiencies  and  that  have  been  employed  for  long 
periods  without  producing  edema.  The  hw.-go  amount  of  water  in  the 
food  has  also  been  blamed.  But  JIawk  and  his  collaborators  found  no 
such  ill  effect  to  follow  the  regular  use  of  large  volumes  of  water. 

Rubner (aa)  (1920)  calculated  the  inorganic  content  of  the  rationed 
food  of  the  German  people  in  1917-8  to  be  3.375  grams  J^2^f  0.226  gram 
CaO,  0.290  gram  MgO,  0.089  gram  Fe._.0:,  and  1.922  grams  P2O5,  per  head 
per  day.  A  similar  calculation  for  the  food  used  before  war  gave  the  fol- 
lowing values:  4.403  grams  KgO,  1.221  gi-ams  CaO,  0.57G  gi-ams  MgO, 
0.154  gram  FcgOg  and  4.472  grams  P2O5.  The  difference  is  marked.  The 
calcium  content  of  the  war-time  diet  is  far  below  Shemian^s  indicated  re- 
quirement and  is  even  less  than  that  of  Japanese  diets,  as  calculated  by 
llubner. 

When  we  consider  how  large  a  part  the  inorganic  constituents  of  the 
body  fluids  play  in  determining  their  osmotic  properties,  it  seems  quite 
likely  that  a  change  in  the  inorganic  content  of  the  food,  in  which  change 
the  lack  of  calcium  may  or  may  not  have  been  the  significant  factor,  should 
have  had  some  influence  in  the  causation  of  the  edema. 

However  that  may  be,  lack  of  food — simple  stai-vation — ^must  be  regard- 
ed as  largely  responsible,  not  only  for  war  edema  but  also  for  the  other 
disastrous  effects  obsei-ved.  It  is  possible  that  a  proper  mixture  of  salts, 
vitamins  and  amino-acids  added  to  the  reduced  diet  would  have  prevented 
some  of  these,  but  for  the  present  it  seems  safe  to  say  that  the  only  practic- 
able way  to  secure  these  needed  substances  is  to  eat  enough  food  of  sufficient 
variety. 

Probably  the  most  complete  and  most  accurate  study  of  nutrition  in 
Germany  during  the  war,  though  limited  to  one  individual,  was  made  by 
N'eumann  upon  himself.  For  seven  months,  from  November,  1916,  to  May, 
1917,  he  confined  himself  to  the  rationed  articles  with  only  such  additions 
as  were  available  to  the  ix)orer  classes  in  his  city  (Bonn).  This  diet 
furnished  him  45  gi*ams  protein,  18.9  gi-ams  fat,  287  grams  carbohydrate 


416  ISIDOK  GREEXWALD 

and  154G  calories  daily.  His  weight  fell  from  107'to  127  pounds.  (The 
chart  is  taken  iwm  Starling. )  Other  studies  (Starling,  Loewy  and  Brahm, 
Maylander,  !Ma?on)  indicate  that  at  about  this  time  Xeuniann's  diet  was 
typical  of  that  available  to  most  of  the  city  population.  The  well-to-do 
town  dwellers  and  the  agricultural  population  fared  much  better,  the  latter 
reducing  their  food  consum})tion  little,  if  at  all. 

The  limitation  of  diet  in  the  investigations  of  Benedict  and  in  the 
experiences  «»f  the  German  people  was  accompanied  by  all  the  stinuilation 
of  war  and  the  fervor  of  patriotic  seiTice.  This  may  have  helped  to  con- 
ceal from  the  subjects  manifestations  that  might  otherwise  have  been  more 
promptly  obseiTcd.  In  his  studies  of  prison  diets,  Dunlop  found  that  much 
smaller  changf?  were  promptly  noticed  by  the  subjects.  He  found  that 
with  a  certain  gi-oup  on  a  diet  containing  179  gi-ams  protein,  54  grams  fat, 
654  gTams  carbohydrate  and  furnishing  3028  calories,  there  was  much 
waste  and  such  complaints  as  there  were  regarded  quality  and  not  quantity. 
The  ration  was  then  reduced  to  one  containing  165  grams  protein,  56  grams 
fat,  566  grams  carbohydrate  and  furnishing  3517  calories,  which  was  tried 
for  two  months.  By  that  time,  82  per  cent  of  the  prisoners  of  average 
weight  (67  kilos )  had  lost  weight.  There  w^as  little  waste  but  there  Avere 
many  complaints  of  lack  of  fo(xl.  The  ration  w^as  then  increased  to  one 
containing  173  grams  protein,  57  gi'ams  fat  and  602  grams  carbohydrate, 
furnishing  3707  calories.  Complaints  as  to  quantity  ceased  but  there  was 
no  more  waste  than  with  3517  calories. 

There  seems  to  be  a  certain  detinite .  level  of  nutrition  to  which  the 
individual  is  accustomed  and  from  which  it  does  not  vary  over  very  consid- 
erable periods  of  time.  Thus,  Zuntz  (Zuntz  and  Lcewy(6))  found  his 
basal  metabolism  the  same  after  fifteen  years.  Any  change  in  food  intake 
from  the  amount  required  to  maintain  the  level,  assuming  the  amount  of 
physical  work  perfoi-med  to  remain  the  same,  is  promptly  indicated  by  a 
change  in  body  weight  which  is,  however,  not  continuous  nor  proportional 
to  the  change  in  the  food. 

It  is  interesting  to  examine  in  this  connection  the  figures  given  in 
Table  TV  for  two  pairs  of  groups  of  dietary  studies  in  the  United  States. 
The  writer  has  selected  from  the  studies  of  Atwater  and  Bryant  ia  Xew 
York  City  in  from  1806  to  1807  and  from  those  of  Wait  in  eastern  Ten- 
nessee in  fiom  1000  to  1004,  those  in  which  the  weight  and  age  of  the  chil- 
dren were  given.-  These  were  then  separated  into  two  groups,  one  of  which 
included  the  studies  of  those  families  in  which  one  or  more  children  were  at 
least  ten  per  cent  below-  the  normal  in  weight  as  judged  by  Griffith's  stand- 
ards and  the  other  in  which  all,  or  all  but  one  in  the  case  of  large  families, 
were  of  normal  weight.  The  distribution  of  protein  and  calories  is  approxi- 
mately the  same  within  each  pair.    In  Xew  York,  milk  and  its  products  sup- 

*  These  are  the  only  publications  in  which  sucIj  information  is  given  that  arc  known 
to  nic. 


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418  ISIDOR  GKEEJ^WALD 

plied  less  of  the  protein  to  those  families  whose  children  woio below  noimal 
weight  than  it  did  to  the  other  faniilieSj  but  these  foods  bupplied  more  of  the 
calories,  indicating  that  the  former  group  used  less  milk  but  more  butter 
than  the  latter.  The  two  Tennessee  groups  show  no  such  difference  in  the 
consumption  of  milk  and  butter  but,  appaieiitly,  the  families  with  children 
below  weight  used  more  peas  and  beans  and  less  cornmeal  than  did  the  fam- 
ilies whose  children  were  of  normal  weight.  But  these  diti'erences  are 
slight.'  The  striking  difference,  in  both  pairs,  is  that  in  energv  content,  8 
per  cent  in  Tennessee  and  14  per  cent  in  Xew  York.  Food  habits  that  do 
lot  secure  to  the  ordinary  family  at  least  3000  calories  per  man  per  day  are, 
apparetttly,  not  suited  to  secure  the  proper  development  of  the  children. 

Of  course,  if  no  work  is  done,  much  less  food  is  needed.  This  is  in- 
dicated by  many  of  the  observations  cited  in  Table  IV  and  also  by  those 
of  Benoit  on  a  group  of  78  Russian  officers,  prisoners  in  Germany,  dur- 
ing a  period  of  480  days.  Their  food  contained  an  average  of  48.7  grams 
protein,  14.6  grams  fat  and  332  grams  carbohydrate,  furnishing  1697  cal- 
ories per  man  per  day.  During  this  period,  they  lost  an  average  of  140 
grams.  Although  they  had  previously  lost  weight,  they  were  still  of  about 
the  ^'normal"  weight,  as  judged  from  the  American  statistics,  the  average 
weight  being  130  pounds  (63  kilos)  with  an  average  height  of  65  inches 
(1.65  meters).  But  they  did  no  work  and  took  very  little  exercise  of  any 
description.  Bread  and  flour  furnished  49  per  cent  of  the  protein,  milk 
and  its  derivatives  23  per  cent,  meat  and  fish  16.3  per  cent  and  vegetables 
11.65  per  cent.  This  was  a  very  satisfactory  distribution  and  no  disturl)- 
ances  of  nutrition  w'ere  observed. 

With  the  foods  ordinarily  consumed,  the  amount  needed  to  maintain 
the  body  in  its  accustomed  condition  distends  the  stomach  to  a  certain  de- 
gree. If,  with  a  change  of  diet,  this  bulk  is  lacking,  the  individual  may  be 
hungry,  even  though  the  energy  content  of  the  food  is  quite  sufficient.  On 
the  other  hand,  in  times  of  scarcity,  the  most  varied,  though  indigestible 
and  worthless  materials  are  used  simply  to  fill  the  stomach.  Such  is  the 
case  in  Russia  and  in  China  to-day. 

Bread  and  flour  supply  half  the  food  of  Europe.  They  are,  ordinarily, 
the  cheapest  f«x>ds  and  in  a  time  of  high  prices,  their  comparative  im- 
portance increases  and  an  adequate  supply  of  bread  becomes  even  more 
essential.  Thus  Miss  Ferguson  found  that  the  same  families  in  Glasgow 
used  less  meat,  potatoes  and  sugar  in  1917  than  in  1916  but  that  they  all 
used  more  bread  and  flour.  It  is  not  without  reason  that  ^'bread^'  is  so 
often  used  as  synonymous  wnth  "food."  A  bread-eating  people  must  have 
bread  or  suffer.  For  this  reason,  the  most  diligent  attempts  were  made 
during  the  war  to  find  suitable  diluents  or  substitutes  to  use  with  wheat 
or  rye  flour  in  bread  making. 

A  very  complete  study  of  the  efl'ect  of  a  large  number  of  such  sub- 
stances as  were  used  in  Russia  in  times  of  scarcity  was  made  by  Popoff. 


A  :nokmal  diet 


419 


Au  account  of  his  experiments  was  published  by  Erismann  in  the  Zeit- 
schrift  fur  Biologie  in  1891.  Xotwithstanding  this  readily  available  aC" 
count,  many  of  these  substances  and  many  others  were  used  in  Gerin,any 
during  the  war,  some  with  very  disagi'f  cable  consequences.  Only  two 
suitable  substances  appear  to  have  been  found.  Blood  obtained  from  slaugh- 
terhouses was,  in  this  manner,  made  directly  available  as  a  food  for  man. 
Finely  railJed  bran  was  also  found  useful.  The  addition  of  either  of  these 
made  the  bread  less  palatable  than  it  formerly  was.     (Xeumannf  ^)  1916.) 

What  is  "Normal"  Weight? — Such  losses  of  weight  as  were  observed 
in  Gemiany  and  by  Benedict  and  his  associates  in  this  country  must  be  re- 
garded as  pathological  but  it  is  probable  that  if  the  reduction  in  the  diet 
had  not  been  quite  so  marked  the  loss  in  weight  would  have  l>cen  much  less. 
Benedict's  subjects  at  an  average  weight  of  CyQ  kilos,  were  accustomed  to  a 
diet  furnishing  '3007  calories.  A  diet  furnishing  19G7  calories  main- 
tained them  at  about  59  kilos,  indicating  a  loss  in  weight  of  1  kilo  for  every 
reduction  of  100  calories  in  the  diet.  If  tliey  had  reduced  the  energy  con- 
tent of  their  food  by  320  calories,  or  approximately  10  per  cent,  they 
would  probably  eventually  have  lost  almost  two  kilos.  If  they  had  in- 
creased it  by  this  amount,  they  would  probably  have  gained  about  the  same 
amount  and  would  then  have  maintained  themselves  at  this  new  level  of 
metabolism  and  of  weight.  Which  of  these,  2777,  3097  or  3417  calories 
is  the  ^'nomial"  ?  That  question  cannot  be  answered  until  we  know  more 
definitely  what  is  the  "noiTnaF'  weight  for  these  men,  64,  66,  or  68  kilos. 

Symonds  collected  and  published  the  height  and  weight  of  men  and 
women  at  different  ages  as  obtained  from  the  records  of  accepted  applicants 
for  life  insurance  in  the  United  States  and  Canada.  The  I'esults  are  in- 
cluded in  the  following  tables,  the  height  including  shoes  and  the  weight, 
ordinary  clothing. 


TABLE  VII.-SYMOND'S  TABLE  OF  HEIGHT  AND  WEIGHT  FOR  MEN  AT  DIFFERENT  AGES  BASED  ON 
74.162  ACCEPTED  APPLICANTS  FOR  LIFE  INSURANCE 

Ages 

15-24 

25-29 

30-34 

35-39 

40-14 

45-49 

50-54 

55-59 

60-« 

65-69 

5  ft.  Oin 

120 

125 
126 

128 
129 

131 
1.31 
133 

133 

134 

134 

134 

I3t 

5  ft.  1  in 

122 

134 

136 
133 

136 

138 

136 
138 

134 
137 
140 
144 

2  in 

124 
127 
131 
134 

128 
131 
135 

131 

136 
139 
143 
146 
1.50 
1.55 

3  in 

134 

136 

141 

141 
145 

141 

145 

140 

4  in 

138 

140 
143 
147 
152 

144 
147 
151 
156 

143 

Sin 

138 

141 

149 
153 
158 

149 

I4S 

147 

6in 

138 
142 

142 

145 

153 

153 

158 

151 

7b 

147 

150 
154 

158 

156 

Sin 

146 
150 
154 

151 

157 

160 
165 

161 
166 
171 
177 

163 

163 

163 
168 
174 

1S2 

9in 

155 

159 

159 
164 

162 

167 

168 

168 

10  in 

167 

170 
175 
180 

172 

173 

174 

11  in 

159 
165 
170 

161 

169 

173 

177 

178 

ISO 
185 
189 

180 

6ft.  0  in 

170 

175 
181 

179 

183 

182 

183 

185 

6ft.  lin 

177 

185 

186 
194 

189 

188 

189 

189 

2in 

176 

184 

188 
195 

192 
200 

196 

194 

194 

192 

192 

3  in 

181 

190 

203 

204 

201 

198 

i 

420 


ISIDOR  GllEENWALD 


TABLE  VIII-SYMOND'S  TABLE  OF  HEIGHT  AND  WEIGHT  FOR  WOMEN  AT  DIFFERENT  AGB3  BASED  ON 
58.855  ACCEPTED  APPLICANTS  FOR  LIFE  INSURANCE 


Ages 

15-19 
111 

20-24 

25-29 

30-34 

35-39 

40-44 

45-19 

50-54 
128 

55-59 

60-64 

4  ft.  11  in 

113 
114 

115 
117 
118 
120 
124 
127 
131 

117 

119 

122 
125 

125 

128 
131 
134 
1.37 

126 

5  ft.  0  in 

113 

119 

122 

128 

130 

129 

1  in 

115 

116 

121 
123 

124 

123 
132 
135 
138 

131 

13.{ 

132 

2  in  

117 

118 
122 
125 

127 

134 

138 

137 
14! 
145 
149 

136 

3  in 

120 

127 

131 

141 
145 

140 

4  in 

123 

130 
135 

134 

142 

144 

5  in 

125 

128 

139 

143 

147 
151 
151 
158 

149 
153 

148 

6  in 

128 

132 

135 

137 

143 

146 

153 

152 

7in 

132 

.135 
140 
144 
147 

139 

143 

147 

150 
155 
159 
163 

157 

156 
161 

155 

8  in 

136 

143 
147 
151 

147 

151 

161 
166 
170 

160 

Sin 

140 

151 
155 

155 
159 

163 

166 
170 

165 

10  in 

144 

16/ 

169 

From  a  study  of  the  records  of  the  relation  of  weight  to  height  and 
of  the  moi-talitj  records,  Sjnionds  concluded  that,  helow  the  age  of  ahout 
30  years,  those  slightly  ahove  the  average  weight  were  the  more  likely  to 
survive  but  that  beyond  this  age  those  slightly  under  the  average  in  weight 
showed  the  greatest  vitality.  But  the  optimum  was  very  near  the  average. 
So  that,  apparently,  the  average  weight  of  the  people  of  this  country  is 
just  about  the  '^nomial"  in  both  senses  of  the  word. 

The  relation  of  weight  to  height  as  calculated  by  Symonds  is,  of  course, 
a  rather  crude  measure  of  the  state  of  nutrition  or  "degi-ee  of  fatness" 
as  Sherman  calls  it.  Attempts  have  been  made  to  devise  others  (Oppen- 
heimer,  Oeder)  but  these  have  not  met  with  general  acceptance. 


Conclusion 

From  what  has  preceded,  it  is  evident  that  it  is  impossible  to  fix  defi- 
nitely a  "normaF'  diet.  It  is  clear  that  its  nature  will  depend  upon 
geographical  location,  economic  status,  degree  of  muscular  activity,  habit, 
etc.  Any  diet  that  will  maintain,  or,  rather,  that  has  maintained  normal 
health  for  generations  must  be  considered  to  be  a  normal  diet. 

Judging  by  the  experience  of  the  raee,  checked  by  obseiTations  under 
lal>oratory  conditions,  or  conditions  approaching  those  of  the  laboratoiy, 
and  by  experiments  upon  animals,  such  a  diet,  if  of  European  or  American 
food  materials,  will  furnish  the  man  of  70  kilos  engaged  at  moderate  work 
3000  calories  and  will  contain  from  75  to  120  grams  of  protein,  at  least  0.4 
gram  calcium  and  0.8  gTam  phosphorus  and  will  include  a  considerable 
amount  of  fruits  and  vegetables  to  furnish  "roughage,"  vitamins,  etc. 

Success  in  maintaining  individuals  upon  exceptional  diets  for  even 
long-continued  periods  cannot  be  accepted  as  a  criterion  of  the  adequacy 
of  a  diet.  Failure  is  proof  that  the  diet  is  not  satisfactory  but  success  can 
only  be  taken  to  indicate  exactly  what  was  observed,  which  is  merely  that 


A  XORMAL  DIET  421 

no  deficiency  was  detected  within  the  penod  of  observation.  We  now  know 
that  animals  may  be  maintained  in  a  satisfactory  condition  for  periods  cor- 
responding to  many  years  in  the  life  of  man  ut)on  diets  that  finally  fail  to 
continue  to  do  so.  Other  diets  will  maintain  the  animal  throughout  life 
but  will  not  pennit  reproduction.  Experiments  of  comparable  extent  upon 
man  are,  of  course,  impossible.  Custom,  carefully  obsei-ved  and  ana- 
lyzed, must  remain  our  chief  reliance  in  deciding  what  is  a  normal  diet. 

As  has  already  been  shown,  the  cereals  play  a  less  important  part  in 
American  diets  than  in  those  of  most  other  peoples.  It  is  probable  that  we 
shall,  in  the  future,  approximate  them  in  this  regard.  Our  per  capita  con- 
sumption of  meat  is  almost  certain  to  fall  due  to  its  abnost  inevitable  in- 
crease in  price,  relative  to  other  foods.  What  changes  in  our  diet  are  physi- 
ologically sound  and  economically  justifiable  ? 

There  seem  to  be  two  foods,  or  classes  of  foods,  in  which  many  Ameri- 
can diets  appear  to  be  deficient  or  to  approach  deficiency.  These  are  milk 
and  its  products  and  fresh  vegetables,  particularly  the  green  leafy  vege- 
tables. Students  of  nutrition  appear  to  be  united  in  this  opinion.  Thu9 
McColluni(c)  wrote:  "Milk  is  our  greatest  protective  food,  and  its  use 
must  be  increased."  "There  is  no  substitute  for  milk  and  its  use  should  be 
distinctly  increased  instead  of  diminished,  regardless  of  cost."  "Milk  is 
just  as  necessary  in  the  diet  of  the  adult  as  in  that  of  the  growing  child." 
According  to  Lusk(/i)  (1917),  the  mother  of  a  family  consisting  of  two 
adults  and  three  children  should  buy  no  meat  until  she  has  first  bought  3 
quarts  of  milk  a  day.  Sherman (c)  (1918)  writes:  "It  therefore  seems  ad- 
visable to  spend  at  least  as  much  for  fruit  and  vegetables  as  for  meat  and 
fish ;  also  to  spend  at  least  as  much  for  milk  as  for  meat  or  for  milk  and 
cheese  as  for  meat  and  fish."  .  .  .  "General  adoption  of  a  dietary  such 
as  wo  now  believe  to  be  best  would  call  for  more  milk  and  perhaps  more 
vegetables  and  fruit  than  now  come  to  our  city  markets." 

To  quote  again  from  McCollum:  "In  the  light  of  facts  presented  in 
the  previous  chapters  of  this  book,  there  can  be  no  reasonable  doubt  that 
the  importance  of  poor  hygienic  conditions  and  of  poor  ventilation  have 
been  great ly  over-estimated,  and  that  of  poor  diet  not  at  all  adequately  ap- 
preciated as  factors  in  promoting  the  spread  of  this  disease."  (Tubercu- 
losis. ) 

It  is  probable  that  the  impoi-tance  of  a  faulty  diet  in  reducing  resistance 
to  other  infectious  diseases  has  similarly  been  overlooked.  Moreover,  when 
we  consider  how  slowly  the  signs  of  such  unquestionably  nutritional  dis- 
orders as  scui-vy  or  rickets  usually  develop,  it  is  not  difficult  to  understand 
that  a  slighter  nutritional  deficiency  may  give  rise  to  general  inefficiency 
and  impaired  health. 

We  cannot  hope  to  maintain  and  improve  our  standards  of  health  and 
efficiency  without  maintaining  and  improving  the  character  of  our  diet. 


SECTION  III 


Body  Tissues   and   Fluids e Victor  C,  Myers 

Com  position,  and  Significance  of  Blood — Blood  Volume— Total  Solids — Spe- 
cific Gravity — Reaction  and  Hydrogen  Ion  Concentration — Blood  Pro- 
teins—Serum Proteins — Fibrinogen — -Hemoglobin — Blood  Cells — ^Blood 
Xitrogen — Total  Nitrogen — Xon-protein  Nitrogen — Urea — Uric  Acid — 
Creatinin — Creatiu — Amino  Acids — Ammoniac-Rest  Nitrogen — Blood 
Sugar — Blood  Lipoids — Total  Fat — Lecithin  —  Cholesterol  —  Acetone 
Bodies — Mineral  Constituents — Sodium — Potassium — Calcium — Magne- 
sium— Iron — Chlorids — Phosphates — Sulphates — Blood  Gases — Oxygen 
— Carbon  Dioxid — Muscle — Liver  and  the  Bile — Connective  Tissues — 
Brain — Phosphatids — Cephalin — Cerebrosids — Sulphatids — Cholesterol — 
Extractives — Cerebrospinal  Fluid — Saliva — Milk. 


Body  Tissues  and  Fluids 

VICTOK  C.  MYERS 

NEW    YORK 

So  mucli  attention  has  recenthj  been  devoted  to  the  study  of  the  chem- 
istry of  the  blood  that  a  consideration  of  the  subject  of  the  body  tissues 
and  fluids  can  hardly  be  made  mthout  undue  emphasis  on  the  hlood.  Some 
of  the  more  recent  methods  have  been  applied  to  advantage  in  the  study 
of  spinal  fluid  and  milk,  and  an  extended  application  of  many  of  these 
methods  to  the  study  of  fresh  autopsy  tissues,  muscle,  liver,  etc.,  would 
probably  yield  equally  valuable  results. 

Composition  and  Significance  of  Blood 

During  tlie  past  decade,  1910-20,  the  chemical  composition  of  the 
blood  has  been  a  topic  of  increasing  interest  and  importance,  quite  eclips- 
ing in  significance  the  studies  carried  out  on  the  urine  during  the  pre- 
ceding decade.  In  the  case  of  urine  the  advances  were  primarily  the  re- 
sult of  the  impetus  furnished  hy  the  new  metliods  of  Folin  and  of  S.  H. 
Benedict,  and  these  same  workers,  together  with  Van  Slyke,  are  responsihle 
for  many  of  our  new  methods  of  blood  analysis.  During  this  latter  period 
the  blood  has  probably  been  the  topic  of  more  studies  than  any  other  body 
tissue,  fluid  or  secretion.  The  practical  importance  now  attached  to  the 
chemical  examination  of  the  blood  would  appear  to  be  rapidly  overshadow- 
ing the  importance  fonnerly  attached  to  the  examination  of  the  urine. 

Blood  has  often  been  referred  to  as  a  fluid  tissiia  That  the  blood 
may  readily  be  compared  with  other  tissues  from  the  standpoint  of  its 
solid  content  is  evident  by  the  fact  that  in  perfect  health  the  total  solids 
are  only  slightly  less  than  those  of  the  muscle  tissue  and  even  more  than 
those  of  some  of  the  glandular  tissues  of  the  body.  According  to  recent 
observations  human  blood  nonnally  constitutes  about  8.5  per  cent  of  the 
body  weight.  Blood  is  the  common  carrier  of  nutritive  materials  to  the 
various  tissues  of  the  body  and  waste  products  such  as  carbon  dioxid,  urea, 
etc.,  to  organs  of  excretion.  From  this  it  is  apparent  that  an  inability 
to  properly  metabolize  certain  food  materials  or  properly  excrete  certain 
waste  products  should  result  in  changes  in  the  composition  of  the  blood. 
Owing  to  the  various  factors  of  safety  in  the  body  it  would  seem  unlikely 

423 


4U 


VICTOR  c.  :myees 

Composition  of  Human  IU.ood 


Constituent  or 

: Calculated  as 

1                  Normal 

Pathological 

Determination 

Bange 

{     Average 

Range 

Blood  Volume  If^i-^BWd 

Per  Cent  of 
Body  Weight 

1         4.5-  5.7 
7.6-  9.1 

5.1 
8.5 

3.8  -     6.2 
4.3  -  1.3.7 

Total  Solids 

Per  Cent 

B>    -23 

22 

10      -  25 
4.2  -     9.1 

Total  Seruni  Protein 

6.7-  8.2 

7.5 

Serum  Albumin    

«<                « 

4.8-  6.7 

5.0 

3.7  -     7.0 

Serum  Globulin    

(«                « 

1.4-  2.3 

1.9 

1.7  -     2.6 
0.1  -     0.9 

Fibrinogen    (plasma) 

a           If 

0.3-  0.6 

0.5 

Hemoglobin  (whole  blood)  . 

<<            « 

12.5-23.0 

10 

3.5  -  24.0 

f  Erythrocytea    

^^""-^  Leucocytes    

Per  cu.  mm. 

4,500.000- 

5,500,000 

100,000- 

12,000,000 

<<     ((      « 

3,000-10,000 

200,000-500,000 

3.0-3.7 

500-600,000 

Platelets   

it     t{      It 

Total  Nitrogen 

Per  Cent 

3.3 

1-4 

Total  Non-protein  Nitrogen. 

Mg.  to  100  c.c. 

25      -35 

30 

20      -400 

Urea  Nitrogen     

<(    (f    «      « 
(t    (I     «<      <t 
«    ti     «      li 

(f        ti          «             Cl 

it     it      it        a 

12     -15 

2-3 

0.5-  2 

3-7 

4-8 

15 
2.5 

1.0 

5 
5 

5      -350 

Uric  Acid 

0.5  -  25 

Creatinin    

0.5  -  35 

Creatin   

2-35 

Ami  no-Acid  Nitrogen    . . . 

4-30 

Ammonia   

tt     tt      (t        ti 
ti     tt      it        ti 

Per  Cent 

u              tt 

-0.1 

4      -18 
0.00-  0.12 
14     -18 

11 

0.10 
15 

Rest  Nitrogen 

Sugar  (glucose)     

0.05-     1.30 

Diastatic  Activity 

10     -  76 

Lipoids 

Total  Fatty  Acids  (whole 

blood )     

tt        It 

0.29-  0.42 

0.36 

to  6. 10 

Total  Fatty  Acids 

(plasma) 

tt          tt 

0.30-  0.47 

0.-39 

to  8.13 

Total  Fatty  Acids 

(corpuscles)     

tt        tt 

0.27-  0.45 

0.32 

f  whole  blood    . . . 

tt        tt 

0.28-  0.33 

0.30 

0.16-0.46 

Lecithin  j  plasma   

[  corpuscles    .... 

tt          tt 

0.17-  0.26 

0.21 

0.14-0.50 

tt        tt 

0.35-  0.48 

0.42 

9.34-0.70 

r  whole  blood  . 

«         tt 

0.14-  0.17 

0.15 

0.06-1.00 

Cholesterol  ]  plasma    

tt        tt 

0.15-  0.18 

0.16 

0.06-1.20 

[corpuscles   .. 

tt          tt 

0.13-  0.17 

0.14 

0.10-0.20 

Acetone  Bodies        

T\  as  Acetone 

:Mg.  to  100  C.C: 

1.3  -  2.6 

2 

Acetone                    ^ 

2-350 

Aceto-acetic   Acid  J 

0-hydroxybutyric  Acid    . . . 

ti    tt     tt     ti 

0.3  -  2.0 

1 

2-  50 

it    it    tt     ti 

0.5  -  3.0 

1 

1-300 

Mineral  Constituents   

280-320 

300 

Sodium  (serum)  asNa  .  . . 

Mg.  to  100  C.c. 

16-  22 

20 

10-  35 

Potassium  (serum)  as  K   . 

Ti      .<       a         ti 

150-250 

200 

50-400 

Potassium  (whole blood)    . 

il      it       li         ti 

9-  11 

10 

2-  25 

Calcium  ( serum )  as  Ca    . . 

ii     ti       a        tt 

2-     3 

2.5 

Magnesium  (serum)  asMg 

a     it      it        it 

50 

Iron  (whole blood)  as  Fe   . 

tt     ti      tt        a 

Chlorids  (whole blood)  as  1 

ti     tt      tt        ft 

450-500 

470 

350-700 

NaCl    1 

n     it      it        a 

570-620 

600 

500-850 

Chlorids  (plasma) as NaCli 

Phosfihates  as  P                       | 

• 

Inorganic  (plasma)    .... 

tt     tt      tt        tt 

1.5-  4.5 

3 

1--  40 

Lipoid  (plasma)     ; 

if     if      ft        tt 

5    -12 

7.5 

Organic  (corpuscles)    ... 

it     tt      tt        tt 

40    -75 

53 

Sulphates   (whole  blood)    .. 

tt     tt      tt        tt 

0.5-  1.0 

0.7 

0.5-16 

BODY  TISSUES  AXD  FLUIDS 

CoMPosiTiox  OF  Human  Blood  (Continued) 


425 


Constituent  or 

Calculated  as 

Normal 

Pathological 

Determination 

Range 

Average 

Range 

Blood  Gases 
Oxygen 
Capacity    

Volumes 

Per  Cent 
««'        « 

((       (( 

K               (( 
(I               (t 

a           (t 

19-23 
18-22 
13-17 

45-55 

50-65 
55-75 

21 

20 
15 

50 

58 
65 

7-33 

Arterial  Content 

Venous  Content    

Carbondioxid 

Arterial  Content  (whole 
blood )    

6-32 
3-27 

Venous  Content  (whole 
blood) 

Capacity  ( plasma )    

5-90 

that  these  changes  should  be  very  marked  except  in  severe  pathological 
conditions.  With  sufficiently  delicate  methods,  however,  these  slight 
changes  should  be  readily  detected.  The  development  of  simple  and  very, 
delicate  colorimetric  methods  has  done  much  to  aid  in  this  type  of  work. 

More  and  more  we  have  come  to  consider  the  various  changes  which 
take  place  in  the  body  from  a  quantitative  point  of  view.  The  various 
blood  constituents,  and  certain  blood  determinations,  with  the  range  of 
their  normal  and  pathological  variations,  are  given  in  the  table  above. 

Blood  Volume. — Owing  principally  to  the  recent  work  of  Keith,  Ex>wn- 
tree  and  Geraghty  the  subject  of  blood  volume  has  received  considerable  at- 
tention. These  investigators  have  introduced  a  new  method  of  determine 
ing  blood  volume  and  have  obtained  somewhat  higher  figures  than  those 
fonnerly  given  for  man.  The  principle  underlying  their  method  is  the 
introduction  directly  into  the  circulation  of  a  non-toxic,  slowly  absorbable 
dye  (vital  red)  which  remains  in  the  plasma  long  enough  for  thorough 
mixing,  and  the  detei-mination  of  its  concentration  in  the  plasma  colori- 
metrically  by  comparison  with  a  suitable  standard  mixture  of  dye  and 
serum.  According  to  this  method  the  plasma  nonnally  constitutes  ap- 
proximately 5  per  cent,  or  one-twentieth  of  the  body  weight.  The  volume 
occupied  by  the  corpuscles  was  calculated  with  the  aid  of  the  hematocrite 
and  found  to  average  43  per  cent  for  the  erythrocytes  and  57  per  cent  for 
the  plasma.  On  this  basis  Keith,  Eowntree  and  Geraghty  have  calculated 
that  blood  normally  constitutes  8.8  per  cent  or  1/11.4  of  the  body  weight. 
With  this  method  they  were  able  to  demonstrate  the  amount  of  decrease  in 
blood  voliune  as  the  result  of  hemorrhage  and  of  the  increase  following 
intravenous  infusion  of  saline. 

Significant  observations  were  made  in  a  few  pathological  conditions. 
Both  the  blood  and  plasma  volume  are  increased  in  pregnancy,  before, 
term,  but  return  to  nonnal  within  a  week  or  two  after  deliveiy.  In  obesity 
the  plasma  and  blood  volumes  are  rehitively  small.    ^Fany  cases  of  anemia 


426 


VICTOR  C.  :^IYERS 


exhibit  a  relatively  higb.  blood  volume,  while  in  some  cases  pol^^cytheniia  in 
the  sense  of  a  high  blood  count  may  be  dependent  on  a  low  plasma  volume. 
Jn  anasarca  accompanying  myocardial  insufficiency  the  blood  voknno  may 
be  absolutely  increased.  In  many,  cases  of  maiked  hypertension  tho 
volume  is  small,  indicating  that  hy|x}rtension  is  not  necessarily  dependent 
upon  a  large  blood  volume. 

More  recently  a  very  elaborate  study  of  the  question  of  blood  volume 
Las  been  carried  out  on  animals  by  Whipple  and  some  of  his  coworkers. 
Since  "vital  red''  was  not  available,  their  earlier  experiments  Avere  made 
with  "brilliant  vital  red."  Later  they  tried  out  a  veiy  large  series  of 
dyes  for  use  in  this  connection,  and  discovered  a  blue  azo  dye  which  ap- 
pears to  be  slightly  superior  to  the  vital  red  group,  especially  as  regards 
ease  and  accuracy  of  colorimetric  readings.  In  the  same  series  of  papers 
McQuarrie  and  Davis  have  employed  a  method  of  deteraaining  blood 
volume  which  consists  essentially  in  reading  refractometrically  the  serum 
non-protein  increase  after  the  intravenous  injection  of  a  known  amount  of 
acacia  or  gelatin  solution,  or  a  mixture  of  the  two.  The  results  obtained 
were  quite  comparable  to  the  dye  methods  and  an  acacia  method  described 
by  Meek  and  Gasser. 

The  most  recent  publication  on  blood  volume  is  that  of  Bock  who  pre- 
sents some  very  interesting  data,  obtained  with  the  vital  red  method,  on 
five  normal  and  twenty  pathological  cases.  The  constancy  of  the  plasma 
volume  under  widely  varying  conditions  is  pointed  to  as  a  striking  fact. 
Although  the  plasma  volume  remains  practically  normal  in  polycythemia 
and  anemia,  as  shown  by  the  table  below  taken  from  Bock,  the  total  blood 
volume  is  increased  in  the  former  and  decreased  in  the  latter  owing  to  varia- 
tions in  the  cell  content 

Data  ox  Blood  Volume 


Condition 


Normal    

PolycytheTnia  . . . , 
Pernicious  Anemia 
Miscellaneous  . . . . 
Diabetes    


Number  of 
Cases 


Total 

Plasma 

Per  Cent  of 

Body 
Weight 


5.1 
5.1 

4.9 
4.9 

4.8 


Total 

Blood 

Per  Cent  of 

Body 

Weight 


8.2 
13.7 
5.7 
7.1 
7.3 


Hemoglobin 

Calculated 

from  Oj 

Capacity 

Per  Cent 


119 

163 

47 

79 

118 


Bed  Blood 
Cells  in 
Millions 


4.8 
9.1 
1.6 
3.9 
4.6 


Blood  volume  methods  have  been  critically  discussed  by  Lamson  and 
Nagayama,  but  the  authors  concede  that  the  plasma  volume  method  of 
Keith,  I-iowntree  and  Geraghty  is  as  correct  as  any  and  the  best  method 
at  our  dis};osal  for  most  purposes. 

Total  Solids. — ^Where  a  careful  quantitative  examination  of  the  blood 
is  being  carried  out,  the  estimation  of  the  total  solids  is  often  of  considei^ 


BODY  TISSUES  AND  FLUIDS  427 

able  value.  In  the  first  place,  the  solid  content  of  the  blood  is  a  xevy 
cxcellont  index  of  the  functional  condition  of  the  blood,  blood  proteins  and 
blood  cells  taken  together,  and  furtherjuore  is  of  value  in  explaining  small 
fluctuations  in  the  content  of  the  individual  constituents.  Kormally  the 
total  solids  amount  to  from  f.>  lo  2*]  per  cent,  although  iii  primary  and  sec- 
ondary anemia,  severe  nephritis,  etc.,  the  amount  may  be  decreased  to 
nearly  one-half  these  fiiiiires.  That  the  total  .<olids  may  be  increased  in 
cholera,  as  a  result  of  the  severe  diarrhea,  was  recognized  by  Carl  Schmidt 
many  years  ago.  An  increase  in  the  blood  solids  was  found  by  Underbill 
to  result  from  poisoning  by  the  lethal  war  gases. 

Specific  Gravity. — The  specific  gravity  of  human  blood  in  the  adult 
male  varies  between  1.041  and  1.0G7,  the  average  being  about  1.055.  For 
the  female  the  figures  are  slightly  lower.  Tlie  specific  gravity  obviously 
varies  in  much  the  same  way  as  the  solids.  The  detenu ination  appears 
to  be  little  used  at  the  present  time.  Gcttler  and  Baker  have  recently 
given  some  new  obsen-ations  on  serum.  They  found  the  specific  gravity 
of  the  serum  of  both  men  and  women  to  range  from  1.02G  to  1,030,  the 
majority  being  between  1.027  and  1.029, 

Reaction  and  Hydrogen  Ion  Concentration. — Xormal  human  blood  as 
it  exists  in  the  body  is  faintly  alkaline  in  reaction,  i.  e.,  it  has  a  hydrogen 
ion  concentration  only  slightly  less  than  pure  water,  and  tbis  degree  of 
alkalinity  tends  to  bo  veiy  constantly  maintained  under  a  variety  of  con- 
ditions. The  blood  itself,  owing  chiefly  to  the  '^buffer"  action  of  the  car- 
bonates  of  the  plasma  and  phosphates  of  the  corpuscles,  can  take  up  con- 
siderable amounts  of  acid  or  alkali  without  much  change  in  its  reaction. 
An  appreciable  cliange  in  its  hydrogen  ion  concentration  indicates  a  failure 
of  tliis  protective  mechanism  and  the  presence  of  a  severe  acidosis.  From 
a  practical  point  of  view  the  COg  combining  power  of  the  blood,  is  much 
more  useful,  since  the  change  occurs  much  earlier  (see  below). 

As  the  result  of  a  series  .of  analyses  on  thirty  normal  individuals  by 
the  gas  chain  method,  as  described  by  Michaelis,  Gettler  and  Baker  found 
pH  to  range  from  7.52  to  7.C0  at  22°C.  Lev^',  Kowntree  and  Marriott 
have  described  a  very  simple  indicator  method  of  determining  the  hydro- 
gen ion  concentration  and  serum.  With  this  method  oxalated  blood  from 
normal  individuals  gave  a  dialysate  with  a  pH  varying  from  7.4  to  7.6, 
while,  that  of  the  serum  ranged  from  7.G  to  7.8.  In  a  small  series  of 
clinical  acidoses,  the  serums  varied  from  T'.SS  to  7.2  and  the  oxalated  blood 
from  7.3  to  7.1. 

Blood  Proteins. — Considerable  experimental  evidence  has  recently  been 
adduced  by  Kerr,  Hunvilz  and  Whipple  (c)  which  points  to  the  liver  as  be- 
ing concerned  in  the  maintenance  of  a  normal  level  of  the  blood  serum 
proteins  (albumin  and  globulin).  The  evidence  is  not  so  convincing  nor 
so  striking  as  that  obtained  by  Whipple  for  the  plasma  protein  fibrinogen 
which  has  such  an  intimate  relation  to  liver  iniurv.     In  the  case  of  the 


428 


VICTOR  C.  MYERS 


Mood  serum  proteins  tlie  stability  of  the  norrnal  level  appears  to  be  fairly 
well  maintained  under  widely  varviuir  conditions  of  health  and  disease. 

Serum  Proteins  (Albumin  and  GlolmUn), — Tlie  subject  of  the  serum 
proteins  in  man  has  recently  been  very  carefully  considered  by  Rowe  (?>), 
who  has  employetl  the  microrefraetonictric  metliod  of  Kolxntson  for  their 
study  in  normal  and  a  nimiber  of  different  pathological  conditions.  In  a 
series  of  twenty-two  normal  cases  the  serum  albumin  was  found  to  vary  be- 
tween 4.G  and  6.7  per  cent,  the  senmi  elubulin  between  1.2  and  2.3  per  cent, 
the  total  serum  protein  between  G.5  and  8.2  per  cent  and  the  nonproteins 
between  1.1  and  1.3  per  cent,  while  the  percentage  of  globulin  in  the  total 
protein  varied  from  16  to  52  per  cent.  Muscular  activity,  even  of  the 
simplest  sort,  increases  total  seinim  proteins,  this  increase  occui'riug  more 
in  the  albumin  than  the  globulin  fraction.  In  tliree  cases  with  severe 
muscular  work  Rowe  (c)  fowid  the  total  protein  increased  from  1.1  to  1.9 
per  cent  and  the  albumin  from  0.8  to  1.5  per  cent,  while  in  one  case  with 
light  exercise  the  totiil  protein  was  increased  0.5  per  cent  and  the  albumin 
0.3  per  cent. 

The  following  table  compiled  from  data  given  by  Rowe  gives  a  com- 
parative idea  of  the  blood  serum  proteins  in  the  normal  human  subject  and 
in  a  variety  of  pathological  conditions. 

Blood  Serum  Proteixs  in  Health  and  Disease  (Averages) 


Condition 

Number  of 
Cases 

Albumin 
Per  Cent 

Globulin 
Per  Cent 

Total 

Protein 

Per  Cent 

Globulin  to 

Total 

Protein 

Per  Cent 

Normal  subjects   

STphilis   

22 

19 

8 

3 

5 

7 

9 

9 

10 

0 

5.6 

5 

3.7 

2.5 

4.2 

4.5 

4.7 
4.8 
5.5 
3.9 

1.9 
2.5 
2.5 

1.7 

2.3 

2.2 

2.G 
2.3 
1.9 
1.7 

7.5 
7.5 
6.2 

4.2 

6.5 

6.7 

7.3 
7.1 

7.4 
5.6 

22.5 
34 

Pneuinonia    

40 

Chronic  nephritis  with 
edema    

40 

Chronic  nephritis  with 
uremia    

35 

Chronic  nephritis 
without   uremia   or 

33 

Cardipc.    decompcnsa- 
tion      »,... 

36 

Arteriosclerosis   

Diab(>te«  

32 
26 

Anen'iia 

30 

From  the  above  it  is  apparent  that  in  syphilis  the  globulin  is  definitely 
increased,  while  the  total  protein  remains  about  normal.  In  pneumonia 
the  globulin  is  increased  more  in  relation  to  the  total  protein  than  in 
syphilis,  while  the  total  protein  is  reduced,  due  probably  in  large  measure 
to  a  dilution  of  the  blood  serum  hy  water  retention,  which  ocxjurs  in  fever. 
The  lowest  values  for  total  serum  proteins  are  obtained  in  chronic  nephritis 
with  edema,  due  probably  to  chronic  intoxication  as  well  as  hydremia. 


BODY  TISSUES  AND  FLUIDS  429 

In  chronic  nephritis  with  uremia  the  total  proteins  may  he  nearly  nonnal 
hut  the  glohulin  is  usually  increased.  Except  in  very  severe  diabetes  the 
findings  are  practically  normal.  In  pernicious  anemia  the  total  proteins 
are  not  as  low  as  would  he  expected  from  examination  of  the  whole 
blood,  being  higher  than  in  nephritis  vvith  edema. 

Fibrinogen. — According  to  Whipple  the  noi-mal  fibrinogen  limits  for 
the  human  subject  may  be  given  as  O.'J  to  0.«>  pf'r  cent  with  an  average  of 
0.5  per  cent  per  11)0  e.c.  of  plasma.  In  pneumonia  and  septicemia  fibrino- 
gen is  much  above  normal,  reaching  0.0  per  cent,  while  in  acute  liver  in- 
jury it  drops  to  a  very  low  level  or  even  zero  in  some  fatal  cases.  In  chronic 
liver  disease  fibrinogen  often  falls  markedly  and  may  cause  bleeding 
(cirrhosis).  In  general  cachexias,  such  as  sarcomatosis,  nephritis  and 
miliary  tuberculosis,  the  fibrinogen  may  be  quite  low,  0.1  per  cent. 

Hemoglobin. — Hemoglobin  is  the  iron  containing  and  oxygen  carry- 
ing pigment  of  the  red  blood  cells.  It  is  a  conjugated  protein,  composed  of 
the  histon,  glohin,  and  hetnochrowogen,  the  iron  containing  pigment.  In 
the  presence  of  oxygen  the  latter  body  is  rapidly  transformed  into  hematin. 
Hemoglobin  is  crystal lizable,  and  peculiar  in  its  high  iron  content,  which 
amounts  to  0.34  per  cent.  Under  normal  conditions  it  is  quite  completely 
saturated  (95  per  cent)  with  oxygen  in  arterial  blood,  although  in  the 
case  of  venous  blood  the  oxygen  is  ordinarily  reduced  to  about  75  per  cent 
of  saturation.  Owing  to  this  fact  the  hemoglobin  of  the  blood  may  be 
more  con-ectly  referred  to  as  oxyhemoglobin.  Oxyhemoglobin  has  a  bright 
red  color  but  (reduced)  hemoglobin  is  darker  and  more  violet  or  purplish, 
hence  the  darker  color  of  Venous  blood.  For  further  properties  of  hemo- 
globin and  its  many  derivatives  reference  may  be  made  to  Hammarsten. 

The  estimation  of  hemoglobin  was  apparently  the  first  chemical  de- 
termination in  the  blood  to  find  extensive  clinical  application.  It  seems  un- 
fortunate that  most  of  the  estimations  recorded  should  have  been  made 
employing  an  empirical  scale  with  100  as  the  normal,  especially  since 
the  100  is  somewhat  of  a  variable  factor  with  different  methods  owing 
to  different  standardizations.  Tlio  hemoglobin  content  of  the  blood 
varies  widely  not  only  in  disease,  but  also  in  different  age  periods  as  re- 
cently pointed  out  by  Williamson.  Far  this  reason  it  would  appear  more 
logical  to  record  the  hemoglobin,  as  we  do  other  blood  detemiinations,  in 
grams  per  100  c.c.  or  per  cent. 

The  table  below  compiled  from  observations  of  Williamson  w^ell  illus- 
trates the  changes  in  the  hemoglobin  content  of  the  blood  over  dift'erent 
age  periods.  The  figures  were  obtained  with  the  accurate  spectrophoto- 
metric  method,  fifteen  or  more  of  both  males  and  fenniles  being  employed 
for  each  age  group.  From  this  table  it  wiU  be  noted  that  during  the  first 
few  days  of  life  the  hemoglobin  content  exceeds  20  per  cent,  bjiit  then 
drops  rather  abruptly  the  third  month  to  below  14  per  cent  and  does  not 
pass  this  figure  until  the  tenth  year.     During  the  adult  period  of  life  in 


^ 


430 


VICTOR  0.  AEYERS 


Hemoglobin  in  Xormal  Males  and  Females  During  Differr.vt  Age  Periods 


1  flay    

2  to    3  davs    

4  to    8  dav.s    

9  to  13  days    

2  weeks  to  2  months 


3  to    5  months 
6  to  11  months 

1  year  

2  years  

3  years  

4  years  

5  years  

6  to  10  years  . 
11  to  15  years  . 


16  to  20 
21  to  25 
26  to  30 
31  to  35 
36  to  40 
41  to  45 
46  to  50 
51  to  55 
56  to  00 
ei  to  65 


years 
years 
years 
years 
years 
years 
years 
years 
years 
years 


66  to  70  years 
71  to  75  years 
76  and  over  . . 


Hemoglobin 
Gm.  per  100  c.c.  of  Blood 


Male 

Female 

Both  Se.xes 

23.3 

23.2 

23..1 

22.5 

23.1 

22.8 

22.1 

22.1 

22.1 

21.4 

21.3 

21.4 

18.7 

18.0 

18.4 

13.1 

14.3 

13.7 

13.2 

14.2 

1.17 

12.8 

12.2 

12.5 

12.4 

12.7 

12.6 

13.2 

13.1 

13.2 

13.3 

14.0 

13.6 

13.8 

13.3 

13.5 

14.6 

13.7 

14.2 

14.5 

14.9 

14.7 

16.8 

15.6 

16.3 

17.2 

15.0 

16.0 

16.4 

15.5 

15.9 

16.9 

15.4 

16.2 

17.0 

15.4 

16.2 

16.9 

15.6 

16.2 

17.1 

15.5 

16.3 

17.0 

16.1 

16.6 

17.0 

15.8 

16.4 

16.5 

15.7 

16.1 

16.2 

15.5 

15.8 

15.2 

15.5 

15.3 

15.7 

15.0 

15.4 

both  sexes  (from  16  to  70  years)  the  henioglobin  maintaius  a  fairlv  con- 
stant level  of  about  10  per  cent.  From  the  third  month  to  the  fifteenth 
year  the  values  obtained  in  the  female  appear  to  slightly  exceed  the  male, 
although  from  16  to  60  years  the  reverse  is  tnie,  the  hemoglobin  of  the 
female  averaging  close  to  15.5  per  cent,  while  in  the  male  it  reaches  nearly 
17  per  cent. 

A  few  observations  taken  from  ^leyer  and  Butterfield  are  given  in-  the 
table  below.     They  employed  the  same  method  as  did  Williamson  and 

Hemocji.obin  Content  of  the  Blood  of  Normal  and  Pathological  Sub.jects 


Subjects 

Specific 
Gravity 

Erythrocytes, 

Million  per 

cu.  mm. 

Hemoglobin 
Content  of 
Blood,  gm. 

per   100  c.c. 

Color 
Inde.Y 

Normal  men,  av.  7  cases    

Normal  women,  a  v.  6  cases    .  . 

Pyrnicioiis  anemia,  I    

Pernicious  anemia,  II    

Secondary  anemia    

1.059 
1.057 
1.040 
1.035 

i.675 

4.92 
4.75 
0.74 
0.87 
2.43 

16.60 
15.20 
3.47 
3.79 
5.59 
23.90 

1.0 
1.0 
1.5 
1.3 
0.7 

Polycythemia 

BODY  TISSUES  AND  FLUIDS  431 

their  figures  for  normal  adults  are  in  substantial  agreement  with  those  re- 
corded above.  The  few  pathological  data  are  of  interest.  In  the  cases 
of  pernicious  anemia  it  will  be  noted  that  the  hemoglobin  dropped  to  the 
low  figure  of  about  3.5  per  cent,  while  in  the  case  of  polycythemia  it  reached 
23.1>  per  cent. 

Since  the  serum  proteins,  albumin  and  globulin,  vary  only  to  a  limited 
extent,  as  previously  noted,  it  is  apparent  that  hemoglobin  is  ordinarily 
not  only  the  largest  but  also  the  most  variable  factor  in  the  make-up  of 
the  total  solids.  For  this  reason  hemoglobin  estimations  provide  a  simple 
method  of  securing  information  regarding  the  total  solid  content  of  the 
blood.  Underbill  used  the  estimation  for  this  purpose  to  excellent  ad- 
vantage in  the  treatment  of  poisoning  with  lethal  war  gases.  It  may  be 
assumed  that  daily  fluctuations  in  the  amount  of  hemoglobin  in  the  cir- 
culating blood  are  slight  and  that  such  fluctuations  in  the  hemoglobin  con-^ 
tent  are  due  to  changes  in  blood  volume.  The  frequent  estimation  of  the 
hemoglobin  content  of  the  blood  in  short  series  of  experiments  therefore 
constitutes  a  simple  means  of  following  small  changes  in  blood  volume. 

There  would  seem  to  be  no  good  reason  why  the  clinical  estimation  of 
hemoglobin  should  not  be  put  on  a  more  exact  basis,  comparable  with  many 
of  our  other  chemical  blood  analyses.  Palmer  (b)  has  recently  described  a 
very  simple  and  accurate  method  of  estimating  hemoglobin  as  carboxy- 
hemoglobin,  while  Van  Slyke's  (c)  method  of  detei-mining  the  oxygen  ca- 
pacity of  the  blood  is  valuable  in  furnishing  an  occasional  check  on  the  col- 
orimetric  methods  and  in  the  preparation  of  a  blood  standard.  It  should 
also  be  noted  that  several  recent  papers  have  shown  that  hemoglobin  can 
be  accurately  estimated  by  the  acid  hematin  method  of  Sahli,  provided 
certain  precautions  are  followed  and  a  good  colorimeter  employed. 

Blood  Cells. — The  blood  cells  (erythrocytes,  leucocytes  and  blood 
plates)  are  of  interest  in  this  connection  only  in  so  far  as  variations  in 
their  content  affect  the  chemical  composition  of  the  blood  as  a  whole.  The 
figures  which  are  generally  given  for  the  erythrocytes  of  the  adult  male 
and  female  are  5  million  per  cubic  millimeter  for  the  foraier  and  4.5  mil- 
lion for  the  latter.  Values  higher  than  these  are  not  uncommon  but  the 
number  rarely  exceeds  six  million  in  perfectly  normal  individuals.  Since 
the  red  cells  are  composed  of  hemoglobin  roughly  to  the  extent  of  90  per 
cent  it  is  apparent  that  the  hemoglobin  content,  and  the  total  solid  content 
as  w-ell,  stand  in  fairly  close  relationship  to  the  number  of  red  cells.  In 
pernicious  anemia  the  number  of  cells  may  be  reduced  to  as  small  a  num- 
ber as  0.5  million  or  even  less,  while  in  some  cases  of  secondary  anemia 
very  low  figures  are  found.  Meyer  and  Butterfield  have  pointed  out 
that  the  high  color  index  obser\^ed  in  many  cases  of  pernicious  anemia  is 
due  to  an  increase  in  the  oxyhemoglobin  content  of  the  red  cells  (see  table 
on  p.  430).  In  the  secondary  anemias  the  color  index  is  frequently  low- 
ered, apparently  for  the  reverse  reason.    As  would  seem  evident  from  the 


432  VICTOR  C.  MYERS 

lirnioglobin  fahio  of  Williamson  above,  the  red  coll  count  is  very  high  at 
t)irth,  roa<-hin<^'  7  million  in  some  instances,  Imt  drops  to  a  fairly  constant 
level  after  the  sixth  to  the  tenth  day.  Owin^-  to  the  diminished  oxygen 
tension  at  Iiigh  altitndes  the  nnmher  of  red  cells  is  iuer«'ase«I  to  maintain 
th«'  oxyiien  carrying  capacity  of  the  blood  at  a  normal  I"vel.  the  nnnd)er 
lieinir  raise* I  to  7  to  0  million  in  extreme  instances.  A  ulative  increase 
in  the  nnmher  of  red  cells,  or  relative  polycythemia,  may  ocf-nr  as  resnlt  of 
^Aveatintr,  diarrhea,  etc.,  while  an  absolnte  polycythemia  is  occasionally  en- 
countered, particularly  in  congenital  heart  disease  and  in  Osier's  disease. 
The  number  of  leucocytes  normally  varies  between  3.00n  and  10,000  per 
cubic  millimeter,  although  figures  between  5,000  and  ♦'»,<»< >0  are  the  most 
often  encountered  in  a  fasting  condition.  The  leucocyrr-s  are  subject  to 
greater  physiological  variation  than  the  red  cells,  but  considering  their 
much  smaller  number  in  comparison  with  the  red  cells,  these  variations 
have  little  influence  on  the  chemical  composition  of  the  blood  as  a  whole. 
In  the  leucemiaSj  however,  the  leucocyte  count  may  nse  to  000,000  and 
even  higher.  With  such  a  marked  leucocytosis,  and  cunse<juent  leucolysis, 
tho  uric  acid  content  of  the  blood  may  be  greatly  increased.  Although  the 
blood  plates  are  normally  regarded  as  amounting  to  fr«»m  2<X),000  to  500,- 
000  per  cubic  millimeter,  on  account  of  their  small  size,  -j  u,  their  variation 
is  apparently  without  influence  upon  the  chemical  composition  of  the  blood. 


Blood  Nitrogen 

Total  Nitrogen. — The  total  nitrogen  content  of  perfectly  noraial  blood 
amounts  to  somewhat  more  than  -*  per  cent.  Of  this.  l»i»  j>er  cent  is  de- 
rived from  the  various  proteins  of  the  blood,  about  three-quarters  being 
from  the  cellular  constituents,  chiefly  the  hemoglobin,  and  one-quarter  from 
the  plasma  proteins,  albumin,  globulin  and  fibrinogen.  The  hemoglobin  is 
obviously  the  most  important  as  Avell  as  the  most  variable  contributor  to 
the  total  nitrogen.  In  pernicious  anemia  the  total  uitr^iien  may  be  re- 
duced to  considerably  less  than  half  the  normal  figure,  while  in  severe 
nephriti;^  the  nitrogen  content  is  frecpiently  very  low. 

Non-protein  Nitrogen. — Although  the  non-protein  nitrogen  normally 
constitutes  only  about  one  per  cent  of  the  total  nitrogen  of  the  blood,  never- 
theless greater  interest  is  attached  at  the  present  time  to  variations  in  the 
bodies  which  form  the  non-protein  than  the  protein  nitrooen.  This  is  due 
largely  to  the  fact  that  the  variations  in  these  non-protein  constituents 
give  us  an  insight  into  some  of  the  processes  of  anabolis-rn  and  catabolism. 
The  focni  nitrog:en  is  carried  by  the  blood  to  the  various  tissues  and  the 
waste  nitrogen  to  the  kidneys,  directly  or  indirectly  by  the  same  medium. 
After  a  meal  containing  protein  there  is  a  temporary  elevation  in  the 
non-protein  and  amino  nitrogen  of  the  blood.     In  diseases  of  the  kidney 


BODY  TISSUES  A:N^D  FLUIDS 


433 


there  may  be  at  first  only  a  slight  rise  in  the  uric  acid  or  urea,  although 
in  the  terminal  stages  of  the  disease  there  is  generally  a  very  marked  ele* 
vation  in  all  the  forms  of  non-protein  nitrogen.  The  normal  range  of  the 
various  non-protein  nitro^renous  components  is  given  in  the  table  below. 
Data  are  also  included  indicating  the  deviations  which  may  occur  in  gout, 
interstitial  and  parenchymatous  nephritis  and  eclampsia. 

As  will  be  noted  in  the  table,  the  normal  range  for  the  non-protein 
nitrogen  is  given  as  25-30  mg.  ner  100  c.c.  of  blood.  In  discussing  the 
question  of  the  normal  values  for  the  non-protein  nitrogen  there  are  two 
very  important  factors  which  should  always  be  considered,  viz.,  the  protein 
precipitant  employed  and  the  proximity  to  the  last  meal.  The  results  re- 
ported with  the  original  method  of  Folin  and  Denis  (/)  are  probably  a  little 
too  low,  owing  to  the  use  of  methyl  alcohol  as  the  protein  precipitant. 
Folin  and  Denis  originally  obtained  figures  of  22-2G  mg.,  while  Tileston 
and  Comfort  found  23-25  mg.  with  a  series  of  five  normal  adults  in  a  fast- 
ing state,  and  26-32  mg.  two  and  a  half  hours  after  a  heavy  protein 
meal.  More  satisfactorv  results  are  obtained  after  the  triehloraccitic 
acid  precipitation  of  Greenwald  (d)  or  use  of  the  tungstic  acid  reagent  re- 
cently employed  by  Folin  and  Wu.  After  these  methods  of  precipitation 
figures  close  to  30  mg.  are  generally  obtained  on  a  normal  individual  in 
the  fasting  state. 


NoM>ROTEix  NrraoGE-Nous  Constituents,  mg.  to  100  c.c.  of  Blood 


Early 

Terminal 

Paren- 

Constituents 

Normal 

Gout 

Interstitial 
Nephritis 

Interstitial 
Nephritis 

chymatous 
Nephritis 

Eclampsia 

Xon-protein    N. 

25-30 

30-50 

to  350 

3.5-55 

Urea  N 

12-15 

12-30 

300 

30-60 

7-16 

Uric  Acid 

2-3 

4-10 

3-10 

25 

3-10 

Creatinin    

1-2 

2-4 

35 

1-2.5 

Creatin  

3-7 

30 

Amino  Acid  N. 

6-8 

30 

• 

4-8 

Ammonia  N. . . 

0.1 

1 

The  figures  for  the  normal  creatin  are  taken  from  observations  of  Denis,  those 
for  amino-acid  nitrogen  from  Bock,  except  in  the  case  of  eclampsia,  where  the  observa- 
tions of  Losee  and  Van  Slyke  are  recorded;  other  data  in  eclampsia  are  from  recent 
observations  of  Killian.  With  these  exceptions  the  data  are  from  the  writer's  observa- 
tions. 

The  figures  for  ammonia  are  very  small,  but  these  figures  may  be  taken  as  the 
maximal  rather  than  the  minimum  values.  The  very  recent  observations  of  Nash  and 
Benedict  on  the  ammonia  content  of  the  blood  (made  on  dogs  and  cats)  give  figures 
between  0.03  and  0.2  mg.  to  100  c.c. 

The  origin  and  role  which  the  various  non-protein  nitrogenous  constit- 
uents play  in  metabolism,  as  well  as  the  ease  of  kidney  secretion,  obviously 
greatly  influence  the  content  of  these  substances  in  the  blood,  both  normally 
and  pathologically.  Folin's  classic  papers  on  the  composition  of  urine 
(for  discussion,  see  Chapter  TV)   published  in  IDO;'),  did  much  to  give 


434 


VICTOR  C.  MYERS 


us  a  correct  appreciation  of  the  sigiiificanco  of  the  nitrogenous  waste  prod- 
ucts which  find  their  exit  throu<i;h  the  kidney.  He  pointed  out  that  the 
urea  and  creatiniii  stood  in  marked  contrast  to  each  other,  since  the  fomier 
was  Largely  exoiicnons  in  origin,  while  the  latter  was  almost  entirely  of 
endogenous  formation.  Uric  acid  stood  in  somewhat  of  an  intermediate 
position,  being  about  half  endogenous  and  half  exogenous  under  ordinary 
conditions  of  diet. 

Satisfactory  interpretations  of  variations  in  these  non-protein  nitrog- 
enous constituents  of  the  blood  can  scarcely  be  made  without  a  knowl- 
edge of  their  origin.  The  following  brief  statement  may  be  made  regard- 
ing the  formation  of  these  compounds.  Urea  is  formed  largely  in  the 
liver  from  the  ammonia  resulting  from  the  deaminization  of  amino-acids 
set  free  in  digestion,  but  not  of  immediate  use  to  the  animal  organism. 
Uric  acid  originates  as  a  result  of  the  enzymatic  transformation  of  the 
amino-  and  oxypurins,  in  which  various  glands  of  the  body  participate. 
Creatinin  would  appear  to  be  fonned  in  the  muscle  tissue  from  creatin. 


COMPARAXn-E  NiTBOGEX    PARTITION   OF   UrIXE  AND   BlOOD  IN   PeR  CeNT  OF 

PROTEIN    NiTBOGEX 

Total  Non- 

Fluid 

Uric  Acid 

N 

Urea 

N 

Creatinin 

N 

Ammonia 

N 

Rest 
N 

Normal  urine 

Normal  blood  

Blood    in    gout    and 
early  nephritis    . . . 

Blootl  in  parenchyma- 
tous nephritis    (ne- 
phrosis)   

Blood  in  terminal  in- 
terstitial nephritis. 

1.5 
2 

6 

2 
2  to  3 

85 
50 

50 

55 
75 

5 
2 

2 

2 

2.5 

4 
0.3 

0.3 

0.3 
0.5 

4.5 
46 

42 

40 
20 

It  is  of  interest  to  compare  the  partition  of  the  non-protein  nitrog- 
enous constituents  in  the  blood  with  similar  partition  in  the  urine.  (See 
above.)  Upon  the  ordinary  mixed  diet  their  approximate  distribution 
in  the  urine  is  85  per  cent  urea  N,  1.5  per  cent  uric  acid  J^,  5  per  cent  cre- 
atinin X,  4  per  cent  ammonia  IN^  and  4.5  per  cent  undetermined  X.  It  is 
quite  natural  to  expect  a  somewhat  similar  relationship  in  the  non-pro- 
tein nitrogenous  constituents  of  the  blood,  but  the  above  table  discloses 
quite  a  different  distribution.  It  will  be  noted  that  even  in  normal  blood 
the  percentage  of  uric  acid  nitrogen  is  greater,  if  anything,  than  in  the 
urine,  while  the  urea  is  definitely  lower,  the  contrast  with  the  uric  acid  in 
the  case  of  the  creatinin  and  ammonia  being  even  more  marked.  As  Folin 
and  Denis  have  pointed  out,  the  human  kidney  removes  the  creatinin 
from  the  blood  with  remarkable  ease  and  certainty,  the  completeness  of  the 
creatinin  excretion  being  exceeded  only  by  the  still  more  complete  removal 
of  the  ammonium  salts.  The  striking  difference  between  the  ability  to  ex- 
crete uric  acid  on  the  one  hand,  and  urea  and  creatinin  on  the  other,  is 


BODY  TISSUES  AND  FLUIDS  485 

brought  out  fn)in  an  oxaini nation  of  the  normal  concentration  of  the  ])lood 
and  urine.  ♦ludginii:  From  their  comparative  conipoji^ition,  the  kidney  nor- 
mally concentrates  the  creatinin  100  times,  the  urea  80  times,  but  the 
uric  acid  only  20  times.  Myers,  Fine  and  Lough  have  pointed  out  that  as 
the  permeability  of  the  kidney  is  h»\vered  in  conditions  of  renal  insutfi- 
ciency,  this  becomes  evident  in  the  blood,  first  by  a  retention  of  uric  acid, 
later  by  that  of  urea,  and  lastly  by  that  of  creatinin,  indicating  that 
creatinin  is  the  most  readily  eliminated  of  these  three  nitrogenous  waste 
products,  and  uric  acid  the  most  difficultly  eliminated,  with  urea  standing 
in  an  intennediate  position. 

Urea. — As  indicated  in  the  table  above  on  non-protein  nitrogenous  con- 
stituents the  blood  urea  of  a  strictly  nonnal  individual  taken  in  the  morn- 
ing before  breakfast  appears  to  fall  within  tlie  comparatively  narrow 
limits  of  12-15  mg.  urea  nitrogen  per  100  c.c.  of  blood.  Occasionally  fig- 
ures outside  of  the  limits  may  be  observed  such  as  10-18  mg.,  but  figures 
above  20  mg.  can  ordinarily  be  regarded  as  pathological.  These  state- 
ments apply  only  to  normal  individuals  on  moderate  pi*otein  diets  where  the 
blood  has  been  taken  in  the  morning  before  breakfast.  As  Tileston  and 
Comfort,  and  Addis  and  Watanabe  have  shown,  high  protein  diets  may 
considerably  raise  these  figures,  especially  in  certain  individuals,  while 
Folin,  Denis  and  Seymour  have  conclusively  shown  that  lowering  the 
level  of  protein  metabolism  serves  to  reduce  the  non-protein  and  urea 
nitrogen  of  the  blood  in  mild  cases  of  chronic  interstitial  nephritis. 

Since  urea  is  the  chief  component  of  the  non-protein  nitrogen,  and 
since  its  estimation  is  considerably  simpler  than  that  of  the  non-protein 
nitrogen,  attention  will  be  directed  especially  to  the  urea.  Mosent!ial 
and  Ilillcr  have  made  a  careful  study  of  the  relation  of  the  urea  to  the 
non-protein  nitrogen  in  disease.  They  point  out  that  the  selective  action 
of  the  kidney  maintains  the  urea  nitrogen  at  a  level  of  50  per  cent  or  less 
of  the  total  non-protein  nitrogen  of  the  blood,  but  that  an  impaimient  of 
renal  function,  even  of  very  slight  degree,  may  result  in  an  increase  of 
the  percentage  of  urea  nitrogen.  In  advanced  cases  this  may  be  even 
higher  than  the  75  per  cent  given  in  the  preceding  table. 

To  give  a  comparative  idea  of  the  values  observed  for  urea  nitrogen  in 
various  pathological  conditions,  illustrative  findings  are  given  for  a  num- 
ber of  different  conditions  in  the  table  l)elow  taken  from  a  recent  paper  by 
the  writer,  the  data  being  from  actual  cases.  As  will  be  noted,  the 
conditions  in  which  nitrogen  retention  may  occur  are  quite  numerous. 
Marked  urea  retention  may  occur  not  only  in  the  terminal  stages  of  chronic 
interstitial  nephritis,  but  also  in  such  conditions  as  bichlorid  poisoning 
and  double  polycystic  kidney,  and  in  some  cases  of  acute  nephritis.  In 
parenchymatous  nephritis  the  findings  are  comparatively  low.  Relatively 
high  figures  are  frequently  noted  in  malig-nancy,  pneumonia,  intestinal 
obstruction,  load  poisoning,  and  sometimes  in  syphilis  and  cardiac  condi- 


436 


VICTOE  C.  MYERS 


CONDITIONS    WITH    SiGXIHCANT   UllEA   MiTliOGEX    FlXDlXGS 


Mg.  to  100  c.c.  of 

llfood 

Case 

Uia^nosirt 

Uric  Acid 

Urea  X 

Croat  in  in 

*-'  f  U^  tl  v^oco 

1 

15.0 

240 

33.3 

Hiclilorid  poisoning 

2 

4.5 

75 

8.5 

Double  polycystic  kidney 

3 

14.3 

263 

22.2 

Terminal  chronic  interstitial  nephri- 
tis 
Karly  chronic  interstitial  nephritis; 

4 

9.5 

25 

2.5 

died  3  years  later 

5 

8.3 

72 

3.2 

Chronic  ditTusc  nephritis;  syphilis 

6 

2.3 

28 

1.9 

Chronic  parenchymatous  nephritis 

7 

11.4 

106 

6.1 

Severe  acute  nephritis;   recovery 

8 

, 

50 

2.5 

Mild  acute  nephritis 

9 

"oj 

58 

3.4 

General  carcintmiatosia 

10 

5.5 

24 

3.1 

Carcinoma  of  larynx 

11 

9.0 

46 

3.3 

Severe  pneumonia;  recovery 

12 

43 

2.9 

Syphilis 

13 

5.5 

44 

3.3 

Intestinal  obstruction 

14 

24 

2.5 

Gastric  ulcer 

15 

S.Z 

20 

2.0 

Duodenal  ulcer 

16 

7.2 

18 

2.2 

Prostatic  obstruction 

17 

... 

14 

2.9 

Myocarditis 

18 

ii.o 

18 

2.2 

Diabetes  of  long  standing 

19 

8.4 

12 

2.9 

Gout 

20 

6.8 

7 

2.2 

Eclampsia 

tians,  although  in  the  last  mentioned  this  is  probably  due  to  renal  com- 
plications. In  uncomplicated  cases  of  prostatic  obstniction  the  findings 
do  not  appear  to  much  exceed  20  mg.  urea  nitrogen.  A  slight  retention 
ib  frequently  noted  in  gastric  and  duodenal  ulcer,  possibly  for  the  same 
reason  that  retention  is  found  in  intestinal  obstruction.  Advanced  cases 
of  diabetes  frequently  show  definitely  high  fig-ures,  apparently  duo  in  some 
instances  to  the  high  protein  diet,  in  others  to  a  complicating  nephritis. 
The  fact  that  a  normal  urea  is  associated  with  a  high  uric  acid  is  of  prac- 
tical value  in  cases  of  gout  not  complicated  by  nephritis.  In  normal  preg- 
nancy, the  findings  for  urea  nitrogen  are,  strangely  enough,  subnormal, 
figures  between  5  and  9  having  been  observed.  In  eclampsia  the  urea  is 
generally  subnormal,  but  the  non-protein  nitrogen  is  increased  and  the  uric 
acid  is  generally  quite  high. 

Since  urea  is  largely  of  exogenous  origin,  while  creatinin  is  endogenous, 
it  is  subject  to  much  greater  variation,  especially  under  dietary  influences. 
It  is  of  less  prognostic  value  than  the  creatinin  in  advanced  cases  of  neph- 
ritis, but  a  much  better  guide  as  to  the  value  of  the  treatment.  In  cases 
of  prostatic  obstruction  the  urea  is  an  excellent  preoperative  prog- 
nostic test,  miich  better  than  the  creatinin,  for  the  reason  that  cases  show- 
ing creatinin  retention  already  show  sufficient  urea  retention  to  make 
them  very  poor  risks.  The  renal  factor  can  be  disregarded  when  the 
urea  nitrogen  is  20  mg.  or  under,  the  patient  operated  on  wdth  cau- 
tion between  20  and  30,  while  with  figures  over  30  the  outlook  is  un- 


BODY  TISSUES  AXD  FLUIDS  437 

favorable.  Xepliritis  in  children  does  not  so  quickly  result  in  urea 
retention  as  in  the  adult.  On  this  account  it  is  an  esjKJcially  helpful 
pro«:M'»stic  test  in  the  nephritis  occui'ring-  in  e-arly  life. 

Uric  Acid. — No  accurate  H^irures  on  the  nric  acid  content  of  normal 
hunijin  blood  were  available  until  the  introduction  <»f  the  colorimetric 
method  of  Folin  and  Denis  (e)  in  li)i:5.  In  a  sc'ries  of  imselected  cases  Fo- 
lin  and  Denis  (h)  found  between  1  and  3  m«:.  to  100  c.c.  of  blood,  the  aver- 
age being  close  ro  2  nig.  Although  the  accuracy  of  the  method  of  estimating 
nric  acid  has  been  considerably  improved,  still  the  figures  which  are  now 
regarded  as  normal  for  the  blood  uric  acid  differ  very  little  from  those 
originally  reported  by  Folin  and  Denis.  Healthy  adults  most  often  yield 
values  between  2  and  '>  mg.  per  100  c.c.  of  blood,  but  figures  as  low  as 
1  mg.  and  as  high  as  3.5  mg.  may  be  encountered  in  strictly  normal  indi- 
viduals, the  difference  probably  depending  in  part  uix»n  dietary  factors. 
Pligh  blood  uric  acids  must  obviously  depend  upon  either  an  increased  for- 
mation or  a  decreased  elimination. 

In  leucemia  the  first  factor  accounts  for  the  increase,  but  high  uric 
acids  in  most  other  conditions  find  a  probable  explanation  on  the  latter 
basis.  Among  these  may  be  mentioned  nephritis,  acute  and  chronic  (but 
not  parenchymatous),  arterial  hypertension^  lead  poisoning,  bichlorid 
poisoning,  malignancy,  acute  infei^tions,  especially  pneumonia,  gx)ut  and 
apparently  some  cases  of  non-gouty  arthritis.  Miscellaneous  cases  illus- 
trating the  uric  acid  findings  in  many  of  these  conditions  are  given  in  the 
urea  table  above.  Sedgwick  and  Kingsbury  have  made  the  interesting  ob- 
seiTation  that  the  blood  uric  acid  is  high  during  the  fii'st  three  or  four  days 
of  life,  in  hannony  with  the  high  uric  acid  excretion  during  that  period. 

That  the  uric  acid  content  of  the  blood  was  increased  in  gout  was 
recognized  more  than  seventy  years  ago  by  Sir  A.  B.  Garrod.  He  put 
the  subject  of  the  uric  acid  content  of  the  blood  on  a  definite  basis  when 
he  identified  this  substance  in  the  blood  of  patients  suflfering  from  gout, 
and  showed  that  whereas  uric  acid  was  normally  present  in  blood  only  in 
traces,  it  was  definitely  increased  not  only  in  gout,  but  also  in  certain 
cases  of  nephritis.  He  further  showed  that  there  is  no  increase  in  the 
blood  uric  acid  in  rheumatism,  such  as  is  found  in  gout,,  and  used  this  as 
a  point  of  differential  diagnosis.  No  noteworthy  advance  in  this  subject 
was  made  until  the  advent  of  the  colorimetric  method  of  Folin  and  Denis 
previously  referred  to. 

In  their  original  paper  Folin  and  Denis  (h)  found  practically  no  eleva- 
tion of  the  uric  acid  in  a  series  of  eleven  nephritic  bloods  with  only  mod- 
erate nitrogen  retention,  but  later  they  rejwrted  data  on  cases  of  advanced 
nephritis  in  some  of  which  ver}'  high  values  were  obtained,  up  to  10 
mg.  These  latter  observations  were  confirmed  by  Myers  and  Fine  (g)y  who 
noted  very  high  figxires  for  uric  acid  in  several  cases  of  terminal  interstitial 
nephritis.    In  one  case  the  uric  acid  reached  the  enormous  figure  of  27  mg. 


438  VICTOR  C.  MYERS 

shortly  l)cforc  death,  while  in  several  cases  figiires  as  high  as  15  mg.  were 
observed,  values  much  higher  than  any  noted  in  gout.  It  is  jx^rfcctly 
logical  to  expect  that  high  figures  would  be  found  in  the  hist  stages  of 
chronic  interstitial  nephritis,  with  the  consequent  accumulation  of  all  the 
wastes  products  of  nitrogenous  metabolism.  That  the  retention  of  uric 
acid  in  nephritis  results  in  a  fairly  even  distribution  of  this  substance 
in  the  various  body  tissues  has  been  shown  by  Fine  (a)  in  tissues  obtained 
at  autopsy.  The  distribution,  however,  is  not  quite  as  uniform  as  in  the 
case  of  the  urea  or  even  the  creatinin,  a  fact  which  might  be  expected  from 
their  physical  properties. 

In  1910  flyers,  Fine  and  Lough  called  attention  to  the  fact  that  very 
high  figures  for  uric  acid  may  be  noted,  not  only  in  cases  of  advanced 
interstitial  nephritis,  but  also  in  the  very  early  stages  of  the  disease,  be- 
fore a  retention  of  either  the  urea  or  ereatinin  had  taken  place.  It  was 
suggested  that,  when  symptoms  of  gout  were  absent,  a  high  blood  uric 
acid  might  be  a  valuable  early  diagnostic  sign  of  nephritis,  possibly  earlier 
evidence  of  renal  impuinnent  of  an  interstitial  type  than  the  classic  tests 
of  proteinuria  and  cylinduria.  This  point  is  w^ell  illustrated  by  the  stair- 
case table  on  page  439,  taken  from  Chace  and  Myers.  As  a  result  of  a 
recent  study  of  this  question  Baumann,  Hansmann,  Davis  and  Stevens 
conclude  that  the  uric  acid  concentration  of  the  blood  is  a  delicate,  if  not 
the  most  delicate,  index  of  renal  function  at  our  disposal. 

Owing  to  the  fact  that  the  tophi  found  in  gout  have  long  been  recog- 
nized to  contiiiu  deposits  of  sodium  urate,  it  is  quite  natural  that  the 
uric  acid  content  of  the  blood  in  this  condition  should  possess  a  special  in- 
terest. Following  the  investigations  of  F^olin  and  Denis  a  number  of 
different  workers  took  up  a  study  of  this  question.  Among  these  in  par- 
ticular should  be  mentioned  Pratt,  Fine  and  their  coworkers.  From  the 
normal  variations  of  from  2  to  3  mg.  to  100  c.c.  of  blood,  the  uric  acid  may 
be  increased  to  as  much  as  from  4  to  9  mg.  in  gout,  but  it  does  not  follow 
that  these  uric  acid  accumulations  are  infallible  signs  of  gout,  since,  as 
noted  above,  similar  uric  acid  figures  may  be  found  in  nephritis.  We  may 
conclude,  however,  that  gout  is  almost  invariably  associated  with  an  in- 
creased uric  acid  content  of  the  blood  and  therefore  a  high  uric  acid  blood 
may  be  of  considerable  diagnostic  value  in  cases  of  gouty  arthritis,  in  which 
tophi  containing  sodium  urate  are  not  already  present. 

High  figures  for  the  blood  uric  acid  may  be  considerably  reduced  in 
many  cases,  where  appreciable  urea  retention  does  not  exist,  by  the  use 
of  purin  free  diets.  Such  diets  will  not,  as  a  rule,  equally  influence  the 
blood  uric  acid  in  gout,  although  appreciably  lowering  the  initial  figures. 

It  is  of  considerable  interest  in  this  connection  that  salicylic  acid, 
phenylcinchoninic  acid  (cinchophen)  and  certain  of  their  derivatives  have 
recently  been  shown  to  have  a  marked  influence  upon  the  elimination  of 
uric  acid  and  upon  the  uric  acid  content  of  the  blood.    In  many  cases  mod- 


'     BODY  TISSUES  AXD  FLUIDS 


430 


s  a. 


nil 


+ I ++    +++ I 


+    -f    + 

+    +    + 


+    +    4- 


^1 1+   +1 +1 


4- 


+       +    +    + 


+    4-    +       +    4-    + 


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«■?:  I*  o  o      o  c  X  •*  o  o  o 

CC  X  —  O         t  I-  ?C  -P  — '  -M  —> 

^  ^  ^  ^         (M  ■— '  CJ  '-  «N  •-•  Ol 


I*:      c       I* 

'i\        <M        <M 

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oc  f^  r^  ifs       rs  :*  s  ?^       ©  c  it  rs  oo  *>! 

i.-i  •#  CC  Tt*         1-1  C4  C'l  rj  -^  (N  '^  C^  1^ 


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440  VICTOR  C.  MYERS 

erate  closes  of  cincbopheu  will  reduce  a  uric  acid  content  of  5  or  G  mg. 
to  a  mere  trace  in  a  comparatively  few  hours.  If  long  continued,  how- 
ever, the  drug  loses  this  influence.  This  uric  acid  eliminating  effect  ap- 
pears to  be  quite  itidept^ndent  of  the  marked  analgesic  effect  of  these  drugs. 

Creatinin. — Unliil  the  advent  of  P'olin's  colorimctric  method  for  the 
estimation  of  creatinin  in  urine  in  1004,  we  possessed  no  reliable  infonna- 
tion  regarding  this  interesting  nitrogenous  waste  product.  Folin  was  the 
first  to  show  that  the  amount  of  creatinin  excreted  in  the  urine  bv  a  nor- 
mal individual  on  a  meat  free  diet  is  quite  independent  of  either  the  amount 
of  protein  in  the  food  or  of  the  total  nitrogen  in  the  urine,  the  amount 
excreted  frcm  day  to  day  being  practically  constant  for  each  individual, 
thus  pointing  conclusively  to  its  endogenous  origin.  In  1014  Folin  (/)  aj)- 
plied  his  color inietric  method,  slightly  modified,  to  the  estimation  of 
creatinin  in  blood,  and  Folin  and  Denis  (g)  presented  some  quite  extensive 
data  on  the  subject.  Almost  simultaneously  iSTeubauer  reported  an  ob- 
servation on  a  case  of  "uremia,"  while  ^Myers  and  Fine  (g)  presented  sev- 
eral analyses  on  two  cases  of  nephritis  showing  marked  retention  of  cre- 
atinin. 

For  perfectly  normal  individuals  the  creatinin  of  the  blood  amounts  to 
1  to  2  mg.  per  100  c.c,  the  findings  for  the  strictly  noraial  being  nearer 

1  than  2  mg.  This  statement  should  probably  be  made  with  some  reserva- 
tion as  the  method  does  not  appear  to  be  entirely  adequate  for  the  de- 
termination. It  is  quite  possible  that  the  actual  content  of  creatinin  may 
not  be  much  more-  than  0.5  mg.,  the  remainder  being  due  to  the  inter- 
ference of  other  substances  in  the  color  reaction.  The  figures  obtainable 
with  present  metliods  are  comparable,  however,  and  serve  as  a  satisfactory 
base  line.  The  importance  of  this  source  of  en-or  w^ould  appear  to  de- 
crease proportionately  with  a  rise  in  the  creatinin  content  of  the  blood, 
so  that  the  absolute  accuracy  of  the  estimation  is  much  greater  with  patho- 
logic than  norma!  values. 

As  soon  as  one  passes  to  hospital  patients  values  higher  than  1   to 

2  mg,  are  found.  Although  the  great  majority  of  cases  without  renal 
involvement  show  creatinin  figures  on  the  whole  blood  below  2.5  mg.  j>er 
100  c.c,  occasionally  figures  as  high  as  3.5  mg.  are  encountered  that  arc 
not  readily  explained.  It  may  be  noted,  however,  that  a  slight  retention 
of  creatinin  (figures  between  3  and  4  mg.)  occurs  in  syphilis,  certain  heart 
conditions,  sometimes  in  fevers,  and  in  some  cases  of  advanced  diabetes. 
Creatinin  figures  above  3.5  mg.  are  almost  invariably  accompanied  by  an 
appreciable  urea  retention  and  this  is  generally  true  of  those  above  3  mg. 
Many  of  the  cases  below  4  mg.  show  improvement,  but  with  over  4  mg.  the 
I'everse  is  the  ease.  It  would  appear  from  this  that  an  appreciable  re- 
tention of  creatinin,  i.  e.,  over  4  mg.,  does  not  occur  until  the  activity  of 
the  kidney  is  greatly  impaired.  That  such  should  be  the  case  is  quite 
natural  to  expect,  since  creatinin  is  normally  the  most  readily  eliminated 


BODY  TISSUES  AND  FLUIDS  441 

of  the  three  nitroj^enons  waste  products,  uric  acid,  urea,  and  creatinin 
(see  staircase  table  on  page  4^]!)). 

In  various  studies  on  nitrogen  retention  by  Alyers  and  associates  it 
was  soon  note(|  tliat  tlie  creatinin  of  the  blood  was  appreciably  increased 
only  after  considerable  ictontion  of  urou  iiad  already  taken  place  and  the 
nephritis  was  rather  far  advanced.  It  was  further  obsc'rved  that  those 
cases  in  which  the  creatinin  had  risen  above  5  nig.  per  100  c.c.  of  blood 
rarely  showed  any  marked  improvement,  and  almost  invariably  died  within 
a  comparatively  limited  time.  The  only  exceptions  w^ere  cases  where  the 
retention  was  due  to  some  acute  renal  condition.  In  a  recent  paper  Myers 
and  Killian  (b)  have  discussed  in  detail  the  observations  on  a  series  of  100 
nephritics  with  high  creatinin  findings,  while  more  recently  !Myers  has 
again  reviewed  the  general  subject.  It  may  be  stated  that  of  85  cases 
having  over  5  mg.  of  creatinin,  all  the  cases,  with  three  exceptions,  are 
known  to  be  dead.  Most  of  these  cases  lived  from  1  week  to  3  months  al- 
though there  were  three  cases  that  lived  1,  2  and  3  years  respectively. 
Of  the  three  exceptions  two  were  acute  cases  that  recovered,  while  one 
was  followed  for  only  a  short  period.  Among  the  cases  having  very  high 
blood  creatinins  there  were  many  who  were  able  to  be  up  and  about  and 
some  who  showed  considerable  clinical  improvement.  In  these  cases  the 
blood  creatinin  gave  a  particularly  good  insight  into  the  true  nature  of  the 
condition. 

The  amount  of  the  increase  of  the  creatinin  of  the  blood  should 
be  a  safer  index  of  the  decrease  in  the  permeability  of  the  kid- 
ney than  the  urea,  for  the  reason  that  creatinin  on  a  meat  free  diet 
is  entirely  endogenous  in  origin  and  its  formation  (and  elimina- 
tion normally)  very  constant.  Urea,  on  the  other  hand,  is  largely 
exogenous  imder  normal  conditions  and  its  formation  consequently 
subject  to  greater  fluctuation.  For  this  reason  it  must  be  evident  that 
a  lowered  nitrogen  intake  may  reduce  the  work  of  the  kidney  in  eliminat- 
ing urea,  but  cannot  affect  the  creatinin  to  any  extent.  Apparently  the 
kidney  is  never  able  to  overcome  the  handicap  of  a  high  creatinin  accumu- 
lation. It  would  seem  that  creatinin.  being  almost  exclusively  of  endog^ 
enous  origin,  furnishes  a  most  satisfactory  criterion  as  to  the  deficiency 
in  the  excretory  power  of  the  kidneys  and  a  most  reliable  means  of  follow- 
ing the  terminal  course  of  the  disease,  though  it  should  be  noted  that 
iirea,  being  largely  of  exogenous  origin,  is  more  readily  influenced  by 
dietary  changes,  and  therefore  constitutes  a  more  sensitive  index  of  the 
response  to  treatment. 

Creatin. — The  methods  of  estimating  the  blood  creatin  are  considerably 
less  satisfactory  than  those  for  creatinin.  Figures  obtained  with  the 
original  Folin  method  were  apparently  too  high.  Eecent  methods  and 
observations  of  Denis (6)  and  Folin  and  Wu  give  the  normal  creatin  con- 
tent of  blood  as  from  3  to  7  mg.,  with  an  avei-age  of  about  5  mg.     The 


442  VICTOR  C,  IMYERS 

amount  does  not  appear  to  be  increased  except  in  terminal  nephritis  with 
marked  nitrogen  retention,  when  values  as  high  as  30  mg.  may  be  attained. 
According  to  Jfuntor  and  Campl^ell  (b)  the  average  creatin  content  of  the 
corpuscles  lies  roughly  between  6  and  9  mg.  per  100  c.c,  while  that  of  the 
plasma  is  not  more  than  0.4  to  0.6,  the  blood  as  a  whole  containing  about  3 
mg.,  and  slightly  higher  figures  Ix^ing  found  in  females  than  males.  Accord- 
ing to  these  investigators  there  is  a  distinct  correspondence  between  increase 
of  plasma  creatin  and  the  appearance  of  creatin  in  the  urine ;  but  whether 
the  plasma,  in  the  absence  of  creatinuria,  is  creatin-freo  or  whether  there 
exists  a  threshold  for  creatin  excretion,  has  not  been  positively  determined. 

Amino-Acids. — That  the  amino-acids  formed  in  proteolytic  digestion 
are  taken  up  directly  by  the  blood  was  first  clearly  shown  by  Van  Slyke 
and  Meyer  (a),  employing  Van  Slyke's  method  for«the  determination.  This 
had  been  made  probable  from  results  obtained  for  the  non-protein  nitrogen 
of  the  blood  by  Folin  and  Denis  shoitly  before,  but  the  work  of  Van  Slyke 
and  Meyer  conclusively  proved  this  point,  thus  definitely  settling  one  of 
the  long  disputed  questions  of  protein  absorption.  They  found,  for  ex- 
ample, that  whereas  the  amino-acid  nitrogen  of  a  normal  fasting  dog 
amounted  to  4  to  5  mg.  per  100  c.c.  of  blood,  it  was  increased  to  0  to  10 
mg.  after  a  heavy  protein, meal. 

Comparatively  few  data  are  available  for  the  amino-acid  nitrogen  con- 
tent of  human  blood.  The  normal  content  of  amino  nitrogen  may  be  given 
a&  4  to  8  mg.,  with  an  average  close  to  5  mg.,  per  100  c.c.  of  blood. 
In  a  series  of  sixty  practically  normal  subjects  Hammett  (c)  found 
the  amino  nitrogen  to  be  relatively  constant  with  an  average  of  4.9  and 
variations  of  3.1  to  7.2  mg.  per  100  c.c.  of  blood.  Bock  has  reported  anal- 
yses on  a  series  of  miscellaneous  pathological  cases,  lie  failed  to  find 
any  noteworthy  deviations  from  the  normal  except  in  severe  nephritis, 
where  in  several  cases  figures  exceeding  10  mg.  and  in  one  instance  30 
mg.  was  reached.  In'general  the  findings  of  Hammett  and  Bock  hannon- 
ize  very  well,  though  the  figures  of  Hammett  average  slightly  lower,  pos- 
sibly due  to  the  fact  that  he  used  tungstic  acid  as  the  protein  precipitant, 
while  Bwk  employed   trichloracetic  acid. 

Ammonia. — ^According  to  the  recent  obsen^ations  of  j^ash  and  Bene- 
dict, the  ammonia  nitrogen  content  of  the  blood  (of  dogs  and  cats)  under 
normal  and  various  experimental  conditions  is  close  to  0.1  mg.  per  100  c.c. 
They  express  the  view  that  the  urea  of  the  blood  is  the  probable  precursor 
of  the  urinary  ammonia,  and  that  the  kidney  is  the  seat  of  this  trans- 
fonnation. 

Rest  Nitrogen. — The  amount  of  undetermined  nitrogen  present  in 
protein-free  blood  filtrates  appears  always  to  be  very  large.  In  the  table  on 
page  434  the  normal  rest  nitrogen  was  given  as  45  per  cent  of  the  total 
non-protein  nitrogen.  Here  the  creatin  and  amino-acid  nitrogen  were  in- 
cluded.    If  deductions  of  4  per  cent  are  made  for  the  creatin  nitrogen 


'  BODY  TISSUES  AXD  FLUIDS  443 

and  14  per  cent  for  the  amino-acid  nitrogen,  28  per  cent  of  the  total  non- 
protein nitrogen  still  remains  unaccounted  for.  AVith  the  rise  in  the  urea 
nitrogen  that  occurs  in  many  cases  of  nephritis  with  marked  nitrogen 
retention  there  is  a  corresponding  decline  in  the  percentage  of  the  rest 
nitnigen,  indicating  that  the  actual  amount  of  the  rest  nitrogen  remains 
fairly  constant  under  abnormal  conditions.  As  pointed  out  by  Ham- 
mett,  there,  is,  however,  considerable  variation  in  the  amount  of  the  rest 
nitrogen  of  practically  normal  individuals.  He  found  variations  of  4 
to  18  mg.  with  an  average  of  11  mg.  to  100  c.c.  in  sixty  cases.  These 
figures  represent  the  difference  betwQcn  the  non-protein  nitrogen  and  the 
sum  total  of  the  urea,  uric  acid,  creatinin,  creatin  and  amino-acid  nitrogen. 
While  our  methods  are  not  sufficiently  accurate  to  make  the  findings  for 
the  rest  nitrogen  reliable,  still  they  do  indicate  that  this  fraction  is  quite 
large.  At  the  present  time  we  possess  no  very  good  information  as  to  the 
nature  of  this  material  in  human  blood,  although  it  would  seem  possible 
from  the  experimental  work  of  Whipple  and  Van  Slyke  on  proteose  intoxi- 
cation that  a  large  part  of  this  nitrogen  was  derived  from  peptids.  From 
the  work  of  Abel  we  also  have  reason  to  believe  that  traces  of  proteoses  are 
present. 

Blood  SugajT. — A  sugarlike  substance  was  first  recognized  in  the  blood 
in  a  case  of  diabetes  by  Dobson  in  1775,  but  it  was  not  until  seventy  years 
later  that  its  presence  in  normal  blood  was  discovered  by  the  noted  French 
physiologist,  Claude  Bernard.  By  means  of  his  sugar  piqure  Bernard 
first  noted  the  connection  between  hyperglycemia  and  glycosuria  (gly- 
curesis).  It  remained  for  Lewis  and  Benedict  in  1913  to  introduce  a 
colorimctric  method  for  blood  sugar  estimation  so  simple  that  it  could  be 
readily  employed  for  clinical  as  well  as  scientific  purposes.  Earlier  in  the 
same  year  Bang  had  described  a  very  ingenious  method  requiring  only 
two  to  three  drops  of  blood,  but  the  fact  that  it  was  a  gravimetric-volu- 
metric procedure  precluded  any  very  extensive  clinical  application.  Stimu- 
lated by  these  metliods,  and  several  others  since  devised,  many  studies 
dealing  w4th  the  sugar  of  the  blood  have  recently  appeared.  Previous  to 
the  introduction  of  these  simple  methods,  however,  Bang  (d)  had  written 
a  very  interesting  monograph  under  the  title  "Dor  Blutzucker,"  while 
Maeleod(/?)  had  discussed  the  subject  of  diabetes  almost  entirely  upon  the 
basis  of  experimental  observations  on  the  blood  sugar. 

If  we  may  rely  upon  the  findings  with  the  Benedict  method,  the  blood 
sugar  of  the  nonnal  human  subject  falls  somewhere  between  0.09  and 
0.12  per  cent,  on  the  average  being  about  0.10  per  cent.  Depending  upon 
the  method  which  is  employed  for  the  estimation,  one  may  obtain  figures 
differing  as  mucli  as  0.02  per  cent  in  the  nonnal  hood,  while  with  patho- 
logical bloods  the  differences,  as  shoAvn  by  Host  and  Hatlehol,  may  be 
somewhat  greater.  Sliglitly  higher  figures  appear  to  be  obtained  by  the 
picric  acid  method  of  Benedict  in  its  various  modifications  than  by  most 


444  VICTOE  C,  MYERS 

of  the  other  methods.  That  the  reducing  power  of  the  blood  is  due  in 
large  part  to  glucose  seems  certain,  although  the  various  methods  appear 
to  be  influenced  by  other  reducing  substances.  Of  the  known  interfering 
substances  crcatinin  is  the  most  often  mentioned.  In  normal  blood,  how- 
ever, it  probably  does  not  introduce  an  error  of  more  than  2  or  3  per  cent. 
Although  the  question  of  the  actual  content  of  glucose  in  normal  blood  is 
one  of  groat  theoretical  interest  and  importance,  the  figures  obtained  by 
the  various  methods  differ  so  little  relative  to  the  variations  which  occur  in 
disease  that  the  question  of  the  method  scarcely  enters  into  a  discussion  of 
blood  sugar  findings  in  disease. 

The  figure  of  0.10  per  cent  for  normal  individuals  given  above  applies 
to  obserA'ations  made  in*  the  morning  previous  to  the  intake  of  any  carbo 
hydrate.  After  a  meal  rich  in  carbohydrate  there  may  be  an  appreciable 
rise  in  the  sugar  content  of  the  blood,  0.12  to  0.14  per  cent,  while  after 
tho  intake  of  even  moderately  large  amounts  of  glucose,  the  hyperglycemia, 
0.15  to  0.16  per  cent,  may  be  sufficient  to  induce  a  slight  temporary  (gly- 
cosuria) glycuresis.  The  great  majority  of  hospital  cases  show  practically 
normal  figures  for  blood  sugar,  although  occasionally  figures  of  0.12  to  0.15 
per  cent  are  encountered  that  are  not  readily  explained. 

Conditions  of  hyperglycemia  are  much  more  common  and  of  greater 
clinical  interest  than  those  of  hypoglycemia,  owing  primarily  to  the  fact 
that  diabetes  belongs  to  the  former  group.  Among  other  conditions  which 
frequently  show  moderate  hyperglycemia  are  pancreatic  disease,  nephritis 
and  hyperthyroidism.  Hypoendocrin  function  would  appear  to  result  in 
hypoglycemia,  and  comparatively  low  blood  sugars  have  been  observed  in 
myxedema,  cretinism,  Addison's  disease,  pituitary  disease  and  other  less 
clearly  defined  endocriu  conditions  such  as  muscular  dystrophy. 

All  forms  of  glycosuria  are  accompanied  by  hyperglycemia,  if  we 
except  the  glycosuria  produced  by  such  suhstances  as  phlorhizin  and  urani- 
um, and  the  analogous  condition,  "renal  diabetes."  In  mild  cases  of  dia- 
bc^tcji  the  hyperglycernia  is  not  excessive,  generally  0.2  to  0.3  per  cent,  al- 
though in  severe  cases  figures  up  to  and  even  above  1.0  per  cent  have  been 
obtained.  The  normal  threshold  of  sugar  excretion  (i.  e.,  the  point  cf 
glycuresis)  is  about  0.16  to  0.18  per  cent.  With  bkwd  sugar  concentrations 
of  0.15  to  0..20  per  cent  the  api>earance  of  sugar  in  the  urine  is  apparently 
dependent  on  whether  or  not  diuresis  exists,  glycosuria  appearing  especial- 
ly in  the  latter  case.  When  the  threshold  point  has  been  passed,  however, 
the  overflow  of  sugar  into  the  urine  may  continue  until  the  concentration 
in  the  blood  has  fallen  nearly  to  normal.  ]\Iild  cases  of  diabetes  usually 
have  a  normal  threshold,  although  some  severe  cases  apparently  have  a 
lowered  threshold,  increasing  the  severity  of  tho  condition.  Ordinarily 
in  the  earlv  stages  of  the  disease  there  is  a  fairly  direct  relationship  be- 
tw^eeu  the  hyperglycemia  and  glycosuria.  In  tho  later  stages  of  the  disease, 
however,  cases  are  frequently  encountered  with  marked  hyperglycemia  and 


BODY  TISSUES  AND  FLUIDS  445 

only  slight  glycosuria,  showing  that  the  threshold  point  has  been  raised, 
apparently  due  in  many  instances  to  an  accompanying  nephritis.  The 
cause  of  glycosuria  in  ^'renal  diabetes"  is  obviously  flue  to  the  reverse  condi- 
tion, viz.,  a  threshold  point  below  the  level  of  the  nonnal  blood  sugar. 

A  simple  method  of  estimating  the  diastatic  activity  of  the  blood  has 
been  described  by  ]Myers  and  Killian  (a)  who  have  called  attention  to  the 
fact  that  conditions  of  hyp(3rglycemia  are  associated  with  an  increased  dias- 
tatic activity  and  have  suggested  that  this  might  be  the  important  factor  in 
the  production  of  the  hyperglycemia  in  both  diabetes  and  nephritis.  The 
increase  in  the  diastase  of  the  blood  in  nephritis  finds  probable  explanation 
in  the  decreased  excretion  of  diastase  in  the  urine,  now  well  kno\^'n  in  this 
condition,  although  a  satisfactory  explanation  of  the  increased  activity  in 
diabetes  is  not  so  readily  given.  So-called  alimentary  glycosuria  is  ap- 
parently due  to  an  increased  activity  on  the  part  of  this  diastatic  ferment, 
thus  impairing  the  body's  power  to  store  glycogen.  Ilyperf unction  on  the 
part  of  the  ductless  glands,  hyperthyroidism  for  example/  appears  to 
result  in  an  increase  in  the  blood  diastase,  while  hypof unction  seems  to 
have  the  reverse  effect. 

Blood  Lipoids 

Material  contributions  to  our  knowledge  of  the  blood  lipoids  and  fat 
metabolism  have  been  made  during  the  past  ten  years.  The  blood  lipoids 
comprise  (1)  the  true  fats— glycerids  of  the  fatty  acids;  (2)  the  phos- 
phatids — lecithin,  cephalin,  etc.,  ordinarily  called  lecithin,  and  (3)  choles- 
terol with  its  fatty  acid  esters.  Although  these  substances  were  originally 
grouped  together  on  account  of  similar  solvent  properties^  it  would  now 
appear  that  they  are  closely  connected  in  metabolism. 

Bloor  (d)  has  carried  out  experiments  w^hicli  support  the  older  concep- 
tion of  fat  digestion,  i.  e.,  the  food  fat  is  saponified  in  the  intestine,  ab- 
sorbed in  water  soluble  form  as  soaps  and  glycerol,  resynthesized  by  the  in- 
testinal cells,  and  passed  into  the  chyle  and  thence  to  the  blood  as  neutral  fat 
suspended  in  the  plasma  in  a  very  fine  condition.  About  60  per  cent  of  the 
food  fat  has  actually  been  accounted  for  in  the  chyle  in  this  way  and  this 
figure  is  probably  low.  The  remaining  smaller  quantity  is  generally  as- 
sumed to  be  absorbed  directly  into  the  blood  stream  by  way  of  the  in- 
testinal capillaries. 

In  a  study  of  the  blood  lipoids  during  fat  assimilation,  Bloor  (e)  has  ob- 
ser^'ed  that  (1)  the  total  fatty  acids  increase  in  both  plasma  and  corpuscles 
but  the  increase  is  generally  more  marked  in  the  corpuscles;  (2)  lecithin 
increases  greatly  in  the  corpuscles,  but  only  sliglitly  in  the  plasma ;  (3)  no 
definite  change  takes  place  in  the  quantity  of  cholesterol  aiid  (4)  a  fairly 
constant  relationship  exists  between  the  total  fatty  acids  and  lecithin  of 


446  VICTOR  C.  :MYERS 

tbo  whole  bfood  and  corpuscles.  From  this  Bloor  suggests:  (a)  that  the 
blood  corpiiaeles  take  up  the  fat  from  the  plasma  and  transfoi-m  it  into 
lecithin;  (b)  that  most,  if  not  all,  of  the  absorbed  fat  is  so  transforaied; 
and  therefore  (c)  that  lecithin  is  an  intennediatc  step  in  the  metabolism 
of  the  fats. 

Since  the  question  of  the  blood  lijx)ids  has  been  very  carefully  con- 
sidered by  iBIoor  in  a  series  of  papers,  an  abbreviated  table  showing  his 
average  noriaial  findings  and  three  illustrative  pathological  (extremely 
severe)  cases  is  given  below.  It  will  be  noted  in  the  data  on  the  normals 
that  the  lecithin  content  of  the  corpuscles  is  approximately  double  that 
of  the  plasjiiSy  ^vhile  the  cholesterol  and  total  fatty  acid  values  are  almost 
always  lower  in  the  corpuscles  than  in  the  plasma.  The  value  for  lecithin 
in  the  corpuscles  is  generally  about  twice  that  of  the  cholesterol,  while  in 
the  plasma  tfceir  values  are  nearly  equal.  According  to  Bloor  the  ratio 
between  these  constituents  is  quite  constant  in  normal  blood  (especially 
plasma)  and  remains  so  in  most  of  the  pathological  samples,  suggesting 
a  definite  relationship  between  these  constituents,  and  making  it  prob- 
able that  chofesterol  (as  its  esters?)  has  a  part  in  fat  metabolism. 

The  most  characteristic  feature  of  pathological  conditions  is  the  in- 
crease of  total  fatty  acids  and  fat  both  in  plasma  and  corpuscles,  and  the 
decrease  of  kcithin  in  the  plasma.  Since  the  fat  is  probably  to  be  regarded 
as  the  inactive  form  of  the  body  lipoids,  the  forai  in  which  they  are  stored 
and  the  lecitliin  as  the  first  step  in  the  utilization,  an  undue  accumulation 
of  fat  or  a  luotably  decreased  value  for  lecithin,  probably  indicates  a  di- 
minished adtivity  of  the  fat  metabolism. 

In  severe  diabetes  the  blood  lipoids  are  all  greatly  increased  but  the 
ratios  betwaoi  those  constituents  are  practically  normal.  The  fact  that 
the  cholesteiwl  increases  parallel  with  the  fat  in  diabetic  blood,  even  in 
severe  lipemia,  supports  the  view  that  probably  cholesterol  plays  an  im- 
portant part  in  fat  metabolism.  Since  cholesterol  may  be  rather  simply 
estimated  it  affords  a  practical  method  of  gauging  the  severity  of  diabetic 
lipemia.    la  mild  diabetes  the  blood  lipoids  may  be  practically  normal. 

While  tliere  is  no  certain  evidence  that  the  abnormalities  ir  the  blood 
lipoids  are  responsible  for  anemia,  the  low  values  for  cholesterol,  which 
is  an  antihemolytic  substance,  and  the  high  fat  fraction,  wdiich  may  indi- 
cate the  presence  of  abnormal  amounts  of  hemolytic  lipoids  in  the  blood, 
are  possible  causative  factors. 

According  to  Bloor  (/)  the  changes  in  the  blood  lipoids  in  severe  neph- 
ritis are  a  high  fat  in  the  plasma  and  corpuscles  and  high  lecithin  in  the 
corpuscles.  These  abnoi-malities  are  the  same  as  are  found  in  alimentary 
lipemia  and  may  be  regarded  as  the  result  of  a  retarded  assimilation  of  fat 
in  blood,  due  possibly  to  a  metabolic  disturbance  brought  about  by  a  lowered 
alkali  reserve  of  the  blood  and  tissues. 


BODY  TISSUES  AND  FLUIDS 


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448 


VICTOR  C.  MYERS 


For  the  different  lipoid  constituents  the  following  statements  may 
be  made :  ♦ 

Total  Fat  (Plasma  Lipoids), — ^Xonnally  the  "total  fat'^  content  of  the 
blood  plasma  amounts  to  0.6  to  0.7  per  cent,  but  in  severe  diabete^  .ignre9 
as  lii^h  as  20  per  cent  have  been  obsen'cd.  In  diabetic  cases  of  ordinary 
severity,  however,  the  figures  amo\int  to  about  1.5  per  cent.  N^ephritics 
frequently  show  a  moderately  increased  fat  although  the  figures  rarely 
reach  1  per  cent. 

Lecithin. — The  normal  figures  for  lecithin  may  be  given  in  round  num- 
bers as  0.2  per  cent  for  the  plasma,  0.3  per  cent  for  whole  blood  and  0.4 
per  cent  for  the  corpuscles.  In  diabetes  there  is  an  increase  in  the  lecithin 
of  both  the  corpuscles  and  the  plasma,  although  in  severe  lipemia  it  is 
more  noticeable  in  the  latter.  In  anemia  the  lecithin  of  the  plasma  in 
particular  is  lowered,  while  in  nephritis  there  is  a  noteworthy  increase  in 
the  corpuscles. 

Cholesterol. — ^AVith  the  method  of  Bloor  comparatively  high  figures  for 
cholesterol  are  obtained,  normals  of  0.20  to  0.24  per  cent  on  whole  blood, 
v/ith  slightly  higher  figures  for  the  plasma.  Figures  for  whole  blood  ob- 
tained with  most  of  the  other  methods  described  in  the  literature  are  0.14 
to  0.17  per  cent  for  normal  individuals.  Figures  obtained  with  Bloor's 
most  recent  method  are  probably  too  high.  The  distribution  of  cholesterol 
in  blood  is  well  illustrated  in  the  following  table  taken  from  Grigaut, 
who  was  the  first  to  suggest  and  use  a  colorimetric  method  for  the  estima- 
tion of  cholesterol. 


Condition 


1.  Normal  man 

2.  Normal  man 

3.  Normal  woman    

4.  Normal  woman    

5.  Carcinoma    of    the  •  pancreas    with 

jaundice    

6.  Pneumonia   

7.  Caroinoma  of  the  liver  with  jaundice 

8.  Dial)^!*--    

9.  Cholelithiasis    

10.  Nephritis 

11.  Nephritis 

12.  Carcinoma    of    the    pancreas    with 

jaundice   


Cholesterol  in  Per  Cent 


Plasma 


O.IOS 
0.170 
0.170 
0.175 

0.068 
0.008 
0.22a 
0.24G 
0.270 
0.450 
0.514 

0.840 


Whole  Blood 


0.540 


Corpuscles 


0.150 

0.141 

0.1.50 

0.130 

0.168 

0.171 

0.165 

0.140 

0.105 

0.110 

0.110 

0.150 

0.108 

0.170 

0.201 

0.137 

0.225 

0.180 

0.285 

0.150 

0.264 

0.135 

0.105 


In  general  it  may  bo  stated  that  hypercholesterolemia  is  found  in 
arteriosclerosis,  nephritis,  diabetes  (especially  with  acidosis)^  obstructive 
jaundice,  in  many  cases  of  cholelithiasis,  in  certain  skin  diseases,  in  the 
early  stages  of  malignant  tumors,  and  in  pregiiancy.  The  chief  condi- 
tion in  which  low  values  are  found  is  anemia. 


BODY  TISSUES  A:^D  FLUIDS  449 

As  pointed  out  alyovc  cholesterol  constitutes  an  excellent  index  of  the 
degree  of  lipeniiii  in  diabetes.  The  decrease  in  this  antihcnioljtic  sub- 
stance in  the  plasma  in  anemia  would  ap[)ear  to  be  of  considerable  sig- 
nificance. 

That  cholesterol  is  partly  present  in  the  bhW  as  an  ester  (fat)  has 
long  been  recognized.  Bloor  and  Ivnudson  have  found  that  in  whole  blood 
the  average  j>ercontagtJ  of  cholestei'ol  in  combination  as  esters  Is  about 
33.5  per  cent,  and  in  the  plasma  58  per  cent  of  the  total  cholesterol. 


Acetone  Bodies 

Owing  to  the  importance  which  the  acetone  liodies  hold  In  tlie  acidosis, 
or  more  specifically  the  ketosis,  occurring  particularly  in  diabetes  the 
quantities  of  these  substances — acetone,  aceto-acetlc  acid  and  ^-hydroxrjhu" 
tyric  acid — present  in  normal  and  pathological  human  blood  is  of  consid- 
erable interest.  Quito  recently  methods  have  been  described  by  ^^Earriott, 
(a)  and  by  Van  Slyke  and  Fitz  for  their  estimation  in  blood.  Since  acetone 
is  very  diffusible  it  is  natural  to  expect  that  it  should  be  fairly  evenly  dis- 
tributed in  the  various  body  fluids,  such  as  the  bl(x>d  and  spinal  fluid.  The 
concentration  in  the  urine,  bow^ever,  is  considerably  greater  than  that  in 
the  blood.  The  amount  of  the  p-hydroxy butyric  acid  present  in  both  blood 
and  urine  is  ordinarily  in  excess  of  the  combined  acetone-aceto-acetic  acid 
fraction,  often  exceeding  the  latter  by  two  or  three  times. 

According  to  Van  Slyke  and  Fitz  the  total  acetone  bodies  of  the  blood 
nonnally  amount  to  1.3  to  2.6  mg.  to  100  c.c.  calculated  as  acetone,  while 
in  diabetes  as  much  as  350  mg.  have  been  obsei^ed,  although  patients 
under  ordinarily  good  control  show  10  to  40  mg.  Allen,  Stillman  and 
Fitz  state  that  there  appears  to  be  no  constant  relation  between  the  plas- 
ma alkali  and  the  plasma  acetone  in  diabetes.  The  acetone  bodies  may 
rise  greatly  even  after  the  carbon  dioxid  combining  power  of  the  blood 
has  been  considerably  raised  by  the  administration  of  alkali,  and  death 
ensue.  The  acetone  bodies  in  the  blood  of  children  have  been  studied  by 
Moore.  He  found  in  a  fairly  large  series  of  nonnal  children,  that  the 
acetone  plus  aceto-acetic  acid  calculated  as  aec*tone  averages  2.4  mg.  to 
100  c.c,  while  the  P-liydroxybutyric  acid  as  acetone  amounted  to  3.9  mg,, 
a  total  of  G.3  mg.  In  one  case  of  ileocolitis  with  acetonuria  the  total 
acetone  bodies  rose  to  183  mg.  per  100  c.c.  shortly  before  death.  Moore 
states  that  in  a  few  cases  showing  acidosis  clinically,  the  acetone  of  the 
blood  has  been  found  sufficient  to  account  for  the  acidosis.  From  a  study 
of  the  acetone  bodies  of  the  blood'  following  ether  anesthesia  Short  con- 
cludes that  the  acetone  bodies  are  not  formed  promptly  enough  to  account- 
for  the  decreased  plasma  bicarbonate. 


450  VICTOR  C.  MYEES 


Mineral  Constituents 

Sodium. — Comparatively  few  figures  are  available  for  the  sodium  con- 
tent of  blood.  Macallum  gives  the  nonnal  range  of  figures  for  nonnal 
human  plasma  as  220' to  31G  mg.  per  100  c.c.,  while  more  recently  Kramer 
has  found  in  adults  and  children  280  to  .310  mg.  per  100  c.c.  of  sei*um. 
Greenwald  has  obtained  quite  similar  figures  for  dog  serum.  It  has 
long  been  recognized  that  sodium  was  found  chiefly  in  the  body  fluids, 
while  potassium  w^as  a  constituent  principally  of  the  cellular  tissue.  As 
might  be  expected,  therefore,  sodium  is  found  chiefly  in  the  blood  plasma, 
and  potassium  in  the  corpuscles.  Xothing  of  special  importance  is  known 
regarding  pathological  variations  in  the  sodium  content  of  the  blood. 

Potassium. — Although  the  infonnation  available  at  present  concern- 
ing the  potassium  content  of  blood  is  somewhat  limited,  considerably 
more  is  known  than  in  the  case  of  sodium.  Some  years  ago  Abderhalden 
reported  analyses  of  the  blood  of  different  animals.  The  figures  obtained 
for  potassium  are  of  considerable  interest.  In  the  dog  and  cat  practically 
identical  figures  were  found  for  the  serum  and  whole  blood.  This  amount- 
ed to  about  22  mg.  per  100  c.c,  which  is  almost  the  exact  amount  found 
in  the  serum  of  the  various  animals  examined.  In  the  ox^  sheep  and  goat 
the  figures  for  the  whole  blood  were  about  one  and  one-half  times  that 
of  the  serum,  while  in  the  horse,  pig  and  rabbit  the  potassium  concentra- 
tion of  the  whole  blood  was  about  ten  times  that  of  the  serum. 

The  potassium  content  of  human  blood  has  recently  been  considered 
by  ]V[acalliim(c),  Greenwald  (/«),  Kramer,  and  Myers  and  Short,  w^ho  are 
in  close  agreement  that  the  potassium  of  normal  human  blood  serum  or 
plasma  is  a  relatively  constant  quantity  and  amounts  to  close  to  20  mg.  K 
per  100  c.c.  Kramer  has  suggested  a  normal  range  of  IG  to  22  mg.  to 
100  c.c.  The  potassium  content  of  whole  blood  depends  in  large  measure 
upon  the  cell  content,  but  appears  to  vary  somewhere  between  150  and 
250  mg.  to  100  c.c.  in  the  normal  human  subject.  In  primary  and  second- 
ary anemia  the  amount  may  obviously  be  very  low.  Pathologically,  the 
potassium  content  of  the  serum  or  plasma  is  of  greater  interest.  It  has 
been  suggested  by  Smillie  that  uremic  symptoms  may  be  due  in  some 
instances  to  potassium  poisoning,  while  IMacallum  has  obtained  some  data 
which  suggest  an  increased  potassium  content  of  the  serum  in  ec-lampsia. 
The  data  so  far  repoi*ted  on  pathological  cases  are  too  limited  to  peiTuit 
any  definite  conclusions  with  regard  to  the  findings.  The  obsen'ations  of 
Myers  and  Short  make  improbable  a  definite  potassium  retention  in 
chronic  nephritis  with  marked  nitrogen  retention. 

Calcium. — As  has  been  shown  by  Abderhalden  and  others,  the  blood 
corpuscles  are  very  low  in  their  content  of  calcium.  This  being  the  case 
significant  changes  in  the  blood  calcium  are  best  shown,  as  pointed  out 


BODY  TISSUES  AND  FLUIDS  *         451 

by  Bergeim,  by  analyses  made  upon  the  senim  or  plasma.  The  senim  nor- 
mally contains  9  to  1 1  mg.  of  Ca  per  100  c.c.  in  the  healtby  adult,  also  iu 
infants.  In  advanced  nephritis  with  acidosis  and  phosphate  retention  Mar- 
riott and  Ilowland(a)  have  found  the  calcium  of  the  serum  to  be  mark- 
edly lowered,  figures  as  low  as  2  to  4  mg.  More  than  ten  years  ago  W.  G. 
^lacallum  and  N'oegtlin  recognized  the  reduction  in  the  calcium  content  of 
the  blood  following  the  removal  of  the  parathyroids  in  animals  and  the  de- 
velopment of  tetany.  The  symptoms  of  tetany  were  found  to  be  relieved  by 
the  administration  of  calcium  salts,  llowland  and  Marriott,  and  more 
recently  Denis  and  Talbot,  have  shown  that  the  calcium  content  of  the 
blood  (serum)  is  greatly  reduced  in  infantile  tetany,  falling  to  2  to  3  mg. 
in  some  extreme  instances.  Howland  and  Marriott  have  shown  that  cal- 
cium administration  produces  a  prompt  effiect  upon  the  course  of  the 
tetany.  In  a  few  hours  the  spasmodic  symptoms  disappear.  The  calcium 
treatment  must  be  continued,  however,  for  a  long  time.  Calcium  chlorid 
administration  causes  an  increase  in  the  cak-ium  of  the  serum  coincident 
with  the  cessation  of  symptoms,  although,  in  most  instances,  the  calcium 
of  the  serum  does  not  return  to  quite  normal  figures.  Howland  and  Mar- 
riott point  to  the  pi'ompt  improvement  in  infantile  tetany  after  calcium 
medication  and  the  absence  of  symptoms  when  the  calcium  of  the  blood 
remains  above  7.5  mg.  as  strong  evidence  of  the  role  that  calcium  plays 
in  the  production  and  dissipation  of  s^Taptoms.  Both  Howland  and 
Marriott,  and  Denis  and  Talbot  have  obsen-ed  some  decrease  in  the  blood 
calcium  in  rickets,  while  Hess  and  Killian  have  noted  a  reduction  in  some 
cases  of  scurvy.  It  is  a  matter  of  clinical  observation  that  in  fractures 
occasionally  cases  are  encountered  which  very  rapidly  regenerate  bone, 
while  others  do  so  very  slowly.  It  is  natural  to  link  this  with  deviations 
in  calcium  metabolism,  but  a  few  unpublished  observations  made  in  the 
writer's  laboratory  on  patients  of  Drs.  Albee  and  Moorhead  have  failed  to 
disclose  abnormal  figTires  for  the  calcium  of  the  senun. 

Magnesium. — The  noi-mal  magnesium  content  of  the  blood  of  both  adults 
and  children  (as  Mg  generally  falls  between  2  and  3  mg.  per  100  c.c. 
of  plasma  or  serum,  although  with  pathological  bloods  a  somewhat  wider 
range  of  1  to  4  mg.  is  found.  A  considerable  num])er  of  different  patho- 
logical conditions  have  been  studied,  but  the  findings  differ  very  little 
from  those  found  during  health  and  do  not  appear  to  be  characteristic 
of  any  special  pathological  condition. 

Iron. — As  already  pointed  out,  iron  is  present  in  hemoglobin  to  the 
extent  of  almost  exactly  one-third  of  one  per  cent,  which  would  make  the 
content  of  normal  human  blood  about  50  mg.  per  100  c.c.  calculated  as 
Fe.  Pathologically,  it  varies  directly  with  the  hemoglobin  content.  Iron 
does  not  appear  to  be  present  nonnally  in  the  plasma. 

Chlorids. — Some  of  the  observations  reeorded  in  the  literature  give 
the  chlorid  content  of  wholo  blood,  others  the  content  of  the  plasma  or 


452  VICTOR  C.  MYERS 

serum,  formally  the  chlorid  content  of  whole  blood  as  XaCl  amounts  in 
round  numWrs  to  0.45  to  0.50  per  cent,  while  for  the  plasma  the  figures 
are  about  0.12  per  cent  higher,  i.  e.,  0.57  to  0.02  per  cent.  Since  the 
plajtma,  rather  than  the  whole  blood,  bathes  the  tissues  of  the  bodv^  it 
W'^iild  seem  more  logi(!al  to  study  the  chlorid  content  of  tlie  plasma.  Un- 
fortunately, unless  the  plasma  is  quickly  separated  from  the  corpuscles 
there  appears  to  bo  a  gradual  change  (increase)  in  its  chlorid  content, 
owing  to  a  passage  of  carbon  dioxid  from  the  plasma  into  the  corpuscles 
(or  its  escajK?  into  the  air)  and  of  chlorids  from  the  corpuscles  to.  the 
plasma.  This  being  the  case,  results  obtained  on  whole  blood  would  ap- 
p€'ar  to  bo  more  trustworthy  than  those  obtained  on  plasma. 

As  far  back  as  1850  Carl  Schmidt,  in  his  classic  studies  on  the  blood 
with  special  reference  to  cholera,  gave  figures  for  the  chlorid  content  of 
whole  blood  and  plasma.  Low  figures  were  obtained  in  many  cases  of 
cholera,  apparently  as  the  result  of  the  concentration  of  the  blood,  while 
in  a  case  of  "chronic  edema  with  albuminuria"  a  definite  increase  was 
observed.  ^IcLean  has  devoted  considerable  attention  to  the  subject  of 
the  chlorids  of  the  blood  working  along  lines  similar  to  those  of  Ambard. 
In  a  fairly  large  series  of  normal  individuals  he  found  the  plasma  chlorid 
to  vary  from  0.57  to  0.62  per  cent  with  a  very  constant  chlorid  threshold 
of  about  0.502  per  cent.  The  threshold  was  calculated  from  the  formula 
of  Ambard  and  Weill  and  confimis  their  observation  on  this  point,  ^fc- 
Lean  considered  the  question  of  the  plasma  chlorids  in  a  number  of  patho- 
logical conditions,  the  lowest  obser\*ation  being  0.50  per  cent  in  a  diabetic 
and  the  highest  0.84  per  cent  in  a  cardionephritic  shortly  before  death. 
In  g^'ne^ll,  relatively  increased  concentrations  of  chlorids  were  found  in 
the  plasma  in  certain  fonns  of  cardiac  and  renal  disease,  while  decreased 
concentrations  were  noted  in  certain  diabetic  and  fever  patients,  also 
after  the  action  of  digitalis,  the  decreased  concentrations  api>arently  re- 
sulting from  a  temporary  or  pei*manent  lowering  of  the  chlorid  threshold. 
Failure  to  excrete  chlorids  in  pneumonia  was  found  to  be  associated  w^ith 
a  lowered  concentration  of  chlorids  in  the  plasma,  excretion  reappearing 
with  a  rise  in  the  plasma  chlorid.  Edema  was  usually  found  to  be  accom- 
panied by  a  relatively  increased  c<incentration  of  chlorids  in  the  plasma, 
which  ordinarily  returned  to  the  normal  state  with  the  disappearance  of 
the  edema. 

In  general  it  may  be  stated  that  high  blood  chlorids  have  been  found  in 
nephritis,  certain  cardiac  conditions,  anemia  and  some  cases  of  malig- 
nancy (possibly  due  to  an  accompanying  renal  involvement),  while  low 
values  have  been  observed  notablv  in  fevers,  diabetes,  pneumonia  and 
Asiatic  cholera.  The  chlorid  retention  in  most  cases  of  nephritis  appar- 
ently results  from  impaired  renal  function.  The  excretion  of  chlorids  and 
nitrog*en  sei»rns  to  lie  a  fairly  independent  renal  function.  In  contrast  to 
so-called  parenchymatous  nephritis,  the  function  of  excreting  chlorids  in 


BODY  TISSUES  AND  FLUIDS  453 

•  chronic  (interstitial)  nephritis  appears  to  he  much  less  impaired  thaii  ex- 
creting nitrogen.  Consequently  a  restriction  in  the  chlorid  intake  in  the 
latter  condition  may  fairly  quickly  restore  the  chlorids  to  normal.  In  fact, 
it  is  sometimes  noted  that  when  cases  with  marked  nitrogen  retention 
are  put  on  a  restricted  chlorid  diet,  the  bkiod  chlorids  fall  to  a  subnormal 
level,  such  as  is  occasionally  found  in  severe  diabetes.  A  possible  ex- 
planation for  this  is  that,  owing  to  the  large  amounts  of  urea  and  sugar 
present  in  the  blood  in  these  conditions,  less  chlorid  is  needed  to  maintain 
normal  osmotic  conditions.  The  high  chlorid  figures  for  whole  blood  in 
anemia  and  low  figures  in  Asiatic  cholera  find  probable  explanation  on 
the  basis  of  the  relatively  high  proportion  of  the  plasma  in  the  former  dis- 
order and  the  reverse  condition  in  the  lattt*r. 

Phosphates. — The  presence  of  phosphonis  in  the  blood  in  lipoid  form 
has  long  been  recognized,  but  exact  data  regarding  the  inorganic  phos- 
phorus is  of  more  recent  origin.  In  191  r>  Green wald  (c)  reported  obseiTa- 
tions  on  the  acid-soluble  (largely  inorganic  i  and  lipoid  phosphorus  of  hu- 
man blood  serum.  He  observed  that  normally  the  acid-soluble  phosphorus 
as  P  varied  between  2  and  G  mg.  per  100  e.e.,  but  that  in  severe  nephritis 
it  might  be  considerably  increased.  A  year  later  ^Marriott  and  Ilowland  (a) 
confirmed  these  observations  and  pointed  out  that  the  retention  of  (acid) 
phosphate  w^ould  seem  to  bo  sufficient  to  account  for  the  degree  of  acidosis 
obseiTed.  Recently  Denis  and  Minot(^)  have  studied  the  inorganic  phos- 
phates of  the  plasma  in  a  large  series  of  pathological  conditions.  In  con- 
ditions other  than  nephritis  and  cardiorenal  disease  figures  varying  from 
1.2  to  3.1  mg.  of  P  per  100  c.c.  of  plasma  were  found,  while  in  one  case 
of  uremia  figures  exceeding  40  mg.  were  observed.  They  believe  that 
the  determination  of  the  inoi'ganic  phosphate  of  the  plasma  gives  promise  of 
being  of  considerable  prognostic  value  in  renal  and  cardiorenal  disease, 
since  fatiil  cases  which  they  examined  showed  a  rapidly  rising  plasma 
phosphate. 

An  idea  of  the  distiibution  of  the  various  phosphonis  compounds  of 
normal  human  blood  may  be  obtained  from  the  table  on  page  454  taken 
from  Bloor(A)  (the  figures  have  been  ivcaleulated  to  tenns  of  P). 

As  is  evident  from  the  table  below  the  phosphoric  acid  compounds  of 
human  blood  may  be  divided  into  two  classes:  (1)  the  acid-soluble — solu- 
ble in  dilute  acids  and  precipitated  with  the  proteins  by  alcohol-ether — 
and  (2)  the  lipoid-phosphoric  acid  compounds — soluble  in  alcohol-ether 
and  precipitated  with  the  proteins  by  dilute  acids.  These  two  groups  are 
apparently  sharply  defined  and  since  their  sum  is  practically  equal  to 
the  total  phosphates,  the  presence  of  other  forms  of  phosphonis  in  blood 
in  significant  amounts  is  doubtful.  Inorganic  phosphates  and  an  un- 
known compound  which  on  decomposition  by  heating  with  acid  yields  phos- 
phoric acid  are  present  in  the  first  group,  while  substances  of  the  typo 
of  lecithin  are  found  in  the  second  group  (lecithin  has  already  been  dis- 


454 


VICTOR  C.  IMYERS 

Phosphorus  Coxie>-t  ov  Human  Blood, 

MiLLIGUAMS    P  FEB    100   C.C. 


Plasma 

Corpuscles 

Sex 

3 

7.6 
1.3.6 
10.0 

o 

^  -2 

►—1 

'I 

li 

^  o 

1 

i 

*S 

a, 

'a 

§1 

Men 

2.3 
4.3 
3.2 

1.9 
3.7 
2.7 

5.0 
7.3 
7.0 

0.1 
1.2 
0.5 

57.8 

101.5 

77.5 

43.8 
78.1 
58.8 

3.8 
8.5 
5.8 

13.6 

20.8 
18.0 

Low 

40.0 

Hich    

74.2 

Average  (16  cases). 

53.8 

Women   

9.9 
12.6 
11.3 

2.9 
4.5 
4.0 

2.5 
4.3 
3.5 

6.0 
9.1 

7.8 

0 

1.2 
0.4 

68.1 
82.8 
77.5 

50.0 
64.4 
58.8 

3.0 
8.2 
4.9 

14.7 
19.5 
17.7 

Low 

High    

41.8 
58.8 

Average  (10  cases). 

52.2 

cussed,  see  p.  440).  As  will  be  noted  the  average  content  of  inorganic 
phosphorus  in  the  plasma  of  both  men  and  women  is  about  3  mg.  per 
100  C.C.  and  of  lipoid  phosphorus  about  7.5  mg.  The  corpuscles  are  rela- 
tively richer  in  all  types  of  compounds  than  the  plasma  and  there  is  also 
considerably  less  variation  in  their  composition  in  different  individuals 
than  is  the  case  with  the  plasma.  The  amount  of  the  unknown  foim  of 
phosphorus  combination  is  very  small,  but  in  the  corpuscles  it  constitutes 
60  to  80  per  cent  of  the  total  phosphorus.  This  large  amount  of  organic 
phosphorus  in  the  corpuscles  is  significant  considering  the  fact  that  Bloor 
has  shown  that  ^'lecithin"  formation  takes  place  "in  the  corpuscles  during 
fat  absorption.  Furthermore  it  would  appear  to  be  the  mother  substance 
of  the  phosphoric  acid  of  the  lipoid  phosphorus  compounds.  Owing  to 
the  fact  that  this  organic  phosphorus  compound  is  relatively  unstable,  it  is 
probably  easily  made  available  to  serve  as  a  "buffer'^  in  case  of  need. 

Sulphates. — According  to  Green wald(cZ)  the  sulphate  sulphur  of 
human  blood  plasma  probably  does  not  exceed  3  mg.  per  100  c.c,  although 
the  content  in  the  cells  may  be  as  high  as  10  mg.  The  figures  appear  to  be 
considerably  increased  in  some  cases  of  nephritis. 

Blood  Gases 

Although  we  possessed  considerable  information  regarding  the  blood 
gases  as  a  result  of  observations  made  with  the  Barcroft-Haldane  method, 
the  development  by  Van  Slyke(c)  of  a  much  simpler  method  of  estimating 
the  oxygen  and  carbon  dioxid  of  the  blood  has  given  a  considei'able  impetus 
to  this  line  of  study.  For  the  extraction  of  the  gas  to  be  determined,  Van 
Slyke  makes  use  of  a  Torricellian  vacuum,  with  which  the  gas  is  easily  and 
completely  extracted  in  a  closed  chamber  without  any  loss.  Furthennore, 
the  Ilaldanc  apparatus  has  recently  been  considerably  simplified  by  lien- 


BODY  TISSUES  AND  FLUIDS  455 

derson,  and  application  niado  to  the  blood  gases  by  Henderson  and  Smith. 
Very  recently  Van  Slyke  and  Stadie  have  introduced  a  number  of  dif- 
ferent refinements  in  the  Van  Slyke  method  of  gas  analysis  and  it  would 
seem  that  this  method  now  left  little  to  be  desired  in  the  point  of  accuracy. 

The  great  practical  importance  of  a  knowledge  of  the  factors  concerned 
in  the  carrying  of  oxygen  to  the  tissues  and  the  removal  of  carbon  dioxid 
is  apparent. 

Oxygen. — As  has  already  been  p<jinted  out,  the  ability  of  the  blood 
to  absorb  and  take  up  oxygen  depends  upon  its  hemoglobin  content.  Since 
hemoglobin  so  readily  takes  up  and  gives  off  oxygen,  it  is  obvious  that 
venous  blood  should  be  partly  unsaturated  and  therefore  differ  from  the 
arterial  blood  in  respect  to  its  oxygen  content,  and  further  that  blood 
obtained  from  different  parts  of  the  venous  system  should  differ  in  its 
oxygen  unsatu ration.  Extensive  studies  on  the  venous  blood  from  single 
organs  have  been  made  in  animals  by  Barcroft  and  his  associates,  but  in 
the  human  adult  the  superficial  veins  of  the  limbs  and  neck,  particularly 
of  the  aiin  (vena  mediana),  are  the  only  sources  from  which  venous  blood 
can  be  obtained.  This  means  that  in  the  human  only  blood  coming  from 
a  limited  region,  consisting  chiefly  of  muscles,  can  be  studied. 

Lunsgaard(«)  has  given  the  following  figures  for  the  oxygen  content 
and  oxygen  unsaturation  of  the  venous  blood  of  the  normal  resting  adult. 
The  results  are  the  average  of  thirty-eight  determinations  on  twelve  indi- 
viduals and  are  given  in  tabular  form  l^elow : 


Oxygen  Content  of  Venous  Blood         i\    Oxjgen  Unsaturation  of  Venous  Blood 


Volume  Per  Cent 


Maximum 

is.a 


^linimum 
9.6 


Av-erage 


Volume  Per  Cent 


Maximum 


13.6  I  9.0 


Minimum 
2.7 


Average 
5.8 


In  studying  this  question  on  circulatory  disorders,  Lurisgaard(?>)  found 
that  in  twelve  patients  with  compensated  heart  lesions  the  unsaturation 
fell  within  normal  limits,  between  2.5  and  8  volume  per  cent,  while  in 
four  patients  with  uncompensated  heart  disease  the  values  for  the  lui- 
saturaticn  were  all  above  the  normal  limits,  from  9.7  to  15.2  volume  per 
cent.  In  these  cases  the  oxygen  unsaturation  ap^x^ars  to  afford  an  objective 
criterion  of  the  positive  effect  of  digitalis  therapy.  From  studies  per- 
formed on  patients  with  varying  amounts  of  hemoglobin  it  has  been  shown 
that  the  oxygen  unsaturation  of  the  venous  blood  is  independent  of  the  oxy- 
gen capacity,  unless  the  latter  is  i-educed  below  the  normal  value  for  oxygen 
unsaturation  (about  5  volumes  per  cent).  Lunsgaard  found,  for  example, 
that  in  a  polycythemic  patient  with  an  oxygen  capacity  of  33.4  volumes 
per  cent,  the  venous  oxygen  unsaturation  was  5.4  volumes  per  cent,  while 


456 


VICTOR  c.  :myers 


in  an  anemic  patient,  with  an  oxygen  capacity  of  G.7  volnmes  per  cent  the 
venons  oxygen  nnsaturation  was  r).2  vnlnnics  per  cent^  indicating  that 
the  tissues  extract  from  tlio  blood  all  the  oxygen  they  need  with  apparently 
equal  readiness,  regardless  of  whether  the  extraction  leaves  a  great,  oxygen 
reserve  in  the  blood  as  in  polycythemia,  or  practically  no  reserve  as  in 
anemia. 

Considerable  additional  information  may  also  be  obtained  when 
the  study  of  the  oxygen  content  of  the  arterial  blood  is  included.  Sucli 
studies  have  been  conducted  on  normal  and  certain  pathological  conditions 
by  Stadie  and  by  IIarrop(6),  the  arterial  blood  being  obtained  from  the 
radial  artery.  Observations  obtained  by  Stadie  for  the  arterial  and  venous 
oxygen,  and  total  oxygen  capacity  of  five  normal  resting  men  are  given 
in  the  table  below.    As  will  be  noted  the  arterial  unsaturation  amounts  to 


O.xygen  Content 

Oxygen 

Capacity 

per  100  c.c. 

of  Blood 

Unsaturation 

.  Arterial 

Venous 

Individual 

Arterial 

per  100  c.c. 

of  Blood 

Venous 
per  100 
c.c.  of 
Blood 

Per  100 
c.c.  of 
Blood 

Per  Cent 

Per  100 
c.c.  of 
Blood 

Per  Cent 

1 

c.c. 
17.9 
21.0 
22.1 
20.2 
19.5 

c.c. 
12.8 
16.7 
17.2 
15.6 
1.5.4 

c.c. 
10.1 
21.6 
23.3 
21.6 
20.3 

c.c. 
1.2 
0.6 
1.2 
1.4 
0.8 

6.3 
2.8 
5.2 
6.5 
3.9 

c.c. 

6.3 

4.9 

6.1 

6.0 

4.9 

33.0 

2    

3    

4    

5    

22.7 
26.2 
27.8 
24  1 

Mean    

20.2 

15.6 

21.2 

1.0 

5.0 

5.6 

26.8 

about  5  per  cent  while  the  venous  unsaturation  slightly  exceeds  25  per 
cent.  Similar  studies  were  made  on  a  series  of  pneumonia  cases  (chiefly 
post  influenza),  a  high  arterial  unsaturation  being  observed  in  the  fatal 
cases.  A  definite  relation  was  found  to  exist  between  the  degree  of  cyanosis 
and  the  per  cent  of  arterial  unsaturation.  With  increa-sing  cyanosis  the 
arterial  unsaturation  becomes  greater.  The  venous  saturation  varies  sim- 
ilarly. Obviously  the  cyanosis  of  pneumonia  patients  is  due  to  the  incom- 
plete saturation  of  venons  blood  with  oxygen  in  tlie  lung's.  The  range 
of  arterial  and  venous  unsaturation  encountered  in  fatal  and  nonfatal 
cases  of  pneumonia  is  well  illustrated  in  the  table  below,  taken  from 
Stadie.    As  will  be  noted  the  arterial  unsaturation  of  the  fatal  cases  aver- 


Type  of  Cases 

No.  of 
Cases 

Arterial  Unsaturation 

Venous  Unsaturation 

Max. 

Min.        Mean 

Max. 

Min. 

IMean 

Normal  individuals 
Is  onfatal  cases    ... 
Fatal  cases    

5 
16 
16 

1       6.5 
33.0 
68.2 

2.8    .         5.0 

1.6           13.V) 

14.1           32.0 

33.0 
61.2 
85.5 

22.7 
14.4 
22.3 

26.8 
36.3 
57.0 

BODY  TISSUES  AND  FLUIDS  ,457 

aged  32  per  cent  and  in  one  case  reached  68  per  cent,  the  venous  im- 
saturation  exceeding  85  per  cent. 

The  oxygen  content  of  the  arterial  blood  in  anemia  and  heart  disease 
has  been  .studied  by  Harrop,  who  likewise  made  a  careful  study  of  the 
\*](Kx\  gases  (oxygen  and  carbon  dioxid)  iu  both  the  arterial  and  venous 
blood  of  fifteen  normal  subjects,  his  figures  for  oxygen  agreeing  closely 
with  those  of  Stadie.  With  severe  anemia  the  saturation  of  the  arterial 
blood  did  not  differ  from  the  normal.  Low  absolute  values  were  found 
for  the  oxygen  content  of  the  venous  blood,  but  the  normal  oxygen  consump- 
tion was  maintained.  'No  deviations  fr(>m  the  normal  were  found  in 
arterial  and  venous  blood  from  cardiac  patients  without  arrhythmias,  well 
compensated,  and  at  rest  in  bed.  With  cardiac  cases  showing  varying 
degrees  of  decompensation  the  arterial  unsaturation  is  frequently  ab- 
normally low  (sometimes  exceeding  15  per  cent),  although  not  so  low  as 
that  found  in  pneumonia.  It  is  apparent  that  in  many  circulatory  diseases 
during  decompensation,  particularly  when  there  are  physical  signs  of 
pulmonary  congestion,  there  is  a  disturbance  of  the  pulmonary  exchange, 
as  indicated  by  the  lowering  of  the  percentage  saturation  of  the  arterial 
blood  with  oxygen. 

Carbon  Dioxid.  — Recent  studies  on  the  carbon  dioxid  of  the  blood  have 
been  devoted  largely  to  the  utilization  of  this  determination  as  a  means  of 
ascertaining  the  carbon  dioxid  capacity  of  the  blood.  This  determination, 
as  Van  Slyke  and  Cullen  have  pointed  out,  furnishes  a  most  excellent 
method  of  ascertaining  the  degree  of  an  acidosis,  since  the  bicarbonate  of 
the  blood  represents  the  excess  of  base  which  is  left  after  all  non-volatile 
acids  have  been  neutralized  and  in  this  sense  constitutes  the  alkaline  re- 
serve of  the  body.  Before  entering  into  a  discussion  of  this  phase  of  the 
subject,  however,  it  may  be  well  to  consider  the  actual  content  of  carbon 
dioxid  in  normal  human  blood. 

Harrop(6)  has  presented  some  interesting  figures  for  the  oxygen  and 
carbon  dioxid  content  (according  to  the  Van  Slyke  method)  of  both  arterial 
and  venous  blood  upon  individuals  with  normal  heart  and  lung  findings, 
A  few  of  these  are  given  in  the  table  on  page  458. 

As  will  be  noted  the  COg  content  of  arterial  blood  in  the  first 
six  cases  tabulated  averages  about  50  volumes  per  cent,  Avhile  that  of  the 
venous  blood  is  4  volumes  per  cent  higher.  After  15  minutes  of  brisk 
exercise  Harrop  found  the  CO2  content  of  both  arterial  and  venous  blood 
reduced,  with  a  considerable  increase  in  the  venous-arterial  whole  blood 
difference.  The  oxygen  consumption  was^  however,  only  slightly  in- 
creased. 

Smith,  Means  and  Woodwell,  employing  the  Henderson  apparatus, 
found  the  COo  content  of  eight  nonnal  whole  bloods  to  average  50.4  vol- 
umes per  cent,  while  the  venous  blood  showed  58.7  volumes  per  cent,  a 
difference  of  8.3,  which  is  considerably  greater  than  that  recorded  below. 


458 


VICTOR  C.  MYERS 


Individual 


1  

2  

3  

4  

5  

6  

Average 

Normal    adult 

resting 

After  exercise  ... 


s-:?         c 


1 

' 

00 

•^ 

ck 

LI 

"5  ~  ti 

=   r  S 

^>- 

II 

>'i^ 

Z'Z  'C 

isl 

H  f- 

Hll 

X   =1 

•y.  T  T 

i,   fc.    — 

•.   X    s 

X  ^.2 

X    Z 

CO 

C^  w 

-<yi 

<OD 

17.6 

C   X 

51.8 

23.7 

23.0 

98 

0.7 

6.4 

17.2 

17.2 

100 

0.0 

14.6 

2.G 

54.7 

16.3 

15.3 

94 

1.0 

10.5 

4.8 

52.9 

20.6 

19.S 

96 

0.8 

13.5 

6.3 

40.5  . 

18.7 

17.8 

9.5 

0.9 

15.1 

2.7 

44.8 

20.6 

19.S 

96 

0.8 

12.7 

7.1 

49.7 

19.5 

18.8 

96 

0.7 

14.0 

5.0 

50.1 

22.0 

21.1 

96 

0.9 

15.1 

6.0 

53.3 

22.4 

19.2 

86 

3.2 

12.9 

6.3 

32.3 

o   » 

57.2 
56.7 
55.9 
51.7 
48.3 
54.6 

54.1 


66.9 
41.1 


According  to  these  workers,  as  the  blood  passes  from  the  arterial  to  the 
venous  side  of  the  circulation  in  normal  man  its  cells  gain  from  4  to  11 
volumes  per  cent  of  COo,  while  the  corresponding  gain  in  the  plasma  is 
only  from  0  to  1.8  volumes  per  cent,  indicating  tliat  the  transport  is  ac- 
complished mainly  by  the  cells.  Theories  regarding  the  ability  of  the 
blood  to  take  up  and  hold  oxygen  and  carbon  dioxid  and  the  equilibrium 
between  these  two  gtises  in  the  blood  have  recently  been  presented  by  L. 
J.  Henderson (c)  and  Y.  Henderson  and  Haggard (&). 

Although  the  removal  of  carbon  dioxid  from  the  tissues  may  be  ac- 
complished mainly  through  the  agency  of  the  cells,  still  the  bicarbonate 
of  the  plasma  is  ordinarily  in  equilibrium  with  that  of  the  cells,  as  Van 
Slyke  and  Cullen  have  pointed  out.  Consequently  the  carbon  dioxid  capac- 
ity of  the  plasma  may  be  used  as  a  simple  practical  method  of  measuring 
the  alkaline  resei*ve  of  the  body.  (Whole  blood  may  be  used,  and  theoret- 
ically is  to  be  preferred,  but  it  easily  gums  up  the  Van  Slyke  apparatus.) 

Acidosis  may  result  from  an  abnonnal  formation  of  acid  substances 
such  as  is  found  in  diabetes,  or  from  a  decreased  elimination  of  nonnally 
formed  substances  as  in  nephritis.  The  carbonates  of  the  blood  have 
been  called  by  L.  J.  Henderson  the  first  line  of  defense  against  acidosis. 
Increased  pulmonary  ventilation  as  occurs  with  dyspnea  or  hyper- 
pnea,  seiTcs  to  increase  the  excretion  of  carbon  dioxid,  thus  keep- 
ing the  reaction  of  the  blood  within  normal  limits.  In  conditions 
of  acidosi.s,  other  acids  may  combine  with  the  bicarbonate,  robbing  the  body 
of  its  alkaline  reserve.  In  diabetes  this  is  brought  about  by  the  abnonnal 
formation  of  ketone  bodies,  while  in  nephritis  the  breakdown  in  the  ex- 
cretion of  acid  phosphate  apparently  brings  about  the  same  result. 

The  range  of  the  carbon  dioxid  combining  power  of  the  blood  plasm^ 
of  the  normal  i-esting  adult,  with  the  Van  Slyke(e)  method,  is  from  56  to 
75  c.c.  of  CO2  per  100  c.c,  with  an  average  of  65  c.c.     For  normal  in- 


BODY  TISSUES  AXD  FLUIDS  459 

fants  the  figures  are  about  10  c.c.  lower  than  in  adults.  With  moderate 
acidosis,  in  which  symptoms  may  or  may  not  be  apparent,  COj  combin- 
ing po'.ver  figures  of  30  or  below  arc  found.  In  the  terminal  stages  of  dia- 
betic c<^ma  figures  of  10  to  15  c.c.  are  encountered,  and  similar  figures 
arc  SMiiietimes  observed  in  "uremia."  In  such  cases  death  may  be  di- 
rectly ascribed  to  the  acidosis.  .Extremely  low  figures  are  encountered  in 
many  cases  dying  from  pneumonia.  Low  figures  may  likewise  be  obtained 
in  the  diarrheal  acidoses  of  infancy.  All  cases  of  chronic  nephritis  with 
marked  nitrogen  retention  show  a  moderately  severe  or  a  severe  acidosis, 
while  occasionally  severe  acidosis  is  encountered  in  acute  nephritis.  Ether 
anesthesia  is  accompanied  by  a  fall  in  the  CO^  combining  power  of  the 
blood,  amounting  to  2  to  20  volumes  per  cent.  The  introduction  of  a 
simple  method  of  estimating  the  CO2  combining  power  of  the  blood  has 
placed  the  diagnosis  and  treatment  of  cases  of  acidosis  on  a  rational  basis. 


Muscle 

The  muscle  tissue  of  the  human  adult  has  been  variously  estimated 
as  comprising  from  30  to  40  per  cent  of  the  body  weight.  Of  the  total 
body  metabolism  about  50  per  cent  takes  place  in  the  muscles  during  rest 
and  75  per  cent  during  activity.  Physiologically,  muscle  tissues  are  di- 
vided into  voluntary  or  striated  and  involuntary  or  non-striated  muscle, 
heait  muscle  belonging  to  an  intermediate  group.  The  involuntary  muscles 
comprise  only  a  comparatively  small  part  of  the  total  muscle  tissue.  The 
muscle  fibers  of  which  muscle  tissue  is  chiefly  composed  are  elongated, 
spindle  shaped  cells.  ]\Iuscle  tissue  in  the  adult  contains  from  22  to  28 
per  cent  solids  with  an  average  of  25  per  cent.  Of  this  about  four^fifths 
is  protein  and  the  remainder  largely  extractives  and  inorganic  salts* 

The  proteins  of  the  muscle  are  ordinarily  divided  into  two  groups, 
the  muscle  plasma  and  the  muscle  stroma.  This  division  or  separation 
is  a  more  or  less  arbitrary  one,  since  the  muscle  plasma  simply  represents 
the  amount  of  protein  which  can  be  expressed  (about  60  per  cent)  from 
fresh  muscle.  In  the  muscle  plasma  there  are  two  distinct  proteins^  as 
may  readily  be  shown  by  the  fractional  coagulation  of  the  plasma.  Para- 
myosinogen (Halliburton (a))  or  myosin  (von  Furth(a))  coagulates  at  46- 
51'^C..  w^hile  myosinogen  or  myogen  coagulates  at  5p-65°  C.  The  former 
constitutes  about  25  per  cent  of  the  protein  in  the  plasma  and  the  latter 
75  per  cent.  The  first  of  these  proteins  is  definitely  a  globulin,  but  the 
latter  is  not  a  typical  globulin  since  it  is  soluble  in  water,  and  belongs 
rather  to  the  class  of  albumins.  The  proteins  of  different  muscles  do  not 
differ  widely  in  their  content  of  amino-acids.  The  phenomenon  of  rigor 
mortis,  according  to  the  now  generally  accepted  view,  first  suggested  by 
Meigs,  is  due  to  the  swelling  of  the  muscle  cells  (taking  up  of  water) 


400  VICTOE  C.  MYERS 

as  a  result  of  the  post-mortem  formation  of  lactic  acid,  increasing  the 
hydrophylic  pro[)€rties  of  the  protein  colloids  of  the  muscle. 

The  so-called  extractives  of  muscle  are  of  considerable  interest  and 
importance.  Tncludin^r  the  inorganic  salts  they  constitute  about  2  per 
cent  of  the  tissue,  the  organic  material  amounting  to  0.7  per  cent  and 
the  inorganic  to  1.3  per  cent.  The  organic  material  is  ordinarily  divided 
into  two  groups,  the  non-nitrogenous  and  the  nitrogenous.  To  the  former 
group  belong  glycogen,  glucose,  para-  or  sarcolactic  acid  and  inositol, 
and  to  the  latter  such  substances  as  creatin,  the  purin  bases,  xanthin,  hypo- 
xanthin  and  guanin,  carnosin,  amino-acids  and  traces  of  creatinin,  uric 
acid  and  urea. 

Glycogen  is  a  polysaccharide  carbohydrate  possessing  some  of  the 
properties  of  starch  and  dextrin.  It  is  present  in  normal  human  muscle 
tissue  to  the  extent  of  about  0.5  per  cent.  From  experiments  on  animals  we 
know  that  the  amount  may  be  markedly  reduced  by  muscular  activity. 
Glycogen  constitutes  the  muscles^  reserve  supply  of  energ}'.  The  glycogen 
of  the  muscle  together  with  that  of  the  liver  is  apparently  transformed  to 
glucose  as  needed.  Judging  from  the  observations  of  Palmer  the  glucose 
content  of  the  muscle  is  only  about  half  that  of  the  blood.  Hopkins  has 
recently  presented  some  interesting  views  regarding  the  transformation  of 
glycogen  into  mechanical  and  heat  energy.  The  facts  which  he  has  brought 
together  indicate  that  there  are  two  phases  in  muscular  activity,  the  first 
anaerobic  and  the  latter  aerobic.  During  the  first,  in  which  muscular  con- 
traction takes  place,  lactic  acid  is  formed.  During  the  second  phase  a  part . 
of  the  lactic  acid  is  oxidized  and  transformed  to  carbon  dioxid  and  water,  § 

while  a  part  is  apparently  reconverted  to  glycogen.  The  heat  liberated 
duiing  this  (second)  period,  however,  is  less  than  that  required  by  the 
oxidation  of  the  lactic  acid,  and  is  apparently  stored  in  the  muscle  in  a 
latent  form  for  the  next  (first)  phase  of  the  reaction,  when  it  is  liberated. 
The  formation  of  lactic  acid  (producing  changes  in  the  hydrogen  ion  of 
tho  muscle)  apparently  plays  an  important  role  in  initiating  the  contrac- 
tion of  the  muscle,  while  a  combination  of  the  glucose  with  phosphoric 
acid  is  necessaiy  to  its  cleavage  into  lactic  acid.  Eigor  may  take  place  in 
the  muscle  as  a  result  of  severe  exertion  or  from  poor  oxidation  as  in  car- 
bon monoxid  poisoning,  while  rigor  mortis  may  be  prevented  if  a  suffi- 
ciently high  concentration  of  oxygen  is  maintained  to  bring  about  an  oxida- 
tion of  lactic  acid.  However,  after  a  time  imtability  is  lost  apparently 
as  a  result  of  the  stabilization  of  the  inorganic  ions  by  the  tissue.  Although 
inositol  possesses  the  same  empirical  formula  as  glucose,  it  is  a  hexahy- 
droxybenzene.  However,  it  probably  stands  in  fairly  close  relationship  to 
sugar  since  lactic  acid  may  be  formed  from  it. 

Of  the  nitrogenous  extractives  of  muscle,  creatin  is  present  in  much 
the  largest  amount  and  is  of  the  greatest  interest,  especially  since  it  is 
apparently  the  precursor  of  the  creatinin  of  the  urine.    In  1913  Myers  and 


BODY  TISSUES  AND  FLUIDS  461 

Fine  called  attention  to  the  fact  that  the  creatiu  content  of  the  muscle 
of  a  given  species  of  animals  was  very  constant  (obviously  that  of  a  given 
animal)  and  suggested  this  as  a  possible  basis  of  the  constancy  in  the 
daily  elimination  of  creatinin  first  noted  by  Folin.  Later  they  pointed  out 
ihat  the  creatinin  content  of  muscle  was  greater  than  that  of  any  other 
tissue,  and  also  that  in  autolysis  experiments  with  muscle  tissue 
the  creatin  (and  any  added  creatin)  was  converted  to  creatinin  at 
i\  constant  rate  of  about  2  per  cent  daily,  which  is  just  about  the  normal 
ratio  between  the  muscle  creatin  and  urinary  creatinin.  They  also  found 
that,  when  creatin  was  administered  to  man  or  animals,  there  was  a  slight 
conversion  to  creatinin  which  corresponds  well  with  the  above  figure.  These, 
facts  all  go  to  support  the  view  that  creatinin  is  formed  in  the  muscle 
tissue  from  creatin,  and  at  a  very  constant  rate,  although  no  explanation 
of  the  physiological  significance  of  this  transformation  can  as  yet  be 
offered. 

For  the  rabbit  Myers  and  Fine(c)  found  a  ci-eatin  content  of  0.52  per 
cent,  for  the  white  rat  0.47  per  cent,  for  the  dog  0.37  per  cent  and  for  two 
human  cases  0.39  per  cent.  This  figure  for  normal  human  muscle  was 
likewise  confirmed  by  Denis(e)  who  has  reported  data  for  the  muscle  cre- 
atin on  nearly  a  hundred  human  cases.  In  a  series  of  determinations  made 
on  persons  dying  from  various  chronic  diseases  the  creatin  of  the  muscle 
was  found  to  be  reduced  absolutely  and  relatively  in  many  cases,  especially 
those  in  an  emaciated  condition.  These  are  the  type  of  cases  which  ex- 
crete creatin  and  show  low  creatinin  coefficients.  Denis  likewise  found 
the  percentage  of  muscle  creatin  in  children  to  be  lower  thanl  that  of 
adults,  which  is  in  harmony  with  the  observation  that  children  excrete 
creatin. 

Of  the  nitrogenous  extractives  carnosin  stands  next  to  creatin  in  point 
of  quantity.  It  is  a  dipeptid  containing  histidin  and  alanin.  By  its  syn- 
thesis Baumann  and  IngTaldsen(&)  have  shown  carnosin  to  be  P-alanyl- 
histidin.  Figures  given  for  its  contents  in  muscle  vary  from  0.035  to  0.30 
per  cent.    About  0.05  per  cent  has  been  reported  for  human  muscle. 

The  amount  of  purin  base  nitrogen  found  in  the  muscle  of  mammals 
is  generally  given  as  about  0.05  per  cent.  This  is  partly  combined  and 
partly  free.  From  the  observations  of  Davis  and  Benedict  on  a  combined 
nric  acid  compound  present  in  beef  blood,  it  is  apparent  that  purins  may 
even  be  oxidized  to  uric  acid  before  they  are  split  off  from  the  sugar  with 
which  they  ^re  combined  in  the  nucleic  acid  molecule.  Of  the  different 
purins  liypoxanthin  is  generally  stated  to  be  present  in  tlie  largest  amoimt, 
although  both  xanthin  and  guanin  are  also  present. 

As  was  pointed  out  b}'  Marshall  and  Davis  ur^a  is  so  diffusible  that  it 
isveiy  evenly  distributed  throughout  the  tissue^  of  the  body,  and  this 
has  been  amply  confirmed  by  the  observations  of  l^p^sjejnthal,  .Clapsen  and 
Ililler  on  human  muscle  tissue  in  cases  with  and  without  niti'ogen  retention. 


462 


VICTOR  C,  MYERS 


iN'ormally  muscle  tissue  contains  rather  more  creatinin  than  the  blood, 
but  in  cases  of  marked  nitrogen  retention  the  blood  may  slightly  exceed 
that  of  the  muscle  (Myers  and  Fine  (c)).  The  uric  acid  of  the  muscle 
scarcely  keeps  pace  with  the  rise  in  the  blood  uric  acid  which  occurs  in 
some  cases  of  advanced  nephritis.  The  figures  for  the  non-protein  nitrogen 
of  muscle  are  much  higher  than  those  of  the  blood,  owing  chieflv  to  the 
much  larger  amounts  of  creatin  and  amino-acid  nitrogen  present  in  muscle 
than  in  blood. 

The  table  below  compiled  from  obsen^ations  of  Mosenthal,  Clausen  and 
Hiller,  and  flyers  and  Fine  (b)  gives  an  idea  of  the  distribution  of  the 
various  non-protein  nitrogenous  constituents  in  the  muscle  tissue  of 
normal  individuals  and  those  suffering  from  severe  nephritis. 

Context  of  Nitroge>t:ous  Constituents  in  Human  Muscle 


Determination 

Normal 

Severe  Nephritis 

Total  solids    per  cent 

24 

3.5 

185 

125 

35 

13 

1 

0.5 

Total  nitrogen    "       " 

Total  nonprotein  N    mg.  to  100  gms. 

CreatinN    "     "   "       " 

Amino-acid  N "     "'*      " 

375 

125 

30 

Urea  N    "     "   "      " 

200 

Creatinin  N    "     "    "       " 

Uric  acid  N  "    "   "      " 

5 
2 

It  is  very  difficult  to  completely  free  muscle  tissue  from  adherent  fat. 
Figures  as  low  as  0.6  per  cent  have  been  obtained  in  lean  oxen  and  as  high 
as  9  per  cent  in  fattened  pigs»  Less  is  known  concerning  the  cholesterol 
and  phosphatids  of  the  muscle,  although  the  latter  are  present  in  much 
higher  concentration,  especially  in  heart  muscle. 

One  may  obtain  an  idea  of  the  inorganic  constituents  of  muscle  from 
the  following  table  taken  from  Katz(&).  Of  the  different  constituents  tabu- 
lated potassium  and  phosphonis  are  present  in  by  far  the  largest  amounts. 

Mineral  Content  of  the  Muscle  of  Mammals 


Constituent 

Range  in  Mammals 

Man 

Potassium     

Per  Cent 
0.254-0.398 
0.0C5-0.156 
0.004-0.024 
0.002-0,018 
0.021-0.0.30 
0.17(W).253 
0.040-0.081 
0.180-0.227 

Per  Cent 
0.320 

Sodium 

0.080 

Iron    

0.015 

Calcium     

0  021 

Magnesium    

Phosphorus     ....    

0  203 

Chlorin    

0  070 

Sulphur     

0  208 

In  striated  muscle  the  phosphonis  is  present  largely  in  inorganic  form, 
but  in  heart  muscle  organic  phosphorus  may  constitute  more  than  half 
of  the  phosphorus  present.     In  the  voluntary  muscle  of  the  rabbit,  which 


BODY  TISSUES  AND  FLUIDS  463 

has  a  relatively  high  content  of  ereatin,  flyers  has  obser\'ed  that  the  potas- 
sium is  present  in  fairly  high  concentration,  0.46  per  cent  calculated  as 
K  (average  for  8  animals).  In  conditions  such  as  starvation,  which  ulti- 
mately bring  about  a  reduction  in  the  ereatin,  it  is  of  interest  that  the 
potassium,  as  a  rule,  shows  a  proportionate  reduction. 

Without  further  discussion  it  may  be  said  that  there  are  many  obser\'a- 
tions  which  lead  one  to  believe  that  glycogen,  ereatin,  phosphoric  acid  and 
potassium  are  closely  associated  in  active  muscle. 


Liver  and  the  Bile 

An  appreciation  of  the  importance  of  the  liver  to  the  animal  organism 
may  be  gained  from  the  following  facts.  The  liver  is  the  largest  gland 
of  the  body.  Its  extirpation  in  mammals  quickly  results  in  death.  The 
blood  from  the  digestive  tract  first  passes  through  the  liver  before  reach- 
ing the  general  circulation.  The  liver  appears  to  be  a  temporary  store- 
house fur  all  classes  of  foodstuffs,  carbohydrate  (glycogen),  fat  and. pro- 
tein (amino-acids).  Many  poisons  both  inoi^anic  and  organic  are  retained 
by  the  liver,  many  of  the  latter  being  detoxieated.  Xumerous  chemical  re- 
actions, in  which  deamidization,  hydrolysis,  oxidation  and  reduction  occur, 
take  place  in.  the  liver.  The  liver  also  appears  to  be  chiefly  concerned  in 
the  synthesis  of  urea  (uric  acid  in  birds),  sugar  from  protein  and  the 
ethereal  sulphates.  The  formation  of  fibrinogen  and  also  serum  albumin 
and  globulin  has  been  ascribed  to  the  liver. 

Less  is  known  concerning  the  proteins  of  the  liver  than  of  the  muscle. 
There  are  two  proteins,  apparently  globulins,  which  coagulate  at  45*^  and 
75°  respectively,  and  a  nucleoprotein  which  coagulates  at  70°  C.  Besides 
these  proteins  which  are  soluble  there  are  others  in  the  cells  which  are 
difficultly  soluble.  The  fat  (fatty  infiltration)  of  the  liver  is  derived 
not  only  frohi  an  excess  of  fat  in  the  diet,  but  also  by  transportation  from 
other  parts  of  the  body.  The  phosphatids  (lecithin)  are  normal  constitu- 
ents of  the  liver  and  are  subject  to  nuicli  less  variation  than  the  fat. 
Cholesterol  is  also  a  normal  constituent  but  found  in  small  amounts.  As 
in  the  muscle,  phosphoric  acid  and  potassium  are  the  mineral  constituents 
which  are  present  in  the  highest  concentrations.  Compared  to  other  tis- 
sues iron  appears  to  be  present  in  fairly  large  amounts.  It  is  of  interest 
that  considerable  iron  is  stored  in  the  liver  during  fetal  life,  apparently 
to  provide  for  the  deficiency  in  the  diet  during  the  period  of  lactation. 

The  storing  of  carbohydrate  in  the  liver  in  the  form  of  glycogen 
is  one  of  the  liver's  many  important  fimctions.  The  credit  for  the  dis- 
covery of  glycogen  and  this  glycogenic  function  of  the  liver,  i.  e.,  the 
ability  of  the  liver  to  convert  glucose  to  glycogen  and  glycogen  to  glu- 
cose, is  due  to  Bernard.     In  nonnal  animals  the  quantity  of  glycogen  in 


464  VICTOR  C.  UYEHS 

the  liver  depaids  essentially  upon  the  food  intake.  In  starvation  the  gly- 
cogen may  alHiost  disappear  from  the  liver,  hut  after  food  very  rich  in 
carhohydrato  it  may  in  exceptional  cases  reach  nearly  20  per  cent.  Ap- 
parently only  the  fennentihle  sugars  of  the  six  carlK)n  series  or  their  di- 
aiul  t)olysaceluirids  are  true  glycogenformers.  The  di-  and  polysaccharide 
must,  however,,  first  he  hroken  down  into  monosaccharids  in  digestion. 
Gluco?e  is  apparently  more  readily  converted  into  glycogen  than  fructose, 
and  much  moare  readily  than  galactose.  These  transformations  are  ap- 
parently broii^it  about  by  the  diastatic  fennent  of  the  liver.  The  liver 
is  the  probahk  source  of  the  blood  diastase.  It  is  of  interest  that  in  dia- 
betes, where  ^e  reserve  supply  of  glycogen  in  the  liver  is  very  small,  the 
diastatic  activity  of  the  blood  is  generally  markedly  increased.  It  is 
further  signiicant  that  when  the  liver  is  cut  out  of  the  circulation  in 
animals,  the  bSood  sugar  rapidly  falls  and  may  almost  disappear.  The  in- 
fluence of  the  various  internal  secretions  and  also  Bernard's  sugar  puncture 
are  of  considerable  interest  and  importance  in  this  connection.  As  regards 
the  formation  of  sugar  from  protein  it  would  seem  probable  that  the  liver 
was  cbiefly  (Maaceraed  in  the  deamidization  of  amino-acids  and  the  trans- 
formation of  (the  carbon  moiety  to  sugar.  Not  all  amino-acids  are  sugar- 
fonners,  althiMigh  it  may  be  noted  that  practically  all  the  amino-acids  with 
straight  chaias,  except  lysin,  yield  sugar.  Prolin  is  the  only  cyclic  amino- 
acid  which  pffiivduces  an  abundance  of  sugar. 

That  ure^  foi-mation  takes  place  in  the  liver  is  unquestioned  as  a 
result  of  the  well-known  experiments  of  von  Schroeder  and  others.  That 
the  liver  is  tfee  only  organ  in  the  body  where  urea  formation  takes  place 
seems  improlable,  still  the  actual  demonstration  of  the  formation  of  urea 
elsewhere  than  in  the  liver  has  not  been  made.  In  autolysis  experiments 
M.  Ringer  \Tas  able  to  demonstrate  urea  formation  in  liver  tissue  but 
not  in  muscle  tissue,  lluscle  tissue  added  to  liver  tissue  was  found,  how- 
ever, to  auc^Bnent  the  urea  formation.  It  would  appear  that  the  liver  was 
the  chief  oi^san  concenied  in  the  synthesis  of  urea,  apparently  deamidizing 
the  amino-a<cMs  no  longer  of  use  to  the  body  or  in  excess  of  the  body's 
requirements.  In  the  case  of  the  amino-acid,  arginin,  Kossel  and  Dakin 
have  shown  ilat  a  specific  liver  enzyme,  arginase^  converts  the  arginin 
to  ornithin  and  urea. 

The  liver  has  its  own  secretion,  bile,  which  it  continuously  secretefs ;  a 
resen^oir,  the  gall  bladder,  being  provided,  so  that  the  bile  need  not  be 
discharged  into  the  intestine  except  as  required.  The  discharge  of  bile  is 
brought  about  by  the  same  stimulus  that  initiates  the  secretion  of  pan- 
creatic juicCy  namely  secretin.  Bile  may  be  regarded  not  only  as  a 
secretion  but  also  as  an  excretion,  since  it  carries  to  the  intestine  certain 
metals,  cholesterol,  lecithin,  decomposition  products  of  hemoglobiuj  and 
certain  foreign  organic  substances,  for  example,  tetrachlorphthalein. 

In  man  bile  is  usually  a  golden  yellow,  rather  viscid  fluid,  amounting 


BODY  TISSUES  AND  FLUIDS 


465 


to  roughly  500  to  1000  c.c.  in  24  hrs.  It  is  usually  alkaline  in  reaction  to 
litmus,  and  ordinarily  possesses  a  decidedly  bitter  taste.  The  specific 
gravity  varies  between  1.010  and  1.040.  As  secreted  by  the  liver  bile  is  a 
rather  limpid  fluid,  but  the  addition  of  mucus  and  the  abstraction  of 
water  in  the  gall  bladder  raise  both  the  specific  gravity  and  the  viscosity. 
The  table  below,  compiled  from  analyses  given  by  Ilammarsten,  gives  a 
good  idea  of  bladder  and  liver  bile. 


Constituents 

Liver  Bile   (Hammarston) 

Bladder  Bile  (Freriehs) 

I 

II 

III 

I 

II 

Water    

Per  Cent 
07.48 
2..52 
0.53 
0.03 
0.30 
0.63 
0.12 
0.06 

i  0.02 

0.81 
0.25 

Per  Cent 
96.47 
3.53 
0.43 
1.82 
0.20 
1.62 
0.14 
0.16 
0.06 
0.10 
0.68 
0.05 

Per  Cent 
97.46 
2.54 
0.52 
0.00 
0.22 
0.68 
0.10 
0.15 
0.07 
0.06 
0.73  i 
0.02  j^ 

86.0 

14.0 

2.7 

7.2 

6!i6 

0.32 
0.65 

85.9 

Solids   

14.1 

Mucin  and  pigments. 

Bile  salts   

Taurocholate    

Glj'CQcholate    

Fatty  acids  and  soaps 
Cholesterol   

3.0 
9.1 

6.26 

Fat         

0.92 

Soluble  salts  

Insoluble  salts 

0.77 

The  most  important  constituents  of  bile  are  the  bile  acids  and  bile 
pigments.  The  bile  acids  may  be  divided  into  two  groups,  the  glycocholic 
and  taurocholic  acid  groups,  the  former  being  considerably  in  excess  in 
human  bile  as  indicated  in  the  table  above.  The  bile  acids  are  conjugate 
amino-acids,  in  which  glycocoll  or  taurin  are  joined  to  cholic  acid.  This 
latter  acid  exists  in  several  foiTas.  There  is  some  reason  for  believing 
that  cholic  acid  is  derived  from  cholesterol.  The  bile  acids  generally  exist 
in  the  bile  in  the  form  of  sodium  salts.  The  bile  salts  have  the  power  of 
holding  the  cholesterol  and  lecithin  of  the  bile  in  solution.  They  also  act 
as  a  coferment  to  the  pancreatic  lipase,  thus  facilitating  fat  digestion. 
The  bile  salts  have  a  strong  hemolytic  action  on  the  red  blood  cells. 

The  bile  pigments  are  derived  from  the  decomposition  of  the  hematin 
portion  of  hemoglobin,  after  the  removal  of  the  iron.  (Whipple  and 
Hooper (&)  have  recently  suggested  the  possibility  of  another  origin.) 
Although  the  liver  is  apparently  chiefly  concerned  in  this  transformation, 
the  formation  of  the  bile  pigments  may  take  place  elsewhere  in  the  body. 
Bilirubin  and  biliverdin,  an  oxidation  product  of  bilirubin,  are  the  two 
chief  bile  pigments,  the  one  possessing  a  golden  yellow  and  the  other  an 
emerald  green  color.  Bilirubin  is  identical  with  the  hematoidin  of  old 
blood  clots,  and  isomeric  with  the  hematoporphyvin  of  pathological  urines. 
Under  the  action  of  intestinal  bacteria  bilirubin  is  reduced.  It  would 
appear  that  hydrohilirubin  prepared  by  the  chemical  reduction  of 
bilirubin,  the  stercobiliu  of  the  feces  and  the  urobilin  of  the  urine  w^ere 


466  VICTOR  C.  MYEKS 

practically  the  same  substance.  It  has  become  customary  to  refer  to  the 
pigment  of  both  feces  and  urine  as  urobilin.  Urobilin  is  generally  excreted 
to  a  large  extent  in  the  fonn  of  a  chromogen,  urobilinogen,  which  on  ex- 
posure to  light  is  converted  to  urobilin.  Normally  a  considerable  part  of 
the  urobilin (ogcn)  of  the  intestines  is  reabsorl)ed  and  reconverted  to 
bile  pigments.  In  certain  diseases  of  the  liver,  the  liver  cells  partially 
lose  this  capacity,  thus  giving  rise  to  an  increased  excretion  of  urobilinogen 
in  the  urine.  Owing  to  the  greatly  increased  destruction  of  red  cells  in 
pernicious  anemia  (but  not  in  secondary  anemia)  the  output  of  urobilin 
in  the  stool  is  greatly  increased,  an  observation  which  is  of  considerable 
value  in  differentiating  the  two  forms  of  anemia. 

Human  biliary  calculi  or  gallstones  are  as  a  rule  composed  largely  of 
cholesterol  in  man.  Occasionally  the  stones  are  pearly  white,  indicating 
that  they  are  almost  entirely  cholesterol,  although  more  often  they  are 
somewhat  pigmented,  sometimes  very  much  so,  indicating  a  mixture  with 
calcium  salts  of  bilirubin  and  biliverdin.  Stones  made  up  largely  of 
pigments  are  not  often  found  in  man.  The  etiology  of  gallstone  formation 
is  not  as  yet  clear. 

Connective  Tissues 

The  cellular  elements  of  typical  connective  tissues  and  gelatin-yielding 
fibrils  are  imbedded  in  an  interstitial  or  intracellular  substance.  The 
fibrils  consist  of  collagen,  while  the  interstitial  substance  contiiins  chiefly 
mucoid,  besides  small  amounts  of  albumin  and  globulin.  In  yellow  elastic 
tissue,  fibrils  containing  elastin  are  also  present.  Four  types  of  con- 
nective tissue  will  be  mentioned,  (1)  white  fibrous  tissue,  (2)  yellow 
elastic  tissue,  (3)  cartilage  and  (4)  bone. 

The  tendo  Achillis  is  generally  taken  as  a  typical  example  of  white 
fibrous  tissue.  According  to  the  analyses  of  Buerger  and  Gies,  the 
tendo  Achillis  of  the  ox  contains  31.6  per  cent  of  collagen  in  the  fresh 
tissue  and  85  per  cent  in  the  dry  tissue,  together  with  4.4  per  cent  of 
elastin  and  3.5  per  cent  of  mucoid. 

The  ligamentum  nuchse  of  the  ox  is  the  classic  illustration  of  yellow 
elastic  tissue.  Vandegrift  and  Gies  give  the  content  of  elastin  in  the 
fresh  tissue  as  31.7  per  cent,  and  in  the  dry  tissue  as  74.6  per  cent,  together 
with  17  per  cent  of  collagen  and  1.2  per  cent  of  mucoid. 

Cartilage  is  closely  related  to  white  connective  tissue,  since  it  con- 
tains a  relatively  large  amount  of  collagen.  In  addition  it  contains  an 
albuminoid,  chondroalbuminoid.  and  chondroitin-sulphuric  acid.  Chon- 
dromucoid  differs  from  the  mucoids  found  in  other  connective  tissues  in 
the  large  amount  of  chondroitin-sulphuric  acid  obtained  on  decomposition. 
This  acid  is  also  found  in  bone,  ligament  and  other  tissues.  Under  the 
action  of  acid  hydrolysis,  chondroitin  is  first  formed,  then  later  cliondrosiyu 


BODY  TISSUES  AXD  FLUIDS 


467 


Chondrosin  has  a  very  strong  reducing  action,  wLich  is  clue  to  a  hexosa- 
mine,  named  by  Levene  and  La  For^e  chondrosamine,  since  it  is  isomeric 
but  not  identical  with  glucosamine.  Levene(  c)  has  recently  shown  that  it 
is  a  derivative  of  galactose.  (Uururonir  acid  is  al?o  present  in  the  molecule 
of  chondroit.in-sulphuric  acid. 

The  organic  intracelhilar  substance  of  bone  is  very  similar  to  cartilage. 
It  differs  in  its  very  large  deposit  of  inorfjauic  salts,  which  nonnally  con- 
stitute about  40  per  cent  of  the  drv  weight  of  the  tissue.  The  ossein  of 
bone  differs  in  no  essential  from  the  collagen  of  the  other  tissues  men- 
tioned. Likewise  the  osseomucoid  and  osseo-albuminoid  are  similar  to 
those  found  in  tendon  and  cartilage.  The  inorganic  material  of  bone  is 
chiefly  calcium  phosphate  and  carbonate,  but  magnesium  is  present  and 
also  traces  of  fluorid  and  chlorid.  McCrudden  has  given  the  following 
figures  for  the  important  inorganic  constituents  of  nonual  human  bone 
and  bone  from  a  case  of  osteomalacia : 


Constituents 

Normal 

Osteomalacia 

Calcium  as  CaO 

Per  Cent 

28.85 

0.14 

19.55 

0.14 

Per  Cent 
15.44 

^Manrnesium  as  MgO 

Phosphorus  as  PjO. 

0.57 
12.01 

Sulphur  as  S 

0.55 

Brain 


The  adult  human  brain  weighs  about  lf?00  to  2000  grams,  of  which 
approximately  19  per  cent  is  water.  It  comain.^  from  100  to  120  grams 
of  protein  after  the  extraction  of  the  various  lipoids.  The  brain  as  a 
tissue  is  characterized  by  its  very  high  conte^ut  of  lipoids,  i.e.,  alcohol  and 
ether  soluble  material.  The  first  worker  to  make  real  progi-ess  in  the 
chemistry  of  the  brain  was  Thudichum,  who  published  a  most  important 
monograph  on  the  subject  in  1SS4.  Of  more  recent  work  the  studies  of 
Waldemar  Koch  (a)  deserve  special  mention,  while  very  important  con- 
tributions regarding  the  constitution  of  many  of  the  lipoid  compounds 
of  brain  tissue  have  recently  been  made  by  Levene  and  his  coworkers. 

Among  the  solid  constituents  of  brain  tissue  are  proteins,  phosphatids 
(lecithin,  cephalin,  etc.),  cerebrosids  or  galactosids  (phrenosin  and  cera- 
sin),  cholesterol,  collagen,  extractives  and  inorganic  salts.  Three  dis- 
tinct proteins,  two  globulins  and  a  nucleoprotein.  have  been  isolated  from 
the  brain.  The  globulins  coagulate  at  47'  C.  and  at  70-75^  C,  while 
the  nucleoprotein  coagiilates  at  56-GO^  C.  The  lipoids  are  of  particular 
interest  and  will  be  specially  considered.  These  bodies^  as  their  name 
would  imply,  resemble  fats  in  some  of  their  physical  properties   and 


468 


VICTOR  C.  :\rYERS 


reactioiiSj  but  are  distinct  chemically.  The  content  of  lipoids  in  the 
white  matter  of  the  hrain  is  very  much  higher  than  in  the  gray  matter. 
A  general  idea  of  the  distribution  of  these  various  substances  iu  human 
hntin  tissue  may  be  obtained  from  the  table  below  taken  from  Koch. 
It  will  Ik?  observed  tlutt  the  brain  of  the  adult  differs  very  materially 
from  the  ehikl,  notably  in  its  higher  content  of  lipoids,  particularly 
cholesterol.  With  tliis  increase  in  lipoids  there  is  a  corresponding  re- 
duction in  protein,  extractives  and  ash. 

Composition'  of  the  Solids  of  the  Humax  Braix 


In   Per  Cent  of   Dry   Matter 

Constituents 

Whole  Brain 
(Child) 

Whole  Brain 
(Adult) 

Corpus  Callosum 

Protein    

40.6 
12.0 
8.3 
24.2 
6.9 
0.1 
1.8 

37.1 
6.7 
4.2 

27.3 

13.6 
0.3 

10.9 

27.1 

Extractives    

3.9 

Ash    

2.4 

Phosphatids    

31.0 

Cerebrosids     

18.0 

Lipoid  sulphur   

0.5 

Cholesterol   

17.1 

Possibly  a  better  notion  of  the  changes  in  the  composition  of  the 
brain  during  growth  may  be  obtained  from  data  given  by  W.  and  M.  L. 
Koch  on  white  rats  at  different  age  periods.  As  will  be  obsen-ed  well- 
marked  and  characteristic  chemical  changes  occur  in.  the  rat  during  its 
growth  which  may  be  correlated  with  its  anatomical  differentiation.  The 
principal  changes  are:  "(1)  A  general  decrease  in  the  per  cent  of  the 
water  which  is  not  due  entirely  to  medullation,  since  the  decrease  begins 
before  medullation;  (2)  a  diminution  in  the  relative  per  cent  of  protein 
in  the  total  solids  due  to  the  formation  of  a  large  amount  of  lipoid  matter; 

(3)  the  lipoids  which  appear  coincident  with  medullation  and  of  which 
the  development  is  part  piissu  with  medullation  are  the  cerebrosids  and 
phosphatids.    These*,  therefore,  are  chiefly  found  in  the  medullary  sheaths. 

(4)  There  is  a  gTeat  outburst  of  phosphatid  formation  at  the  very  be- 
ginning of  medullation.  The  phosphatids  are  present,  therefore,  in  the 
cells  as  well  as  the  sheaths. '^ 

The  chemistry,  so  far  as  known,  of  the  various  lipoid  substances 
present  in  brain  is  of  considerable  interest.  From  the  studies  of  Posner 
and  Gies,  and  others,  it  is  apparent  that  the  nitrogenous  phosphorized 
substance  isolated  by  Liebreich  and  named  "protagon^^  is  a  mixture. 

Phosphatids. — The  best  examples  of  the  phosphatids  are  lecithin  and 
cephalin.  Recently  Levene  and  West  have  shown  that  it  is  possible  to 
prepare  perfectly  pure  lecithin.  The  lecithin  molecule  is  known  to  be 
made  up  of  two  molecules  of  fatty  acid,  one  of  glycerol,  one  of  phosphoric 
acid  and  one  of  the  base,  cholin.     The  lecithin  of  brain  tissue  appears  to 


BODY  TISSUES  AND  FLUIDS 


469 


The  Rexative  Proportions  of  the  Constituents  of  the  Brain  of  the  Albino  Rat 

AT  DiFFKKENT   ACES 


Proteins    

Phosphatids    

Cerebrosids   

Sulphatids 

Organic  extractives ^ 

Inorganic  extractives   5 

Cholesterol    (by  difference)  . 

Total  sulphur   

Total  phosphorus  


A^f  in  Days 

1 

10 

20 

40 

120      ;      210 

Solids  in  per  cent 

10.42 
100 

12.5 

40 

17..3 
54 

20.34 
35 

21.65 
30 

21  9 

Number    of    brains    in    each 
sample 

31 

CONSTITUENTS  IN  PER  CENT  OF  TOTAL  SOLIDS 

58.25 

5G.5 

53.3 

48.4 

47.6 

15.2 

12.3 

21.4 

21.8 

21.6 

3.0 

5.9 

8.4 

1.45 

2.6 

2.5 

2.55 

3.55 

17.9 

15.1 

14.55 

14.85 

9.75 

7.2 

13.5 

5.25 

6.5 

9.1 

1.00 

0.83 

0.7«» 

0.55 

0.56 

1.87 

1.48 

i.i>; 

1.52 

1.42 

48.5 

22.0 

8.4 

4.5 

9.8 

6.8 

0.58 

1.39 


DISTRIBUTION  OF   SULPHUR  IN  PLR  CENT  OF  TOTAL  S 


Protein  S... 
Lipoid  S. .  . , 
Neutral  S. . 
Inorganic   S. 


30.5 

44.2 

56.4 

63.75 

61.8 

3.0 

6.1 

7.1 

9.65 

12.7 

48.2 

45.4 

28.0 

18.15 

18.7 

18.3 

4.3 

7.9 

8.45 

6.8 

63.8 

15.6 

14.5 

6.1 


DISTRIBUTION  OF  PHOSPHORUS  IN  TERMS  OF  TOTAL  P 


Protein  P 

Lipoid    P 

Water  Soluble  P. 


13.3 

13.45 

33.2 

.34.95 

53.5 

51.6 

5.9 
52,8.-» 
41.25 


8.7 
57.3 
34.0 


7.3 
64.1 
28.6 


6.8 
67.6 
25.6 


contain  one  molecule  of  oleic  and  one  of  palmitic  acid  as  the  fatty  acids. 
The  formula  would  thus  be  written : 

II2C  -  O  -  COC17H33 

I 

H  C  ~  0  -  COC15TJ3, 

H2C-0-P==0 

HO       O—  CHo.CH. 

\ 

(CH3)3^N 

/ 

HO 

Cephalin  differs  from  lecithin  chiefly  in  containing  as  its  basic  sub- 
stance amino-ethyl  alcohol  instead  of  cholin.    Levene  and  Rolf  have  shown 


470  VICTOR  C.  ^lYEJiS 

that  the  glycerophosplioric  acid  of  cophalin  is  identical  with  that  of  lecithin. 
It  also  appears  to  contain  another  unsaturated  fatty  acid,  namely, 
cephalinic  acid,  in  place  of  oleic  acid.     The  formula  would  thus  he: 

II2C  —  O  -  COCi^Hgi 

I 
HC  —  O— COC17H3, 

I 
ILC  — O  — P  =  0 

/\ 

HO       O-CII2.CH2.Kn2 

Two  other  monaminophosphatids  found  in  brain  tissue  are  paramyelin 
and  myelin,  the  latter  being  present  only  in  very  small  amounts.  Diamino- 
inonophosphatids  are  also  present  in  brain  tissue.  Two  have  beea 
recognized,  aynidarnyelin  and  sphingomyelin.  In  the  case  of  this  latter, 
compound  Thudichum  recognized  that  it  did  not  contain  glycerol.  Leveiie 
has  recently  obtained  on  hydrolyzing  sphingomyelin,  phosphoric  acid,  two 
fatty  acids,  cerebronic  and  lingoceric,  and  three  basic  substances,  cholin, 
sphingosin  and  a  base  of  the  composition  CiYlIagNO. 

Cerebrosids.— The  cerebrosids  are  nitrogenous  substances  free  frona 
phosphonis,  which  yield  galactose  on  boiling  with  dilute  mineral  acids. 
They  also  contain  a  complex  fatty  acid.  As  would  seem  evident  from 
the  table  above  they  are  not  found  in  the  embiyonic  brain,  but  develop  as 
medullation  comes  on  and  are  found  chiefly  in  the  medullary  sheaths  ia 
the  white  matter  of  the  brain.  The  most  important  of  the  cerebrosids 
are  phrenosin  and  cerasin.  On  hydrolysis  phrenosin  apparently  yields 
cerebronic  acid,  galactose  and  sphingosin,  w^hile  cerasin  yields  ligno- 
ceric  acid,  galactose  and  sphingosin.  Thus  the  important  difference  in 
the  two  substances  appears  to  be  in  the  fatty  acid  they  contain.  Phrenosin 
has  been  somewhat  more  studied  than  cerasin. 

Sulphatids. — It  has  been  suggested  by  Koch  that  the  oxidized  sulphur 
always  present  in  cerebrosids  when  impure  has  a  union  in  the  form  of 
sulphuric  acid  with  a  cerebrosid  and  a  phosphatid  as  follows: 

O 

II 
Cerebrosid  —  O  — S  —  O  —  Phosphatid 


Its.  nature  is  unknown. 

Thudichum  has  also  isolated  in  small  amounts  two  amino-lipotida, 
crinosi?i  and  bregenin. 

Cholesterol. — Cholesterol  is  the  chief  sterol  present  in  brain.  Choles- 
terol melts  at  145^.    There  is  another  sterol  present  which  melts  at  137®^ 


BODY  TISSUES  AND  FLUIDS  "      471 

which  has  been  called  phrenosterol.     Cholesterol  is  present  chiefly  in 
the  free  state. 

Extractives. — The  most  important  nitrogenous  extractives  recognized 
are  hypoxanthin,  and  creatin,  which  is  present  to  the  extent  of  about  0.1 
per  cent.  Among  the  amino  acids  isolated  have  been  tyrosin  and  normal 
leucin,  or  caprin.  Lactic  acid  and  inositol  are  also  present.  About  1  per 
cent  of  ash  is  present  and  this  is  composed  in  great  part  of  alkaline 
phosphates  and  chlorids.    Potassium  is  probably  the  most  important  base. 


Cerebrospinal  Fluid 

lITormally  the  cerebrospinal  fluid  is,  a  perfectly  clear  and  colorless 
fluid  with  a  specific  gravity  of  1.005  to  1.008,  and  a  solid  content  between 
1  and  2  per  cent.  The  normal  amoimt  of  spinal  fluid  has  been  estimated 
roughly  as  60  c.c,  but  pathologically  the  amount  may  be  much  larger, 
especially  in  hydrocephalus.  The  trace  of  protein  present  in  the  fluid  is 
globulin  in  character.  Fibrinogen  and  albumin  are  absent.  The  fluid  is 
hypertonic.  It  is  probably  formed  by  the  secretory  cells  covering  the 
choroid  plexus,  according  to  recent  studies  of  Gushing  and  his  coworkers. 
Its  function  is  unknown.  It  would  seem  probable  that  the  secretion  of 
the  pituitary  passes  into  the  fluid.  Normally  not  more  than  3  to  5  white 
cells  per  cu.  mm.  of  fluid  are  present. 

From  time  to  time  many  studies  have  been  carried  out  on  the  spinal 
fluid,  although  scarcely  as  accurate  data  are  available  as  in  the  case  cf 
blood,  for  the  probable  reason  that  the  work  has  been  carried  out  less 
systematically.  In  the  table  below  are  given  figures  for  the  average  normal 
content  of  the  various  constituents  in  the  spinal  fluid,  the  data  being  taken 
from  various  sources.  From  the  figures  given  it  is  apparent  that  the 
ipinal  fluid  may  be  considered  as  a  dialysate  or  ultrafiltrate  of  the  blood 
plasma.  It  contains  very  little  protein  so  long  as  the  fluid  remains  normal, 
but  nearly  as  much  urea  and  glucose,  and  rather  more  salt  than  the  blood. 

In  pathological  cases  the  properties  may  change,  particularly  in 
meningitis.  The  fluid  may  bo  greatly  increased  in  amount,  under  high 
pressure,  and  have  a  considerable  increase  in  protein. 

Denis  and  Ayer  have  presented  recently  some  quantitative  figures  on 
the  protein  content  of  spinal  fluid.  Normally  they  found  the  fluid  to 
contain  from  0.04  to  0.1  per  cent  of  protein.  In  active  tabes,  moderately 
active  syphilis  of  the  nervous  system  and  lethargic  encephalitis  the  protein 
content  ranged  from  0.1  to  0.2  per  cent,  in  recent  cerebral  vascular 
disturbances  such  as  hemiplegias  and  cei'ebral  embolus  from  0.1  to  0.3  per 
cent,  in  acute  syphilis  of  the  ncrvons  system  and  general  paresis  from  0.2 
to  O.G  j>er  cent,  while  in  tubercular  and  acute  meningitis  such  high  figures 
as  0,2  to  1.0  and  0.4  to  1.3  per  cent  respectively  were  observed.    By  taking 


472 


VICTOR  C.  MYERS 


Composition  of  Normal  Spinal  Fluid 


Determination,  Recorded  in 


Total  solids,  per  cent    

Ash,  per  cent 

Trotein,  per  cent    

Nonprotein  nitrogen,  mg.  to  100  c.c.    . . 

Urea  nitrogen,  mg.  to  100  c.c 

Crcatinin,  mg.  to  100  c.c 

Uric  Acid,  mg.  to  100  c.c 

Sugar,  per  cent    

C(  )j  combining  power,  volumes  per  cent 

Chlorids  as  NaCl,  per  cent    

Phosphates  as  P,  mg.  to  100  c.c 

Sulphates  as  S,  mg.  to  100  c.c 

Sodium  as  Na,  mg.  to  100  c.c 

Potassium  as  K,  mg.  to  100  c.c 

Calcium  as  Ca,  mg.  to  100  c.c 

Magnesium  as  Mg,  mg.  to  100  c.c 

pH  (when  first  drawn)    

pll    (on  standing) 


Range 


0.8  -  1.6 

0.04-  0.1 
17.0  -26.0 

7.0  -14.0 

0.7  -  1.5 
trace 

0.07-  0.1 
08.0  -63.0 

0.60-  0.75 


14.0  -28.0 


Average 


1.0 

0.88 

0.7 

21.0 

10.0 
1.0 
0.1 
0.08 

60.0 
0.7 
2.5 

trace 
320.0 

20.0 
7.0 
3.0 
7.4 
8.3 


advantage  of  the  changed  reaction  of  the  fluid  in  the  last  mentioned 
conditions  and  the  rate  of  change  of  alkalinity  on  standing,  Tashiro  and 
Levinson  have  devised  a  very  valuable  method  of  differentiating  tubercular 
from  epidemic  meningitis.  If  to  1  c.c.  of  spinal  fluid  there  is  added  1  c.c. 
of  3  per  cent  sulphosalicylic  acid,  and  to  another  1  c.c.  of  fluid  a  like 
amount  of  1  per  cent  mercuric  chlorid,  then  in  tubercular  meningitis  the 
protein  which  settles  down  on  standing  24  hrs.  is  more  voluminous  in 
the  mercury  tube,  whereas  in  epidemic  meningitis  it  is  more  voluminous 
in  the  sulphosalicylic  acid  tube. 

The  nonprotein  nitrogen  of  spinal  fluid  averages  only  about  70  per 
cent  of  the  figures  obtained  in  blood,  but  this  statement  does  not  apply  to 
its  chief  component,  urea.  It  is  now  well  known  that  the  various  mem- 
branes of  the  body  are  very  permeable  to  urea,  resulting  in  an  even 
distribution  of  this  waste  product  throughout  the  tissues  of  the  body,  as 
shown  by  Marshall  and  Davis.  Cullen  and  Ellis  have  strikingly  pointed 
this  out  in  the  case  of  spinal  fluid.  Myers  and  Fine(n)  likewise  have  found 
this  to  be  true  in  nephritis  with  marked  nitrogen  retention.  In  their 
series  of  fifteen  cases  the  spinal  fluid  urea  averaged  88  per  cent  of  that 
of  the  blood.  The  concentration  of  creatinin  averaged  46  per  cent  of 
that  found  in  the  blood  in  the  same  series,  indicating  that  it  did  not 
diffuse  as  readily  as  the  urea.  In  one  case  with  the  high  blood  crcatinin 
of  14.5  mg.,  the  spinal  fluid  content  was  4.8,  while  in  a  similar  case  the 
figures  were  11.0  and  4.2  mg.  respectively.  Uric  acid  does  not  readily 
pass  into  the  spinal  fluid,  if  one  is  to  judge  from  observations  on  the  same 
cases,  since  the  amount  present  averaged  only  about  5  per  cent  of  that 
found  in  the  blood.  In  a  few  exceptional  cases  the  figures  for  the  spina] 
fluid  reached  only  about  1  mg.,  and  this  despite  the  fact  that  the  blood 
content  was  about  10  mg. 


BODY  TISSUES  AND  FLUIDS         C  473 

The  sugar  normally  amounts  to  0.07  to  0.09  per  cent,  in  comparison 
with  figures  of  0.09  to  0.11  per  cent  for  the  blood.  Sugar  appears  to  be 
fairly  readily  admitted  to  the  spinal  fluid,  since  in  diabetes  comparatively 
high  figures  may  be  found.  ]\[yers  and  Fine(n)  obsei*ved  a  sugar  content  of 
0.30  per  cent  in  a  case  of  diabetes  showing  a  blood  sugar  of  0.44  per 
cent.  In  meningitis  the  sugar  content  may  bo  either  very  low  or  entirely 
absent,  negative  findings  more  often  being  observed  in  epidemic  and 
pneumococcus  meningitis  than  in  tubercular  meningitis..  The  estimation 
of  the  sugar  in  meningitis  may  therefore  be  of  considerable  practical 
value. 

The  CO2  combining  power  of  spinal  fluid  averages  60  volumes  per 
cent,  which  is  slightly  lower  than  that  of  normal  blood  plasma.  It  like- 
wise seems  to  vary  within  narrower  limits. 

Of  the  mineral  constituents  of  the  spinal  fluid  the  chlorids  are  by 
far  the  most  significant  in  point  of  quantity.  Calculated  as  NaCl  the 
chlorids  normally  appear  to  average  0.7  per  cent,  more  than  half  of  the 
total  solid  content.  The  content  is  considerably  greater  than  that  of  the 
blood  plasma.  It  is  ordinarily  stated  to  be  hypertonic  to  lymph,  but 
theoretically  it  would  seem  more  likely  that  the  high  content  of  salt  was 
required  to  render  this  fluid  isotonic  with  the  blood.  The  ehlorid  content 
of  the  spinal  fluid  is  apparently  increased  in  those  conditions  in  which 
an  increase  is  found  in  the  blood. 

The  phosphates  of  the  spinal  fluid,  which  normally  amount  to  about 
2.5  mg.  per  100  c.c,  calculated  as  P,  are  increased  (8-10  mg.)  in  certain 
mental  disorders,  notably  paresis.  In  view  of  the  importance  afttached 
at  the  present  time  to  the  increase  in  the  inorganic  phosphates  of  the 
blood  in  nephritis  with  acidosis,  it  may  be  of  interest  to  note  that  Myers 
in  1909  observed  a  P  content  of  19  mg.  in  the  spinal  fluid  of  a  patient 
dying  from  "arteriosclerosis."  In  view  of  the  close  relation  of  both 
phosphoric  acid  and  cholin  in  lecithin,  note  may  be  made  regarding 
cholin  at  this  time.  The  presence  of  cholin  in  the  spinal  fluid  of  paretic 
patients  was  first  claimed  by  Mott  and  Halliburton,  and  confirmed  by  a 
numher  of  workers  in  this  and  other  conditions  involving  nerve  de- 
generation.   Later,  however,  the  presence  of  cholin  was  disputed. 

The  metallic  elements,  sodium,  potassium,  calcium  and  magnesium, 
with  the  exception  of  the  first  named,  apparently  exist  in  the  spinal  fluid 
in  practically  the  same  concentration  as  in  the  blood.  Sodium  appears 
to  be  present  in  somewhat  larger  amounts  as.  the  high  chlorin  content 
of  the  fluid  would  indicate.  Some  years  ago  Hosenheim  reported  that 
potassium  was  present  in  relatively  large  amounts  in  cases  of  acute 
degenerative  insanity  where  cholin  was  present.  In  reinvestigating  this 
question  Myers  (h)  found  that  the  potassium  content  of  the  fluid  in  demen- 
tia paralytica  and  several  other  conditions  during  life  averaged  20  mg.  per 
100  c.c,  but  that  after  death  the  figures  amounted  to  slightly  more  than 


474  VICTOE  C.  MYERS 

80  mg.,  indicating  that  the  high  figures  for  potassium  were  due  to  post- 
mortem causes  and  possessed  no  pathological  significance.  This  post- 
mortem increase  is  quite  striking,  however,  since  as  high  figures  are 
found  one-half  hour  post  mortem  as  at  any  other  time.  This  very  rapid 
post-mortem  rise  in  the  potassium  is  significant.  The  findings  for  calcium 
and  magnesium  differ  little  from  those  obtained  in  blood.  Levinson(6)  has 
found  that  the  pH  determined  immediately  on  withdrawing  the  fluid 
varied  between  7.4  and  7.6.  It  was  normal  in  all  pathological  conditions 
observed,  except  epidemic  meningitis,  where  figures  of  7.3  to  7.4  were 
generally  observed. 

Saliva 

Mixed  human  saliva  is  composed  of  the  secretion  of  three  pairs  of 
glands,  the  submaxillary,  sublingual  and  parotid,  supplemented  by  the 
secretion  of  numerous  small  glands  called  buccal  glands.  The  saliva 
secreted  by  the  different  pairs  of  glands  possesses  different  characteristics, 
the  secretion  of  the  parotid  being  thin  and  watery,  while  that  of  the 
sublingual  and  submaxillary,  particularly  the  former,  is  thick  and  viscid, 
owing  to  the  large  amount  of  mucin  present.  The  amount  of  saliva 
secreted  by  an  adult  in  twenty-four  hours  has  been  variously  estimated 
as  between  1000  and  1500  c.c,  the  exact  amount  depending,  among  other 
conditions,  upon  the  character  of  the  diet.  The  specific  gravity  varies 
between  1.002  and  1.008,  with  an  average  of  1.005. 

According  to  Frerichs  mixed  saliva  has  the  following  composition : 

Composition  of  Human  Saliva 


Constituents 

In  Per  Cent 

Water                            

99.41 

Solids • 

0.59 

Mucin  and  epithelium 

0.213 

Soluble  organic  matter       

0.142 

Inorsjanic   salts    

0.219 

Potassium  thiocyanate   

0  to  0.010 

IN^ormally  saliva  is  alkaline  to  litmus  and  acid  to  phenolphthalein,  the 
reaction  being  practically  the  same  as  that  of  the  blood.  The  chief  con- 
stituents of  the  ash  are  potassium,  phosphate  and  chlorids,  which  together 
constitute  about  80  per  cent  of  the  mineral  content. 

The  important  organic  constituents  of  the  saliva  aro  the  mucin  (a 
glycoprotein)  and  the  salivary  amylase,  ptyalin,  the  former  aiding  in 
swallowing  and  the  latter  in  the  digestion  of  starch.  At  one  time  it 
was  argued  that  ptyalin  could  be  of  little  value  in  starch  digestion  since 
it  was  probably  destroyed  by  the  hydrochloric  acid  of  the  gastric  juice  as 
soon  as  it  reached  the  stomach.     It  has  been  shown  by  Cannon,  however, 


BODY  TISSUES  AjND  FLUIDS    ,  475 

that  salivary  digestion  may  proceed  for  a  considerable  period  after  the 
food  reaches  the  stomach,  owing  to  the  slowness  with  which  the  food 
contents  are  mixed  with  the  acid  gastric  juice.  Ptyalin  acts  best  in  a 
neutral  or  faintly  acid  medium,  (combined  acid)^  but  is  readily  destroyed 
by  a  trace  of  free  hydrochloric  acid.  It  acts  more  efiiciently  when  some- 
what diluted. 

It  has  been  shown  by  Chittenden  and  Smith  that  the  diastatic  action 
of  human  saliva  can  be  taken  as  a  definite  measure  of  the  amount  of 
ferment  present,  only  when  the  saliva  in  the  digestion  mixture  is  diluted 
at  least  50  or  100  times.  They  have  found  that  the  limit  of  dilution  at 
which  decisive  diastat'c  action  manifests  itself  with  foiination  of  reduc- 
ing bodies  is  1  to  2000  or  3000.  Myers  and  Dellenbaugh,  working  with  a 
very  delicate  method,  have  recently  ol>served  that  when  0.01  c.c.  of  normal 
human  saliva  is  allowed  to  act  on  10  mg.  of  soluble  starch  in  a  volume  of 
2  c.c.  for  30  minutes  at  40"^  C,  30  to  45  per  cent  of  the  starch  is  con- 
verted to  sugar  when  the  diluent  is  water  and  46  to  60  per  cent  when 
the  diluent  of  the  saliva  is  0.3  per  cent  sodium  chlorid.  The  CI  ion  has 
long  been  recognized  to  have  a  pronounced  facilitating  action.  Essentially 
the  same  range  of  figures  were  found  in  such  pathological  conditions  as 
diabetes,  nephritis  and  gastric  ulcer.  A  few  individuals  were  encoun- 
tered, however,  who  for  periods  showed  low  activities,  figures  10  to  20, 
that  were  not  readily  explained,  although  it  may  be  noted  that  they 
complained  of  gastric  distress.  Representatives  of  different  nationalities 
were  found  to  vary  within  the  same  normal  limits,  which  opposes  the 
view  advocated  by  some  of  the  adaptation  of.  salivary  secretion  to  diet. 
As  show^n  by  Chittenden  and  Richards,  saliva  secreted  after  a  period  of 
glandular  activity,  as  before  breakfast,  manifests  greater  amylolytic  power 
than  the  secretion  obtained  after  eating.  Corresponding  with  this  in- 
crease in  amylolytic  powder  occurs  an  increase  in  the  proportion  of  alkaline- 
reacting  salts,  but  the  increased  amylolysis  is  due  primarily  to  an  increase 
in  the  amount  of  active  enzyme  contained  in  the  saliva. 

Marshall  has  suggested  that  the  ratio  between  the  mathematical  ex- 
pressions for  the  total  neutralizing  power  of  normal  resting  saliva  and 
normal  activated  saliva  from,  a  given  individual  is  a  "salivary  factor" 
the  magnitude  of  which  appears  to  be  indicative  of  immunity  from  caries 
or  the  reverse.    Shepard  and  Gies  were  unable  to  substantiate  this  claim. 

The  thiocyanate  content  of  human  saliva  has  been  the  topic  of  a 
number  of  studies.  The  saliva  of  smokers  has  been  shown  to  have  a  much 
higher  content  of  potassium  thiocyanate  than  (hat  of  nonsmokers.  Schnei- 
der found  that  the  average  content  for  six  smokers  was  0.013  per  cent, 
while  for  ten  nQnsmokei*s  it  was  0.003  per  cent.  Sullivan  and  Dawson 
have  studied  the  thiocyanate  content  of  the  saliva  in  pellagra.  With 
active  symptoms  the  thiocyanate  content  is  lower  than  later  when  the 
characteristic  symptoms  have  disappeared.     The  thiocyanate  content  of 


476 


VICTOR  C.  MYERS 


eighteen  patients  on  admission  averaged  0.0035  per  cent^  while  on  dis- 
charge it  was  0.0047  per  cent. 

Milk 

Milk  is  a  product  of  the  secretory  activity  of  the  mammary  gland. 
It  is  the  most  satisfactory  food  material  elaborated  by  nature.  As  a  food 
it  is  deficient  in  only  one  respect,  viz.,  its  iron  content.  This  is  without 
significance  when  milk  is  used  as  a  food  for  infants,  since  a  considerable 
quantity  of  iron  is  stored  up  in  the  liver  during  fetal  life.  Milk  contains 
the  proteins,  casein  and  lactalbumin,  such  fats  as  olein,  palmitin,  stearin 
and  butyrin,  the  disaccharid,  lactose,  together  with  phosphates  of  calcium, 
potassium  and  magnesium,  citrates  of  sodium  and  potassium,  and  chlorid 
of  calcium.  In  addition  it  is  evident  from  recent  observations  that  milk 
is  well  supplied  with  the  water  soluble  and  fat  soluble  vitamins,  to- 
gether with  a  sufficient  quantity  of  the  antiscorbutic  element. 

The  physical  appearance  of  milk  suggests  that  the  various  constituents 
are  not  all  in  solution.  Fat  is  present  in  a  finely  divided  suspension, 
while  casein  is  either  in  suspension  or  in  a  colloidal  solution.  Van  Slyke 
and  Bos  worth  have  been  able  to  separate  the  insoluble  portion  of  milk 
by  filtration  through  a  Pasteur-Chamberland  filter.  With  the  aid  of  this 
method  they  have  been  able  to  divide  the  constituents  of  milk  into  three 
groups  as  shown  by  the  table  below: 

Milk  Constituents 


In  True  Solution 
in  Milk  Serum 

Partly  in  Solution  .and 

Partly  in  Suspension  or 

Colloidal  Solution 

Entirely  in  Suspension 
or  Colloidal  Solution 

Lactose 
Citric  acid 
Potassium 
Sodium 
Chlorid 

Lactalbumin 
Inorganic  phosphates 
Calcium 
Magnesium 

Fat 
Casein 

Perfectly  fresh  milk,  both  human  and  cow's,  is  amphoteric  in  reac- 
tion toward  litmus  and  acid  to  phenolphthaleiu.  The  acidity  to  phenol- 
phthalein  is  due  in  considerable  part  to  acid  phosphates,  although  acid 
caseinates  may  be  responsible  for  some  of  the  acidity.  The  specific  gravity 
of  milk  most  often  varies  between  1.028  and  1.032.  Milk  has  a  very 
slight  yellow  color,  which  is  more  noticeable  in  the  cream  on  standing. 
The  yellow  pigments  of  butter  fat  are  the  vegetable  pigments  carotin  and 
xanthophylls.  They  are  present  in  the  colostrum  in  mjich  higher  con- 
centration than  in  mature  milk. 

The  milk  of  different  species  of  animals  differs  very  materially,  the 
animals  with  a  rapid  rate  of  growth  secreting  a  milk  with  a  mucli  higher 


BODY  TISSUES  AND  FLUIDS 


477 


content  of  protein  and  salts  and  a  somewhat  lower  lactose  content.  The 
following  table,  compiled  largely  from  analyses  made  in  Bunge's  labora- 
.  tory,  nicely  illustrates  this  point : 


Rate  of  Growth  and  Composition  of  Milk 

Number  of  Days 

Required  to 

Double  Weight 

at  Birth 

Percentage  Composition  of  Milk 

Species 

Protein 

Ash 

• 

Lactose 

Humarii         

180 
60 
47 
22 
15 
14 
9 
6 

1.6 
2.0 
3.5 
3.7 
4.9 
5.2 
7.4 
10.4 

0.2 
0.4 
0.7 
0.8 
0.8 
0.8 
1.3 
2.5 

7.0 

6.7 

Cow 

4.9 

Goat   

4.4 

Sheep    

4.0 

Swine       • 

4.0 

Dog 

3.2 

Rabbit      

Holt,  Courtney  and  Fales  have  recently  made  a  quite  elaborate  study 
of  the  composition  of  human  milk.  A  summary  of  some  of  their  results  is 
given  in  the  table  below.    As  will  be  noted  in  the  colostruni  period  human 


PFRrENTAOE  COMPOSITION  OF  HUMAN  MiLK 

BY  Periods 

Period 

en 

'I- 

1 

1 

a 

1 

.S 

a 
< 

1 

il 

Colostrum  ( 1-12  days)    

5 

6 

17 

-10 

2.83 
4.37 
3.26 
3.16 

7.59 
7.74 
7.50 
7.47 

2.25 
1.56 
1.15 
1.07 

0.31 
0.24 
0.21 
0.20 

13.4 

Transition  ( 12-30  days ) 

Mature  (1-9  mos. ) 

0.43' 

0.32 

0.72* 
0.75 

13.4 
12.2 

Late  ( 10-20 mos.) 

12.2 

milk  has  a  high  protein  and  high  ash  with  rather  low  fat,  in  the  transition 
period  the  protein  and  ash  are  lower  while  the  fat  is  higher,  but  after 
one  month  the  composition  of  normal  milk  does  not  vary  in  any  essential 
or  constant  way  quite  up  to  the  end  of  lactation.  The  only  striking 
feature  of  late  milk  is  a  decline  in  quantity,  though  there  is  noted  a 
slight  fall  in  all  the  solid  constituents  except  the  sugar.  Of  the  different 
constituents  of  milk,  the  least  variation  in  both  individuals  and  periods  is 
seen  in  the  sugar.  It  will  be  obsei^^ed  in  the  table  that  the  sugar  amounts 
to  about  7.5  per  cent,  which  is  higher  by  a  half  per  cent  than  the  generally 
accepted  figure  of  7  per  cent.  The  greatest  individual  variations  are 
observed  in  the  fat  (figures  from  1  to  6  per  cent),  although  as  recorded 
above,  the  period  variations  in  the  fat  are  not  marked.  The  protein  is 
highest  in  the  colostrum  period  aiid  falls  to  a  little  over  half  the  propor- 
tion in  mature  milk,  during  which  ])eriod  it  is  seldom  over  1.25  per  cent; 
of  this  about  one-third  is  casein  and  two-thirds  lact albumin. 
3     Meigs  and  Marsh  give  the  following  table  as  representative  of  the 


478 


VICTOR  C.  MYERS 


limits  of  noi-mal  variation  in  the  constituents  of  human  and  cow's  milk 
from  the  beginning  of  the  second  month  of  lactation  onv/ard,  the  figures 
representing  percentages  of  wliole  milk: 


Fat 

Lactose 

Protein 

Iluiiian  mitk 

2-4 
2-4 

6-7.5 
3.5-5.0 

0  7-1  5 

Cow's  milk 

2.5-4  0 

It  is  apparent  that  human  milk  contains  less  protein  but  more  sugar  than 
cow^s  milk.  The  protein  of  human  milk  differs  from  that  of  cow's  milk 
in  one  very  important  respect,  quite  aside  from  the  total  quantity  of 
protein.  It  contains  much  less  casein  but  rather  more  lactalbumin.  Ac- 
cording to  Meigs  and  Marsh,  both  human  and  cow's  milk  contain  im- 
portant non-nitrogenous  substances  of  an  tinknowai  character.  Early 
human  milk  contains  about  1  per  cent  of  these  unknown  substances ;  milk 
from  the  middle  period  of  lactation  about  0.5  per  cent..  Cow's  milk  from 
the  middle  period  of  lactation  contains  about  0.3  per  cent  of  the  unknown 
substance. 

Denis,  Talbot  and  jMinot  have  studied  the  nonprotein  nitrogenous 
constituents  of  human  milk.  Thev  summarize  the  results  of  the  examina- 
rion  of  71  samples  as  follows : 


Nonprotein  Nitrogenous  Constituents 

mg.  to  100  c.c. 

Minimum 

Maximum 

Total  nonprotein  nitrogen    

20.0 
8.3 
3.0 
1.0 
1.9 
1.7 

37.0 

Urea  nitrogen     

16.0 

8.9 

Preformed  creatinin „ 

1.6 

Creatin    

3.9 

Uric  acid             .                        

4.4 

In  some  of  the  cases  the  nonprotein  and  urea  nitrogen  were  also  deter- 
mined in  the  blood  and  practically  the  same  figures  obtained  as  in  the  milk. 

In  a  series  of  about  forty  cases  Denis  and  ^linot(c)  found  the  choles- 
terol content  of  human  milk  to  vary  from  10  to  30  mg.  per  100  c.c.j  figiires 
of  10  to  20  mg.  being  obtained  chiefly  in  milk  with  a  low  fat  content  and 
figures  of  20  to  30  mg.  with  a  high  fat  content.  According  to  Bosworth 
r*nd  Van  Slyke,  cow's  milk  contains  0.052  per  cent  of  potassium  citrate 
and  0.222  per  cent  of  the  sodium  salt,  w^hile  in  human  milk  the  j^otassinm 
salt,  0.103  per  cent,  is  in  excess  of  the  sodium  salt,  0.055  per  cent.  Sommer 
and  Hart  have  shown  that  the  citric  acid  of  cow's  milk  (0.2  j>er  cent) 
is  not  destroyed  or  changed  on  heating. 

The  mineral  content  of  milk  is  of  great  interest  and  importance. 
Holt,  Courtney  and  rales(6)  have  given  the  average  composition  of  the 


BODY  TISSUES  AXD  FLUIDS 


479 


ash  of  human  milk  for  different  periods  and  also  for  cow's  milk,  their 
figures  being  given  in  the  table  below.    As  will  be  noted  the  high  ash  of 


Average  Percentage  Composition  of  the 

Ash  of  Human  and  Cow's 

Milk 

CaO 

MgO 

PaO, 

Xa,0 

K,0 

CI 

'  Colostrum    

TT Transition    

Human  J  ^^j^^^^^   

14.2 
17.0 
23.3 
19.8 
23.5 

3.5 
2.4 
3.7 
3.6 
2.8 

12.5 
16.0 
16.6 
15.5 
26.5 

13.7 
10.9 

7.2, 
10.1 

7.2 

28.1 
30.8 
28.3 
28.8 
24.9 

20.6 
22.9 
16.0 

Late 

22.3 

Cow's  milk 

13.6 

the  colostrum  period  is  due  chiefly  to  the  amount  of  !N*a20  and  KgO.  Of 
the  salts  which  make  up  the  ash,  the  greatest  individual,  as  well  as  the 
greatest  period,  variations  are  seen  in  the  !N^a20.  The  largest  constituent 
of  the  ash  of  human  milk  is  KgO,  this  with  the  CaO  together  making  up 
more  than  half  the  total  ash.  Although  in  amount  the  total  ash  of  cow's 
milk  is  about  three  and  one-half  times  as  great  as  that  of  human  milk, 
the  proportion  of  different  salts  which  make  up  the  ash  is  nearly  the 
same,  the  only  exception  being  that  cow's  milk  has  more  ^2^6   ^^^ 


less  iron. 


imy^ 


SECTION  IV 


Excretions  ..........  c Victor  C.  Myers 

Urine — Physical   Properties — Organic  Constituents — Inorganic   Constituents 
— Feces — Sweat. 


Excretions 

VICTOR  C.  MYERS 

NEW   YOBK 


There  are  four  mediums  for  the  excretion  of  waste  products  from 
the  body,  viz.,  urine,  feces,  perspiration  and  expired  air.  Under  normal 
conditions  and  on  a  readily  digestible  diet,  nearly  100  per  cent  of  the 
carbohydrate,  about  95  per  cent  of  the  fat  and  more  than  90  per  cent 
of  the  protein — if  no  correction  is  made  for  the  "metabolic  nitrogen"  of 
the  feces — are  completely  digested  and  absorbed.  The  carbohydrate  and 
fat  absorbed  are  almost  entirely  converted  to  carbon  dioxid  and  water, 
and  this  is  also  true  of  the  carbon  moiety  (about  80  per  cent)  of  the 
protein.  The  carbon  dioxid  thus  fonned  is  excreted  by  way  of  the 
lungs,  as  is  a  large  amount  of  the  water  in  the  fonn  of  water  vapor. 
Considerable  water  may  be  lost  from  the  body  by  way  of  the  perspiration 
but  the  amount  of  solids  excreted  in  this  way  is  never  large,  although  with 
severe  exercise  and  sweating  from  0.3  to  0.5  gram  of  nitrogen  and  0.5  to 
1.5  grams  of  sodium  chlorid  may  be  eliminated.  The  chief  paths  for 
the  excretion  of  solids  are  the  kidney  and  intestine,  the  daily  elimination 
by  these  two  channels  in  the  adult  amounting  to  about  50  gi'ams  in  the 
urine  and  30  grams  in  the  feces.  The  nitrogenous  waste  products  find 
their  principal  exit  through  the  kidneys,  but  in  the  case  of  the  mineral 
elements  the  kidneys  and  intestines  both  take  part,  the  salts  of  sodium 
and  potassium  being  largely  eliminated  in  the  urine,  while  the  salts  of 
calcium,  magnesium  and  iron  are  excreted  in  the  feces.  Although  the 
excretion  of  the  latter  compounds  in  the  feces  may  be  due  in  part  to  lack 
of  absorption,  still  there  is  likewise  a  definite  selective  action  regarding 
their  excretion.  An  excellent  illustration  of  how  changes  in  compounds 
may  affect  their  mode  of  excretion  is  the  elimination  of  the  two  phenol- 
phthalein  derivatives,  phenolsulpbonephthalein  and  tetrachlorphthalein. 
The  former  is  eliminated  entirely  by  the  kidneys,  while  the  latter  after 
being  secreted  in  the  bile  by  the  liver  is  excreted  by  way  of  the  intestines. 

Urine 

Since  the  end  products  of  the  metabolism  of  nitrogenous  and  mineral 
substances  find  their  principal  exit  through  the  kidneys,  a  study  of  the 

481 


482  VICTOR  C.  MYERS 

secretion  of  these  glands  under  various  conditions  may  be  expected  to 
throw  light  upon  the  processes  involved  in  the  metabolism  of  the  above 
substances.  With  a  knowledge  of  the  principal  constituents  of  the  urine 
and  a  partial  understanding,  at  least,  of  their  history  in  the  body,  the 
appearance  of  any  unusual  substance  or  the  presence  of  a  nonually 
occurring  constituent  in  an  amount  inconsistent  with  the  attending  con- 
ditions may  bring  to  light  derangements  of  body  functions. 

The  mechanism  of  kidney  secretion  has  been  a  much  controverted 
question.  The  view  (modified  Heidenhain)  which  has  been  most  gen- 
erally held  for  some  years  past  is  that  the  renal  cells  actively  participate 
in  the  secretion,  the  water  and  inorganic  salts  being  eliminated  in  the 
capsular  r^ion,  while  the  urea,  creatinin,  uric  acid,  etc.,  find  their  exit 
through  the  uriniferous  tubules.  Quite  recently  our  conception  of  urine 
secretion  has  undergone  material  change  partly  as  a  result  of  advances 
in  our  knowledge  of  physical  chemistry  and  partly  from  added  anatomical 
data.  From  a  study  of  the  blood  vessel  structure  of  the  glomerulus,  it  is 
apparent  that  the  blood  pressure  in  the  glomerular  capillaries  must  be 
high,  much  higher  than  that  of  the  fluid  in  the  capsule.  According  to 
the  "modern  theory''  (Cushny  (&)),  the  secretion  of  urine  consists  of  two 
distinct  processes  differing  not  only  in  site  but  also  in  nature.  The  first 
of  these,  the  filtration,  occurs  in  the  glomerulus,  and  is  purely  physical; 
the  second,  the  reabsorption,  occurs  in  the  tubules,  and  depends  upon  the 
vital  activity  of  the  epithelium.  By  the  first  process  the  protein  colloids 
of  the  blood  plasma  are  filtered  off.  By  the  second  process  water  and  so- 
called  threshold  bodies  such  as  chlorids  and  sugar  are  largely  reabsorbed, 
while  no-threshold  substances,  such  as  urea,  are  rejected  and  can  only 
escape  by  the  ureter. 

That  the  cells  of  the  tubules  actively  participate  in  the  secretion  of 
urea,  however,  seems  apparent  from  recent  experiments  of  Oliver.  With 
the  aid  of  xanthydrol  he  has  shown  that  urea  is  present  in  the  cells  of 
the  proximal  convoluted  tubules  in  a  concentration  higher  than  that  of 
the  blood  or  that  of  the  cells  of  any  of  the  other  kidney  tubules,  which 
condition  can  only  be  reconciled  to  an  assumption  of  an  active  secretion 
(excretion)  on  the  part  of  these  ceils. 

Physical  Properties. — Volume. — The  volume  of  urine  eliminated  de- 
pends in  great  part  upon  the  volume  of  fluid  ingested.  Under  normal  con- 
ditions 1000  c.c.  may  be  taken  as  the  average  volume  o:^  nrine  excreted  in 
24  hrs.  This,  however,  is  subject  to  gi-eat  variations  imder  both  normal 
and  pathological  conditions. 

The  volume  of  urine  is  diminished  by  conditions  which  cause  an 
increased  elimination  of  water  through  other  channels,  for  example 
through  the  alimentary  tract  during  diarrhea  and  vomiting,  or  through 
the  skin  as  perspiration.  On  the  other  hand  during  cold  weather,  when 
cutaneous  evaporation  is  reduced,  the  volume  of  urine  is  increased.    Thus 


ExcEETIo:^^s  :•       483 

in  warm  weather  the  volume  may  be  as  low  as  350  e.c,  while  a  volume  of 
1500  to  1800  e.c.  may  be  encountered  during  cold  weather. 

The  condition  of  the  cardiovascular  system  and  kidneys  has  much  to 
do  with  the  volume  of  urine  eliminated.  In  interstitial  nephritis,  the 
volume  of  urine  is  usually  large,  frequently  2000  e.c.  or  over.  Of  par- 
ticular interest  is  the  observ^ation  that  in  this  condition  an  abnormally 
large  volume  of  dilute  urine  is  eliminated  during  the  hours  from  8  P.M.  to 
8  A.M.  This  night  polyuria  commonly  results  in  an  elimination  con- 
siderably in  excess  of  400  e.c,  the  usual  output  during  these  hours.  In 
parenchymatous  nephritis,  the  relations  are  not  so  constant,  but  in  general 
the  urine  is  concentrated  and  the  volume  reduced.  The  variations  in 
volume  in  such  cases  are  usually  referable  to  the  formation  or  disap-. 
pearance  of  edema.  A  very  large  volume  of  dilute  urine  (5000  c.c.  or 
more)  may  be  eliminated  in  diabetes  insipidus,  due  probably  to  dilatation 
of  the  renal  vessels.  The  volume  is  increased  when  it  is  necessary  to 
eliminate  a  large  amount  of  material,  as  is  the  case  with  sugar  in  diabetes 
mellitus.  A  temporarily  increased  output  of  urine  may  result  through 
nervous  influences. 

Color. — The  color  of  urine  may  vary  under  normal  conditions  from  a 
very  pale  yellow  to  a  reddish  yellow  or  deep  amber,  depending  upon  its 
density.  The  color  is  due  principally  to  a  pigment  called  iirochrome, 
although  small  amounts  of  urobilin,  and  occasionally  traces  of  iiroerythrin 
may  be  present.  Pathologically  the  cojor  may  vary  from  a  perfectly 
colorless  fluid  to  dark  brown  or  black.  A  red  color  may  be  due  to  blood, 
occasionally  to  hematoporphyrin ;  very  dark  colored  urines  may  arise 
from  taking  carbolic  acid ;  the  excretion  of  melanin  fi-om  pigmented 
tumors  may  likewise  be  the  cause  of  a  dark  color,  especially  after  being 
exposed  to  the  air  for  some  time  or  on  the  addition  of  an  oxidizing  agent. 
A  green  or  brownish  yellow  color  maj^  be  due  to  bile,  also  recognized  by 
the  yellow  tinged  foam.  In  alkaptonuria  the  unne  may  become  dark 
owing  to  the  presence  of  homogentisic  acid.  This  is  especially  so  if  the 
urine  is  allowed  to  become  alkaline. 

Specific  Gravity. — The  specific  giMvity  of  normal  urine  most  commonly  • 
falls  between  1,015  and  1.025.  It  may,  however,  be  as  low  as  1.008  or  as 
high  as  1.040  without  necessarily  indicating  pathological  conditions.  Nor- 
mally the  specific  gravity  is  inversely  proportional  to  the  volume.  In 
diabetes  mellitus  one  may  obsen'c  both  a  large  volume  and  a  high  specific 
gravity  owing  to  the  presence  of  sugar.  In  interstitial  nephritis  the 
specific  gravity  is  persistently  low  and  fixed  regardless  of  variations  in 
volume. 

Odor. — Normal  urine  has  a  faint  but  characteristic  aromatic  odor.  As 
urine  undergoes  alkaline  fermentation,  a  di.sagi*eeable  ammoniacal  odor 
develops. 

Reaction  and  Aciditjj. — The  principal  factor  involved  in  the  regula- 


484  VICTOR  C.  MYERS 

tion  of  urinary  acidity  is  the  proportion  between  the  acid  sodium 
phosphate  (H2XaP04)  and  the  basic  sodium  phosphate  (HNa2P04),  the 
former  raising  the  acidity  and  the  latter  lowering  it.  The  principal  acid 
supply  is  found  in  the  metabolism  of  protein,  during  which  sulphuric  acid 
is  formed  from  the  oxidation  of  the  sulphur  of  the  protein,  while  phos- 
phoric acid  is  set  free.  The  organic  acids,  uric,  hippuric,  oxalic,  and 
certain  of  the  lower  fatty  acids  also  contribute  to  the  acidity.  The  basic 
radicals  concerned  are  sodium,  potassium,  ammonium,  calcium  and  mag- 
nesium. The  excretory  function  of  the  kidney  normally  prevents  any 
undue  accumulation  of  either  acids  or  bases  in  the  body,  thereby  main- 
taining a  remarkable  constancy  in  the  reaction  of  the  body  fluids. 

Urine  is  most  commonly  acid  to  litmus.  The  reaction  and  degree  of 
acidity  may,  however,  experience  marked  change  under  both  physiological 
and  pathological  conditions.  The  diet  is  one  of  the  most  important  factors 
involvied.  In  general,  the  metabolism  of  animal  foods,  except  milk,  results 
in  an  increased  acidity,  while  vegetable  foods,  except  the  cereal  grains, 
tend  to  diminish  the  acidity  or  even  yield  alkaline  urines.  The  reason 
for  this  general  difference  between  animal  and  vegetable  food  materials  is 
due,  as  pointed  out  by  Sherman  and  Gettler,  to  their  excess  of  acid-  or  base- 
forming  elements.  These  considerations  probably  account  for  the  fact 
that  the  urine  of  dogs  is  normally  acid,  while  that  of  rabbits  is  habitually 
alkaline. 

The  pathological  formation  of  acids  (as  in  diabetes)  is  counteracted 
in  a  measure  by  the  neutralizing  action  of  the  bases,  sodium,  potassium, 
calcium  and  magnesium.  When  the  acidity  is  so  great  that  an  adequate 
supply  of  these  elements  can  no  longer  be  economically  furnished  by  the 
body,  ammonia  is  called  upon  to  meet  this  need.  This  accounts  for  the 
increased  elimination  of  ammonia  in  diabetic  ketosis.  The  proximity  to  a 
meal  may  affect  the  reaction  of  the  urine.  For  example,  the  secretion  of 
hydrochloric  acid  in  the  stomach  during  the  process  of  digestion  may  so 
reduce  the  store  of  acids  in  the  body  that  for  a  time  after  a  meal  the 
urine  may  be  neutral  or  even  alkaline,  giving  rise  to  the  so-called  "alka- 
line tide." 

Quantitative  expression  may  be  given  to  the  acidity  of  the  urine  by 
determining  the  number  of  cubic  centimeters  of  tenth  normal  sodium 
hydroxid  required  to  neutralize  the  total  volume  of  urine  eliminated  in 
24  hrs.  This  represents  the  titratable  acidity,  and  may  range  from  200 
to  500,  with  an  average  of  about  350. 

The  titratable  acidity  should  be  distingiiished  from  the  true  acidity, 
the  latter  depending  upon  the  concentration  of  ionized  hydrogen  (H"^). 
From  this  point  of  view,  a  solution  is  acid,  neutral  or  alkalinCj  depending 
upon  the  relative  concentrations  of  hydrogen  ions  (H^)  and  of  hydroxyl 
ions  (Oil").  An  acid  solution  therefore  contains  a  greater  concentration 
of  (H*)  than  of  (OH").     For  convenience  in  recording  the  hydrogen  ion 


EXCRETIOISrS  485 

concentration  a  simplified  logarithmic  notation  is  generally  employed. 

Pure  water,  our  standard  of  neutrality,  contains of  a  exam  of 

'  - '  10,000,000  ^ 

II'  to  a  liter,  and  is  therefore  a  X  solution  of  H.     For  con- 

venience the  logarithmic  notation  is  employed,  thus: 

10,000,000  IT  ==  (10)'  N  =  I''"'-  •S'''««  **"«  ^'^^'^  i«  ^Iws  10,  and 
the  logarithm  always  negative  the  expression  is  further  simplified  by 
dropping  both  the  figure  10  and  the  minus  sign.  The  hydrogen  ion  con- 
centration of  pure  water,  then,  is  expressed  in  terms  of  its  exponent, 
pH  =  7.  Since  the  sum  of  the  logarithmic  expressions  H  and  (OH)  ion 
concentrations  is  alw^ays  14,  it  will  be  readily  seen  that  the  concentration 
of  either  ion  may  be  estimated  when  one  is  known.  In  practice  the 
determination  of  the  hydrogen  ion  has  been  found  simpler. 

formally  the  urine  appears  to  vary  from  an  acid  solution  of 
pll  =  4.82  to  an  alkaline  solution  of  pli  =  7.45,  the  average  being  close 
to  a  solution  of  pH  =  6.0.  By  the  administration  of  sodium  bicarbonate 
and  sodium  citrate  (which  is  oxidized  to  the  carbonate),  Henderson  and 
Palmer(a)  were  able  to  lower  the  pH  to  8.70,  a  condition  of  alkalinity.  As 
pointed  out  by  Blatherwick(ci)  foods  yielding  basic  ashes  may  likewise  re- 
duce the  urinary  acidity  to  that  of  neutrality  (pH  ==  7),  or  even  beyond 
this  to  alkalinity.  Among  30  vegetarians  the  pH  varied  from  5.30  to  7.48, 
averaging  6.64.  Palmer  and  Henderson (6)  have  shown  that  in  cases  with- 
cardiorenal  diseases,  the  acidity  of  the  urine  is  usually  increased.  The 
average  pH  of  57  cases  was  5.33,  representing  a  five-fold  increase  in 
urinary  acidity  over  the  normal  average  of  6.0. 

Transparency. — ^\Vhen  voided  the  urine  of  a  normal  individual  is 
usually  perfectly  clear.  On  standing  a  few  houi*s  a  cloud  or  "nubecula" 
forms,  even  in  nomial  urine.  This  cloud  consists  of  mucus  threads, 
epithelial  cells,  etc.,  from  the  urinary  passages.  Under  pathological  con- 
ditions, the  latter  may  be  greatly  increased  and  accompanied  by  casts  or 
blood.  If  the  acidity  of  the  urine  is  somewhat  diminished  (as  after  a 
meal)  a  turbidity  due  to  phosphates  will  fonn.  This  will  disappear  on 
adding  a  little  acetic  acid.  On  standing  in  the  cold,  urates  may  settle 
out  but  will  again  go  into  solution  on  warming. 


Organic  Constituents 

By  far  the  greater  number  of  organic  compounds  present  in  normal 
urine  contain  nitrogen,  and  those  that  do  not  contain  nitrogen  constitute 
an  extremely  small  part  of  the  total  solids.  Fifty  grams  may  be  given 
as  a  rough  figure  for  the  solid  content  of  urine  and  of  this  amount  about 


486 


VICTOR  C.  MYERS 


60  per  cent  is  ordinarily  organic  and  the  remainder  inorganic.  Since  the 
organic  constituents  of  urine  are  chiefly  nitrogenous  and  since  the  nitro- 
genous waste  products  are  eliminated  principally  in  the  urine,  i.e.,  to  the 
extent  of  85  to  90  per  cent,  a  study  of  their  elimination  in  the  urine 
under  different  conditions  of  diet  should  furnish  considerable  insight 
into  the  controlling  factors  in  protein  metabolism. 

The  most  satisfactory  discussion  of  this  subject  has  been  given  by 
Folin(6)  in  his  now  classic  papers  published  in  1005.  With  the  aid  of 
many  new  methods  which  he  had  developed,  Eolin  found  it  possible  to  make 
fairly  complete  analyses  of  single  24  hr.  specimens  of  urine.  By  a  study  of 
the  comparative  distribution  of  the  nitrogenous  compounds  in  the  urine  on 
two  diets,  one  containing  rather  more  than  100  grams  of  protein  and 
the  other  (starch-cream)  containing  about  1  gram  of  nitrogen,  he  was 
able  to  differentiate  between  the  endogenous  and  exogenous  origin  of  the 
different  waste  products.  As  a  result  of  these  observations  he  evolved  a 
new  theory  of  protein  metabolism,  whicli  quickly  supplanted  the  un- 
tenable theories  of  PflUger  and  Voit. 

The  important  components  of  the  total  nitrogen  of  the  urine  are  the 
nitrogen  of  the  urea,  creatinin,  ammonia  and  uric  acid.  The  following 
data  taken  from  Folin  illustrate  the  distribution  of  these  compounds  (like- 
wise the  various  sulphur  compounds  which  are  also  derived  from  the 
protein)  in  the  urine  of  the  same  individual  on  a  high  and  on  a  low 
protein  diet. 


•  • 

Normal  Protein  Diet 
July  13 

Low  Protein  Diet 
July  20 

Volume  of  urine 

1170  c.c. 

16.80  gm. 

14.70     "    =87..5%  ^ 
0.40     "    =    3.0 
0.18     "    =    1.1 
0..58     "    =    3.6 
0.8.5     ""   =   4.9 
3.64 

3.27     "    =90.0 
0.11)     "    =   .5.2 
0.18     "    =    4.8 

385  c.c. 

Total  nitrogen  

3.60  gm. 

2.20     "   =61.7% 

0.42     "    — 11.3 

Urea  nitroo^en    

Ammonia  nitrogen     

Uric  acid  nitrogen     

0.09     "    =   2.5 

Creatinin  nitrogen    

0.60     "    —17.2 

Undetermined  nitrogen    

Total  SO3    

0.27     "   =   7.3 
0.76 

Inorganic  SO3   

0.46     "    =60.5 

Ethereal  SO3    

0.10     "   =13.2 

N  eutral  SO, 

0.20     "   =26.3 

From  the  above  data  it  is  apparent  that  the  distribution  of  the  nitrogen 
in  the  urine  among  urea  and  the  other  nitrogenous  constituents  depends 
on  the  absolute  amount  of  total  nitrogen  present  (the  distribution  of  the 
fculphur  likewise  being  dependent  upon  the  amount  of  the  total  sulphur). 
As  will  be  noted  urea  is  the  only  nitrogenous  substance  which  suffers  a 
relative  as  well  as  an  absolute  diminution  with  a  decrease  in  the  total 
protein  metabolism.  On  the  other  hand,  as  Folin  was  the  first  to  point 
out,  the  absolute  quantity  of  creatinin  eliminated  in  the  urine  on  a 
meat  free  diet  is  a  constant  quantity,  different  for  different  individuals,* 


EXCEETIONS 


487 


but  wholly  independent  of  quantitative  changes  in  the  total  amount  of 
nitrogen  eliminated.  It  may  be  obseiTed  in  the  case  of  the  uric  acid 
that  when  the  total  amount  of  protein  metabolism  is  greatly  reduced,  the 
absolute  quantity  of  uric  acid  is  diminished,  but  not  nearly  in  proportion 
to  the  diminution  in  the  total  nitrogen,  and  the  per  cent  of  the  uric  acid 
nitrogen  in  tenns  of  the  total  nitrogen  is  therefore  much  increased.  From 
these  observations  Folin  pointed  out  that  urea  and  creatinin  stand  in 
marked  contrast  to  each  other,  since  the  former  is  largely  exogenous  in 
origin,  while  the  latter  is  almost  entirely  of  endogenous  formation.  Uric 
acid  stands  in  an  intermediate  position,  being  about  half  endogenous  and 
half  exogenous  under  ordinary  conditions  of  diet. 

Since  urea  is  largely  exogenous  in  its  origin  the  amount  of  its  excre- 
tion in  the  urine  obviously  depends  upon  the  protein  intake.  With  the 
dietary  standards  of  Voit  and  of  Atwater  calling  for  118  to  125  grams  of 
protein,  the  urea  output  should  be  30  to  35  grams.  Comparatively  few 
healthy  adults  appear  to  eliminate  as  much  urea  as  this  at  the  present 
time.  Probably  25  grams  ma3^  be  taken  as  more  nearly  representing  the 
average  output  of  urea  in  the  human  adult,  although  judging  from  the 
very  extensive  data  given  in  the  Referee  Board  reports,  many  individuals 
average  hardly  more  than  20  grams,  corresponding  to  a  protein  intake 
of  75  to  80  grams.  It  is  obvious,  therefore,  that  the  daily  excretion  of 
10  to  15  grams  of  urea  by  many  hospital  patients  finds  explanation  as  a 
rule,  not  in  defective  kidney  function,  but  in  a  low  protein  intake.  Even 
here  the  urea  excretion  represents  a  protein  consumption  of  40  to  60 
grams,  an  amount  which  Chittenden(&)  has  shown  may  quite  adequately 
supply  the  requirements  of  the  average  individual. 

Assuming  that  the  average  urea  output  of  the  human  adult  is  25 
grams,  the  content  of  the  various  nitrogenous  constituents  with  their  dis- 
tribution in  the  total  nitrogen  may  be  represented  as  given  in  the  table 
below.  With  this  output  of  urea  the  urea  nitrogen  would  probably  con- 
stitute about  85  per  cent  of  the  total  nitrogen,  thus  making  the  figure  for 

Average  Content  of  the  Nitrogenous  Constituents  in  the  Urine  of  the  Human 

Adult 


Constituent 

Weight  of 
Substance 

Nitrogen 
Equivalent 

Relation  of 

Nitrogen  Equivalent 

to  Total  Nitrogen 

Total  nitrogen   

Grams 

25.0 

1.5 
0.5 

Giams 

13.8 

11.7 
0.5 
0.56 
0.17 
0.79 

Per  Cent 
100.0 

Urea    

85.0 

Ammonia    

3.6 

Creatinin   

4.1 

Uric  acid    

1.6 

Undetermined  N    

6.7 

Hippuric  acid    

0.7 
0.5 
0.03 

0.06 
0.10 
0.01 

Amino  acids 

Purin  bases    

488  VICTOR  C.  MYEKS 

total  nitrogen  13.8  grams.  If  allowance  is  made  for  a  fecal  nitrogen 
excretion  of  1.5  grams,  the  nitrogen  intake  would  be  15.3  gi'ams,  which 
corresponds  to  about  05  grams  protein.  The  output  of  creatinin  for  the 
average  human  adult  is  about  1.5  grams  and  of  uric  acid  0.5  gram. 

Urea. — Urea,  annnonia  and  amino  acids  are  intimately  related  in  their 
physiological  history.  It  will  be  recalled  that  the  amino-acids,  resulting 
from  the  digestion  of  protein  in  the  intestine,  are  absorbed  and  carried 
to  all  the  tissues  of  the  body.  The  greater  part  of  the  amino-acids  thus 
absorbed  and  disseminated  are  deaminized,  i.e.,  the  amino  gTOup  (NHg) 
is  split  off,  forming  ammonia.  This  process  of  deaminization  may  be  illus- 
trated as  follows,  taking  alanin  as  a  typical  amino-acid: 

NHo  OH 

I  •■      I 

CH3 .  CH .  COOH  +  HOH  -»  NH3  +  CH3 .  CII .  COOH 

Alanin  Water  Ammonia         Lactic  Acid 

The  ammonia  unites  with  the  carbonic  acid  of  the  blood  and  tissues  to 
form  ammonium  carbonate.  Two  molecules  of  water  are  then  split  off 
from  the  ammonium  carbonate,  yielding  urea.  The  formation  of  am- 
monium carbonate  and  its  subsequent  dehydration  to  form  urea  are  indi- 
cated below: 

OH  ISTHa  0:^114  ISTHg     H2O 

t         .  I  I 

0  =  0      +  -»     C--0        -^0  =  0    h 

I  I  I 

OH  :^H3  OXH4  XHo      HoO 

Carbonic     Ammonia  Ammonium        Urea      Water 

acid  Carbonate 

Kossel  and  Dakin  have  also  shown  that  arginin  may  be  directly 
split  into  oraithin  and  urea  under  the  action  of  a  liver  enzyrpe,  arginase. 
The  deaminization  of  amino-acids  and  the  transfomiation  of  ammonium 
carbonate  into  urea  takes  place  in  the  liver  and  possibly  in  other  tissues. 
(See  preceding  article,  p.  464.)  Because  of  the  prominence  pla3^ed  by  the 
liver  cells  in  these  processes,  considerable  importance  has  been  attached 
to  apparent  abnormalities  in  the  elimination  of  urea,  ammonia  and  amino- 
acids.  In  acute  yellow  atrophy  of  the  liver,  interstitial  Jiepatitis  and 
cirrhosis  of  the  liver,  there  is  a  veiy  extensive  degeneration  of  the  liver 
cells.  The  association  of  hepatic  disturbance  with  increased  elimination 
of  ammonia  and  amino-acids,  and  diminished  output  of  urea  has  not  bf3en  a 
constant  finding  (Fiske  and  Karsner),  and  in  many  instances  has  been 
the  result  of  employing  old  and  inadequate  methods.     However,  there  is 


EXCRETI0:N^S  480 

generally  some  reduction  in  the  amount  of  urea  in  the  urine,  and  an 
increase  in  the  ammonia  content.    > 

Urea  is  an  extremely  soluble  and  relatively  non-toxic  substance. 
These  two  properties  have  a  particular  significance  in  view  of  the  fact 
that  urea  is  the  chief  end  product  of  protein  metabolism^  and  is  almost' 
wholly  eliminated  through  the  kidney,  the  portion  excreted  through  other 
channels  such  as  the  skin  being  relatively  unimportant.  The  quantitative 
output  of  urea  is  closely  proportional  to  the  amount  of  protein  ingested. 
Variations  of  10  to  40  gTams  may  be  encountered  in  pei-f ectly  normal  indi-* 
viduals.  The  percentage  of  urea  is  dependent  upon  the  volume  of  urine 
in  addition  to  the  protein  of  the  diet,  and  when  it  is  considered  that  the 
former  may  vary  from  500  to  2000  c.c.  it  is  evident  that  but  little  informa- 
tion concerning  the  quantity  eliminated  can  be  gained  from  a  knowledge 
of  merely  the  percentage  of  urea.  The  urea  nitrogen  in  proportion  to 
the  total  nitrogen  excreted  may  likewise  be  greatly  influenced  by  the 
amount  of  protein  in  the  diet.  Thus  with  a  high  protein  intake,  the  urea 
nitrogen  may  make  up  as  much  as  90  per  cent  of  the  total  nitrogen; 
while  with  a  diet  containing  relatively  little  protein  but  considerable 
carbohydrate  and  fat,  the  proportion,  may  be  as  low  as  60  per  cent.  (See 
table  on  p.  486.)  With  a  nitrogen  intake  of  20  grams  the  urine  would 
contain  approximately  18  grams  of  nitrogen,  of  which  about  16  grams 
would  be  in  the  form  of  urea ;  whereas  with  a  nitrogen  intake  of  7  gi*ams 
the  excretion  of  urea  nitrogen  may  be  as  low  as  4  grams.  An  average 
quantitative  output  of  urea  with  its  nitrogen  equivalent  and  the  relation 
of  the  latter  to  the  total  nitrogen  output  is  given  in  the  table  on  page 
487.  It  will  be  readily  seen  that  it  is  quit€  essential  in  considering 
the  excretion  of  total  nitrogen  and  urea  to  compare  these  values  with 
the  nitrogen  of  the  food,  because  only  when  the  nitrogen  output  is  out 
of  proportion  to  the  intake  can  an  abnormal  condition  be  presumed  to 
exist. 

When  the  rate  of  metabolism  is  accelerated  as  in  fevers,  exophthalmic 
goiter,  etc.,  or  by  the  consumption  of  large  amounts  of  protein  as  in 
diabetes,  the  total  nitrogen  and  urea  may  be  gi'eatly  augmented. 
Although  the  function  of  excreting  urea  may  be  much  impaired  in 
nephritis  a  recognition  of  this  fact  simply  from  the  output  of  urea  is 
difficult.  Information  in  this  regard  may  be  more  readily  secured  from 
an  analysis  of  the  blood. 

Ammonia. — Under  ordinary  conditions  the  nitrogen  of  ammonia,  in 
combination  with  urinary  acids,  is  present  in  the  urine  to  the  extent  of 
2.5  to  4.5  per  cent  of  the  total  nitrogen  eliminated,  i.e.,  about  0.5  gram  per 
day.  A  considerable  portion  of  this  probably  represents  urea  which  has 
been  reconverted  into  ammonia  so  that  it  might  be  utilized  to  neutralize  the 
sulphuric,  phosphoric,  uric  acid,  etc.,  formed  in  the  process  of  noraaal  me- 
tabolism or  introduced  with  the  food.    This  procedure  probably  operates  to 


490  VICTOR  C.  MYERS 

prevent  undue  strain  upon  the  body's  supply  of  sodium,  potassium,  calcium 
and  magnesium.  As  shown  by  Janney(6),  if  sufficient  fixed  alkalies  or  al- 
kali-earths are  administered,  so  that  ammonia  is  not  required  for  neutral- 
izing the  acids,  then  the  ammonia  excretion  may  be  greatly  reduced, 
cr  in  fact  almost  completely  disappear  from  the  urine.  On  the 
other  hand,  the  ammonia  output  may  be  greatly  increased  when  there  is  an 
abnormal  acid  production,  as  occurs  in  severe  diabetes.  Sherman  and 
Gettler  have  demonstrated  that  the  ammonia  output  is  dependent  to  a 
considerable  extent  upon  the  balance  between  the  acid-forming  and  base- 
forming  elements  of  the  foods.  Increased  elimination  of  ammonia  has 
been  observed  in  pernicious  vomiting  of  pregnancy,  but  it  is  important 
to  note  that  here  the  individual  is  essentially  in  a  condition  of  inanition, 
which  itself  is  characterized  by  a  relative  increase  in  ammonia  elimina- 
tion. 

Amino-Acids.— Small  amounts  of  amino-acids  normally  escape  deam- 
inization  and  appear  in  the  urine.  They  represent  about  0.5  per  cent 
of  the  total  nitrogen,  and,  unless  specifically  determined,  are  recorded  as 
undetermined  nitrogen.  In  severe  liver  disease,  i.e.,  yellow  atrophy, 
phosphorus  poisoning,  the  output  of  amino-acids,  may  be  increased,  and 
occasionally  certain  amino-acids,  such  as  leucin  and  tyrosin,  actually 
crystallize  out  in  the  urine.  As  already  noted,  however,  increased  amino- 
acid  excretion  and  hepatic  disturbances  are  not  constantly  associated. 
In  certain  individuals  the  amino-acid  cystin  is  eliminated  in  considerable 
amounts.    This  is  regarded  as  an  anomaly  of  protein  metabolism. 

Creatinin. — Creatinin  is  the  anhydrid  of  creatin.  It  is  the  second 
largest  nitrogenous  constituent  of  urine,  the  daily  elimination  in  the 
healthy  human  adult  ordinarily  varying  between  1  and  2  grams. 

HIS^— CO 

H1^  =  C      i 

II 
CH3K— CH2 

Our  accurate  knowledge  with  regard  to  the  elimination  of  creatinin 
dates  from  the  introduction  of  the  Folin  colorimetric  method  in  1904. 
As  the  result  of  his  original  studies  on  the  elimination  of  creatinin,  Folin 
considered  the  excretion  of  this  substance  from  the  standpoint  of  a  new 
theory  of  protein  metabolism.  lie  was  the  first  to  poiJit  out  tliat  the 
amount  of  creatinin  excreted  in  the  urine  on  a  meat  free  diet  is  quite 
independent  of  either  the  amount  of  protein  in  the  food  or  of  the  total 
nitrogen  in  the  urine,  the  amount  excreted  from  day  to  day  being  prac- 
tically constant  for  each  individual,  thus  pointing  conclusively  to  its 
endogenous  origin.     The  constancy  of  this  creatinin  excretion  has  been 


EXCRETIONS  491 

fully  confirmed  by  many  subsequent  investigators  and  Shaffer(a)  has  fur- 
ther observed  the  same  uniformity  in  its  hourly  excretion.  (According  to 
Neuwirth  the  hourly  creatinin  excretion  is  generally  slightly  decreased 
din'ing  one  hour  in  the  later  afternoon  or  early  evening).  Even  a  con- 
siderable diuresis  has  little  effect  on  this  hourly  output,  while  a  great 
increase  or  decrease  in  the  amount  of  total  nitrogen  excreted  per  hour  is 
likewise  without  effect.  Furthermore,  neither  increased  nor  decreased 
muscular  activity,  uncomplicated  by  other  factors,  has  any  effect  upon 
the  creatinin  elimination.  Such  results  are  a  definite  indication  that 
the  regularity  of  the  creatinin  excretion  can  be  explained  only  on  the 
basis  of  a  similar  regular  formation. 

While  the  creatinin  excretion  is  practically  constant  for  each  healthy 
individual,  different  persons  excrete  different  amounts,  and  Folin  early 
pointed  out  that  the  chief  factor  determining  this  appeared  to  be  the 
weight  of  the  person.  He  further  noted  that  the  fatter  the  subject,  the 
less  creatinin  is  excreted  per  kilo  of  body  weight  and  concluded  from  this 
that  the  amount  of  creatinin  excreted  depends  primarily  upon  the  mass 
of  active  protoplasmic  tissue,  or  as  Shaffer  has  expressed  it,  "Creatinin. 
is  derived  from  some  special  process  in  normal  metabolism  taking  place 
largely,  if  not  wholly,  in  the  muscles,  and  upon  the  intensity  of  this 
process  appears  to  depend  the  muscular  efficiency  of  the  individual."  It 
has  been  found  convenient  to  express  the  daily  creatinin  elimination  in 
milligrams  of  creatinin  nitrogen  per  kilo  of  body  weight  and  this  has 
been  called  the  creatinin  coefficient.  For  a  strictly  normal  individual 
Shaffer  has  shown  that  this  coefficient  is  between  7  and  1 1.  Women  elimi- 
nate less  creatinin  than  men,  and  thus  have  slightly  lower  creatinin 
coefficients.  The  creatinin  excretion  of  children  is  much  lower  than  that 
of  adults. 

That  the  creatinin  elimination  is  affected  by  different  pathological 
conditions  has  been  shown  by  numerous  observations.  A  low  creatinin 
elimination  has  been  found  associated  with  a  large  number  of  abnormal 
conditions,  especially  those  accompanied  by  muscular  weakness.  Benedict 
and  Myers  observed  creatinin  coefficients  as  low  as  2  in  two  very  old 
decrepit  women,  while  Levene  and  Kristeller  found  coefficients  of  1.5  in 
several  cases  of  muscular  dystrophy  in  young  male  adults.  A  marked 
decrease  in  the  excretion  of  creatinin  has  been  obsei'ved  to  be  associated 
with  such  conditions  as  exophthalmic  goiter,  the  leucemias,  diseases  of 
the  liver,  especially  carcinoma,  muscular  dystrophy,  anterior  poliomyelitis, 
certain  cases  of  nephritis,  etc  An  interesting  fact  to  note  in  this  con- 
nection is  that  most  of  these  subjects  eliminate  considerable  amounts  of 
creatin. 

Only  in  the  terminal  stages  of  chronic  nephritis  is  a  decreased  elimi- 
nation of  creatinin  due  to  retention.     Creatinin  appears  to  be  the  most 


492  VICTOR  C.  MYERS 

readily  eliminated  of  the  three  nitrogenous  waste  products,  uric  acid,  urea 
and  creatinin,  and  it  is  only  in  chronic  nephritis  or  acute  nephritis  with 
partial  or  complete  suppression  of  urine  that  retention  occurs.  A  hlood 
content  of  more  than  5  mg.  of  creatinin  to  100  c.c.  has  been  found  to  be  a 
very  unfavorable  prognostic  sign  (see  preceding  article,  p.  441), 

The  excretion  of  creatinin  has  been  found  to  be  increased  in  fevers— 
typhoid,  pneumonia  and  erysipelas.  Here  the  rise  in  temperature  is 
followed  by  a  corresponding  rise  in  the  creatinin  output.  Myers  and 
Volovic  have  shown  that  the  excretion  of  creatinin  follows  closely  the 
rise  in  temperature  during  fever,  whether  the  hyperthermia  is  of  infective 
origin  or  artificially  induced.  From  this  it  would  appear  that  the  rise  in 
the  creatinin  elimination  was  due  entirely  to  the  hyperthermia. 

That  the  creatinin  of  the  urine  has  its  origin  in  the  creatin  of  the 
muscle  would  seem  obvious  on  a  priori  grounds,  but  a  definite  proof  of 
this  hypothesis  has  been  beset  with  many  difficulties.  The  older  inves- 
tigators stated  that  both  administered  creatin  and  creatinin  reappeared 
in  the  urine  as  creatinin.  When  Folin  first  reinvestigated  this  question 
with  accurate  methods  and  pure  creatin  and  creatinin,  he  found  that  80 
per  cent  of  the  administered  creatinin  did  reappear  as  creatinin,  but  that 
when  creatin  was  given  in  moderate  amounts  (1  gram  to  man)  it  not 
only  failed  to  reappear  as  creatinin,  but  completely  disappeared.  From 
this  Folin  quite  naturally  concluded  that  creatin  and  creatinin  were  rela- 
tively independent  in  metabolism.  In  1913  Myers  and  Fine(c)  called 
attention  to  the  fact  that  the  creatin  content  of  the  muscle  of  a  given 
.species  of  animals  was  very  constant  (obviously  also  that  of  a  given 
animal)  and  suggested  this  as  a  possible  basis  of  the  constancy  in  the 
daily  elimination  of  creatinin  first  noted  by  Folin.  Later  they  pointed 
out  that  the  creatinin  content  of  muscle  was  greater  than  that  of  any  other 
tissue,  and  also  that  in  autolysis  experiments  with  muscle  tissue  the 
creatin  (and  any  added  creatin)  was  converted  to  creatinin  at  a  constant 
rate  of  about  2  per  cent  daily,  which  is  just  about  the  normal  ratio 
between  the  muscle  creatin  and  urinary  creatinin.  They  also  found,  as 
did  Rose  and  Dimmitt,  Lyman  and  Trimby,  and  others,  that  when  creatin 
was  administered  to  man  or  animals,  there  was  a  slight  conversion  to 
creatinin  although  a  considerable  percentage  of  the  creatin  reappeared  in 
the  urine  unchanged  if  large  amounts  were  given.  These  facts  all  go  to 
support  the  view  that  creatinin  is  formed  in  the  muscle  tissue  from  creatin, 
and  at  a  very  constant  rate,  although  no  explanation  of  the  physiological 
significance  of  this  transformation  can  as  yet  be  offered.  Excepting 
possibly  the  kidney,  the  muscle  normally  contains  more  creatinin  than 
any  other  body  tissue  and  is  followed  by  the  blood  which  indicates  that 
after  its  formation  in  the  muscle  the  creatinin  is  carried  to  the  kidney 
by  the  blood  stream. 


EXCRETIONS  493 

Greatin. — Creatin  is  methyl  imaiiidin  acetic  acid. 

HKII 

I 
HN  =  C 

I 
CH,.N  — CH2  — COOH 

It  is  a  constant  constituent  of  striated  muscle,  the  concentration  in  man 
being  about  0.39  per  cent.  The  creatin  content  of  striated  muscle  appears 
to  be  both  constant  and  distinctive  for  a  given  species  (see  preceding  arti- 
cle, p.  401).  Creatin  is  also  present  in  heart  muscle  in  about  two-thirds  the 
concentration  of  striated  muscle  and  in  the  testis,  brain,  smooth  muscle 
and  liver  in  much  lower  concentrations,  the  figures  varying  from  about  0.1 
per  cent  in  the  testis  and  brain  to  0.3  per  cent  in  the  smooth  muscle  of 
the  intestine  and  uterus,  and  slightly  less  in  the  liver. 

Folin,  in  his  original  discussion  of  the  subject,  pointed  out  that 
although  creatin  is  normally  absent  from  urine,  occasionally  small  amounts 
may  be  detected.  This  phase  of  the  problem  received  renewed  interest 
when  F.  G.  Benedict (c)  noted  in  starvation  experiments  on  man  that  con- 
siderable quantities  of  creatin  appeared  in  the  iirine.  Following  up  this 
observation,  Benedict  and  Myers  observed  the  elimination  of  varying 
amounts  of  creatin  in  a  large  number  of  undernourished  insane  patients. 
Subsequent  observers  have  shown  that  creatin  is  regularly  excreted  par- 
ticularly in  carcinoma  of  the  liver,  diabetes,  muscular  dystrophy,  exoph- 
thalmic goiter,  anterior  poliomyelitis,  pernicious  vomiting  of  pregnancy, 
typhoid  fever  and  pneumonia.  In  all  except  the  last  two  conditions 
mentioned  (fevers)  this  is  accompanied  by  a  lowered  creatinin  output, 
and  even  in  fevers  this  is  true  during  convalescence.  Judging  from  the 
observations  of  Denis  on  the  creatin  content  of  human  muscle  obtained  at 
autopsy,  it  would  appear  that  the  excretion  of  creatin  was  generally 
associated  with  a  low  muscle  content.  In  carcinoma  of  the  liver  the 
creatin  elimination  may  be  very  large,  1-1.5  grams. 

From  the  foregoing,  it  would  appear  that  the  excretion  of  creatin 
was  pathological,  but  Rose,  and  also  Folin  and  Denis (&),  have  recently 
observed  the  interesting  fact  that  growing  children  excrete  creatin  while 
according  to  Krause  normal  women  periodically  excrete  small  amounts 
of  creatin. 

Muscle  creatin  has  quite  generally  been  regarded  as  the  source  of  the 
urinary  creatin  in  starvation  and  pathological  conditions  associated  with 
undernutrition,  although  some  workci-s  have  opposed  this  view.  In  the 
case  of  stai'ving  rabbits  Myers  and  rine(c?)  believed  that  they  were  able  to 
account  for  the  creatin  lost  from  the  muscle  on  the  basis  of  urinary 
findings,  but  these  observations  can  hardly  be  directly  compared  with 
pathological  conditions  in  the  human  subject.     McCollum  and  Steenbock 


494  VICTOR  C.  MYERS 

have  shown  that  the  pig  on  a  high  protein  diet  from  certain  sources  will 
excrete  creatin,  while  Benedict  and  Osterberg(a.)  have  found  that  the  phlor- 
hizinized  dog  may  eliminate  very  large  amounts  of  creatin  when  fed  on  a 
diet  of  thoroughly  washed  meat. 

Different  hypotheses  have  been  advanced  to  explain  the  excretion  of 
creatin  in  children,  such  as  under  carbohydrate  feeding,  high  protein 
feeding  and  acidosis,  but  the  experimental  evidence  advanced  in  their 
support  is  not  entirely  convincing,  although  all  these  factors  undoubtedly 
exert  an  influence  under  certain  circumstances.  It  is  now  well  known 
that  the  administration  of  carbohydrate  in  starvation  causes  a  disappear- 
ance of  the  creatinuria.  Denis  and  Kramer  believe  that  the  creatinuria 
in  normal  children  is  due  to  the  relatively  high  protein  intake  which  ia 
the  rule  with  practically  all  children,  also  that  creatinuria  may  be  pro- 
duced in  women  by  very  high  protein  diets.  In  this  view  they  are  opposed 
by  Rose,  Dimmit t  and  Bartlett.  Denis  and  Kramer  further  suggest  that 
the  excretion  of  creatin  in  children  may  also  be  due  to  the  low  saturation 
point  of  immature  muscle  owing  to  the  low  creatin  content  of  the  muscle 
of  children  and  the  relatively  low  level  of  protein  consumption  at  which 
appreciable  quantities  of  creatin  appear  in  the  urine.  In  support  of  this 
argument  Gamble  and  Goldschmidt(a.)  have  observed  a  practically  complete 
elimination  of  ingested  creatin  in  an  infant  on  a  high  protein  diet. 

Granting  that  creatinin  does  come  from  creatin,  the  natural  question 
is :  What  is  the  precursor  of  creatin  ?  For  this  we  have  as  yet  no  definite 
answer.  On  account  of  its  guanidin  group,  arginin  naturally  suggests 
itself.  The  ver>'  close  chemical  relationship  between  arginin  and  creatin 
is  apparent  from  the  formula  of  arginin. 

I  . 

I 
HK  -  CHo  -  CH2  -Clio  -  CH(NIl2)  -  COOH 

Arginin,  or  guanidin-amino-valerianic  acid. 

If  arginin  is  the  source  it  is  transfoiTned  only  in  small  part  to  creatin, 
since  the  amount  of  the  daily  creatinin  excretion  could  account  for  only  a, 
small  part  of  the  arginin  normally  metabolized.  From  the  studies  of 
Kossel  and  Dakin  it  appears  that  the  greater  part  of  the  arginin  is 
hydrolyzed  to  ornithin  and  urea  by  the  enzyme  arginase,  but  experimental 
data  to  show  that  creatin  is  derived  from  arginin  are  inconclusive.  That 
creatin  is  not  present  in  invertebrate  muscle  has  long  been  known,  although 
the  presence  of  arginin  and  likewise  betain  has  been  shown.  The  possi- 
bility that  betain,  and  also  the  closely  related  cholin,  are  the  percursors 


EXCRETIONS       -  495 

of  creatin  in  the  vertebrate  has  been  suggested  by  Riesser(&),  who  has  pre- 
sented evidence  in  experiments  on  rabbits  suggesting  that  both  the 
creatin  content  of  the  muscle  and  the  creatinin  elimination  are  increased  af- 
ter the  administration  of  these  substances,  ^fyers  and  Fine(y)  found  that 
the  creatin  content  of  the  muscle  of  rats  was  very  slightly  increased  (2.5 
per  cent)  as  a  result  of  feeding  with  edestin,  a  protein  relatively  rich  in 
arginin.  Bauman  and  IIines(6)  have  perfused  arginin,  sarcosin,  methyl- 
guanidin,  betain  and  cholin  through  dog  muscle  (hind  leg)  without 
obtaining  conclusive  evidence  of  their  being  creatin  formers. 

Uric  Acid. — Uric  acid  results  from  the  cleavage  and  oxidation  of 
uucleoprotein,  which  is  the  chief  constituent  of  all  cell  nuclei.  Nucleo- 
protein  is  split  into  protein  and  nucleic  acid.  When  the  nucleoprotein 
is  present  in  the  food,  this  process  takes  place  in  the  alimentary  tract 
under  the  influence  of  trypsin ;  wdien  the  body  cells  are  the  source  of  the 
nucleoprotein  this  transformation  takes  place  in  the  tissues  probably 
through  the  agency  of  a  similar  enzyme.  The  protein  fraction  is  digested 
in  the  usual  way,  and  the  nucleic  acid  is  further  transformed,  ultimately 
yielding  uric  acid.  K^ucleic  acid  is  a  complex  substance  containing  phos- 
phoric acid,  carbohydrate,  pyrimidin  and  purin  groups.  In  the  molecule 
there  is  a  union  of  4  complex  radicals  called  nucleotids,  A  nucleotid  is 
a  combination  of  phosphoric  acid,  a  carbohydrate  and  a  basic  group  which 
may  be  purin  (e.g.,  adenin  or  guanin)  or  a  pyrimidin  (e.g.,  cytosin, 
uracil  or  thymin).  In  nucleic  acids  of  plant  origin,  the  carbohydrate  is 
usually  a  pentose  (d-ribose),  while  a  hexose  is  the  carbohydrate  found 
in  animal  nucleic  acids.  Animal  nucleic  acids  further  differ  from  the 
plant  variety  in  having  the  pyrimidin,  thymin,  instead  of  uracil. 

The  nucleic  acid  is  split  into  its  component  nlicleotids,  which  experi- 
ence another  cleavage  resulting  in  the  liberation  of  phosphoric  acid, 
leaving  carbohydrate-purin  and  carbohydrate-pyrimidin  combinations.  The 
latter  compounds  are  known  as  nucleosids  and  are  eventually  split,  liberat- 
ing the  free  purin  and  pyrimidin  bases.  The  purin  bases,  adenin  and 
guanin,  are  then  converted  respectively  into  hypoxanthin  and  xanthin,  this 
change  being  accomplished  by  the  enzymes  adenase  and  guanase.  Finally 
by  means  of  an  oxidizing  enzyme,  xanthin  is  transformed  to  uric  acid. 
This  process  is  graphically  represented  on  the  following  page,  the  en- 
zymes being  enclosed  in  parenthesis. 

The  pyrimidins,  especially  cytosin,  have  been  suggested  as  possible 
purin  precursors  by  Kossel,  but  no  experimental  evidence  has  been  ad- 
duced in  support  of  this  hypothesis.  The  fate  of  the  pyrimidins  appears  to 
be  quite  uncertain.  Mendel  and  Myers  found  that  when  the  three  pyrim- 
idins found  in  nucleic  acid  were  administered  to  man  or  animals  they 
reappeared  in  the  urine  unchanged,  and  Wilson  has  made  similar  observa- 
tions regarding  the  pyrimidin  nucleosids. 


496 


VICTOK  C.  MYERS 


Nucleic  Acid 
(nuclease) 

I 
Nucleotids 

(nucleotidase) 

i 
Nucleosids 


I  nucleosidase) 
Adenin 


Nucleoprotein 
(protease) 


(adenase) 

I 
Hypoxanthin 

(oxidase) 


Guanin 
(guanase) 

I 
-^  Xanthin 

(oxidase) 


Protein 


Uric  Acid 


We  are  familiar  with  the  chemical  structure  of  the  purins  owing 
chiefly  to  the  researches  of  Emil  Fischer  and  his  pupils.  An  apprecia- 
tion of  the  chemical  structure  of  this  group  of  compounds  is  of  material 
aid  in  obtaining  an  adequate  understanding  of  purin  metabolism. 


IN— 60  N=:C(NH2)  HN— CO 

II  II  II 

20      50  — N7\      HO       0~NH        rNH2)0      0- 

(I  C8     II        II  \CH  '  II        II 


3N  — 40— NO/ 

Purin  Nucleus  or 
Skeleton 


N  — 0~N/ 

Adenin 
(0-amino-purin) 
I 
HN  — 00 

I         I 
110       0  — NH 

II        II  \CH 

N—  0  — N/ 
Hypoxanthin 
(G-oxypurin) 


NH 
\0H 

N/ 


N—  0 
Guanin 
(2-amino-6-oxypurin) 
I 
HN— 00 


00       0  — NH  -> 
I        II  XCH" 

HN  — O  — N/ 

Xanthin 
(2,  G-dioxypurin) 


HN  — CO 

I         I 
00       0  — NH\ 

I        II  CO 

HN'-C-NH/ 

Uric  Acid 
2,  6,  S-trioxy-purin 


It  has  been  claimed  that  in  man  about  half  the  uric  acid  is  Subject  to 
a  further  enzynuitic  change  (uricolysis).  This,  howeverj  is  still  a  dis- 
puted question  although  in  animals  the  greater  part  of  the  uric  acid  is 
vuidoubtedly  converted  to  allantoin. 


EXCKETIONS  497 


KE2 
\ 
CO 

/ 


HX  — CO  HX— -CO 

I         I  I 

oc     0  — :n^h  I 

I         II  /^^  I 

HN  — C  — NH  HN  —  CH  — NH 

Uric  Acid  Allantoin 

The  difference  in  the  fate  of  uric  acid  in  man,  on  the  one  hand,  and  in 
the  dog,  rabbit,  etc.,  on  the  other,  is  probably  a  quantitative  one.  Qualita- 
tively there  is  no  dissimilarity,  for  traces  of  allantoin  do  appear  in  human 
urine,  and  the  urines  of  the  lower  animals  do  contain  small  amounts  of 
purins  (Hunter  and  Givens(c)).  It  is  especially  significant  from  the 
standpoint  of  comparative  physiology  to  learn  that  as  far  as  their  purin 
metabolism  is  concerned,  the  monkey  ranks  with  the  lower  animals  rather 
than  with  man.  The  purin  metabolism  of  man,  then,  is  unique  in  that  uric 
acid  represents  the  principal  excretory  product.  It  is  of  further  interest 
to  note  that  human  blood  contains  from  10  to  60  times  as  much  uric  acid 
as  the  blood  of  the  rabbit,  cat  and  sheep.  Whereas  the  blood  of  these  ani- 
mals contains  from  0.05  to  0.2  mg.  of  (free)  uric  acid  per  100  c.c.  of  blood, 
normal  human  blood  contains  2  to  3  mg.  A  similar  difference  has  been 
found  in  the  tissues  of  man  and  animals  (Fine).  This  furnishes  addi- 
tional evidence  pointing  to  the  relative  indestructibility  of  uric  acid  in 
man. 

From  the  fact  that  in  birds  the  end  product  of  nitrogenous  metabo- 
lism in  general  is  uric  acid,  apparently  of  synthetic  origin,  the  attempt 
has  been  made  to  demonstrate  a  similar  formation  in  man,  but  without 
conspicuous  success.  For  the  present,  uric  acid  must  be  regarded  as  aris- 
ing solely  from  the  oxidative  transformations  of  the  purin  bases,  whether 
they  already  exist  in  the  body  or  have  been  introduced  from  without. 

The  precursors  of  uric  acid,  nucleoprotein  and  purin  bases,  may  be 
present  in  the  food  or  disintegi-ating  cellular  material  of  the  body.  In  the 
former  case,  the  uric  acid  is  said  to  be  of  "exogenous  origin,"  in  the  latter, 
of  "endogenous  origin.'^  The  output  of  endogenous  uric  acid  will  be  de- 
termined by  the  extent  of  the  body  cell  activity.  During  starvation,  for 
example,  the  24  hr.  uric  acid  elimination  may  vary  from  Q.l  to  0.2  gram, 
v/hich  may  be  increased  to  0.2  to  0.4  gi-am  on  a  purin-free  diet.  This 
diet  contains  no  uric  acid  precursors,  and  could,  therefore,  cause  the  in- 
creased uric  acid  output  only  indirectly.  It  is  quite  generally  accepted 
that  the  aug-mented  output  of  uric  acid  following  the  ingestion  of  a  purin- 
free  diet  is  due  to  the  necessarily  increased  activity  of  the  digestive  glands, 
thus  raising  the  level  of  endogenous  purin  metabolism  (Mares,  Mendel  and 
Stehle).  The  administration  of  drugs,  such  as  pilocarpin,  which  stimu- 
lates glandular  activity,  also  increases  the  uric  acid  output,  while  atrophin, 


408  VICTOR  C.  MYERS 

.  a  glandular  depressant,  causes  a  reduction.  With  uric  acid  yielding  foods 
as  meat,  meat  extracts,  pancreas,  liver,  thymus,  peas,  beans,  etc.,  the  out- 
put will,  of  course,  be  the  sum  of  endogenous  and  exogenous  uric  acid. 
Mendel  and  Wardell  have  demonstrated  that  uric  acid  excretion  may  be 
'  very  definitely  increased  by  the  taking  of  methylated  xantliins  in  coffee, 
tea  and  cocoa,  obviously  indicating  a  demethylation  of  these  purins.  On 
a  mixed  diet  0.5  to  0.6  gram  of  uric  acid  may  be  taken  as  the  average 
output  of  the  human  adult. 

The  greatest  increase  in  uric  acid  elimination  is  observed  in  leucemia, 
as  much  as  12  grams  having  been  found  to  be  excreted  in  24  hours.  This 
high  elimination  of  uric  acid  is  without  doubt  to  be  referred  to  the  enor- 
mous increase  in  the  number  of  leucocytes  and  consequent  leucolysis. 
An  increased  uric  acid  excretion  is  observed  in  other  diseases  associated 
with  a  high  grade  of  leucocytosis.  Although  in  gout  deposits  of  sodium 
urate  may  be  found  in  certain  of  the  articular  cartilages,  and  the  blood 
uric  acid  increased  owing  to  faulty  elimination,  still  the  quantitative  ex- 
cretion of  uric  acid  in  gouty  individuals  does  not  differ  markedly  from  that 
found  nonnally.  It  may,  however,  be  noted  that  for  two  or  three  days 
preceding  an  attack  of  acute  gout  the  uric  acid  elimination  is  diminished; 
Avhile  during  and  for  a  few  days  after  the  attack  it  may  maintain  a  level 
somewhat  above  normal. 

It  has  been  recognized  for  some  time  that  the  excretion  of  uric  acid 
was  stimulated  by  the  administration  of  salicylic  acid  and  phenylcincho- 
ninic  acid  and  their  derivatives,  and  they  have  frequently  been  referred  to 
as  "uric  acid  eliminants."  Myers  and  Killian(c)  have  recently  pointed  out, 
however,  that  this  action  is  not  specific  for  uric  acid.  It  has  been  found 
that  in  suitably  selected  cases,  having  slightly  increased  blood  urea  (and 
possibly  also  creatinin)  findings,  administration  of  the  above  compounds 
will  lower  the  blood  concentration  of  these  constituents  as  well  as  the  uric 
acid. 

Ordinarily  uric  acid  is  present  in  the  urine  in  combination  with  sodium, 
potassium  or  ammonium.  Only  when  the  urine  is  especially  acid  does 
uric  acid  itself  separate  out.  When  the  urine  is  concentrated  or  after  the 
ingestion  of  considerable  meat,  pancreas,  etc.,  urates  may  be  deposited 
shortly  after  the  urine  is  voided.  In  other  cases  such  deposits  may  form 
on  standing  in  a  cool  place. 

Purin  Bases. — A  small  portion  of  the  purin  bases,  adenin,  guanin, 
hypoxanthin  and  xanthin  escape  convci^sion  to  uric  acid,  and  appear  un- 
changed in  the  urine.  About  0.02  to  0c05  gram  of  such  compounds  may 
be  eliminated. 

Hippuric  Acid. — Hippuric  acid  is  a  combination  of  glycocoll  and  ben- 
zoic acid.  By  this  conjugation  which  takes  place  in  the  kidney,  although 
it  may  be  formed  elsewhere  (Kingsbury  and  Bell),  the  body  is  able  to  de- 
fend itself  against  the  more  toxic  benzoic  acid.     For  this  reason  small 


EXCRETIONS  499 

amounts  of  benzoic  acid  or  sodium  benzoate  would  appear  to  be  harmless. 
Hippuric  acid  is  found  in  the  urine  of  herbivorous  animals,  such  as  the 
horse  and  cow,  in  large  amount,  but  only  about  0.7  gram  per  day  occurs 
in  human  urine.  Certain  fruits  and  berries,  cranberries  in  particular, 
contain  appreciable  amounts  of  benzoic  acid,  while  certain  aromatic  sub- 
stances of  vegetables  are  ultimately  converted  to  benzoic  acid.  It  may  also 
be  formed  by  the  putrefactive  decomposition  of  the  phenylamiuo  acids  in 
the  intestine.  Benzoic  acid  or  sodium  benzoate  is  often  used  as  a  pre- 
servative in  canned  fruit  and  catsup.  All  these  factors  contribute  to  the 
hippuric  acid  output.  It  is  stated  that  hippuric  acid  is  decreased  in  fevei*s 
and  in  certain  kidney  disorders  where  the  synthetic  activity  of  the  renal 
cells  is  diminished. 

Oxalic  Acid. — Oxalic  acid  in  the  form  of  calcium  oxalate  usually  oc- 
curs in  the  urine  in  very  small  amounts,  about  0.02  gram  in  2-1:  hrs.  Oxa- 
lic acid  is  probably  formed  from  the  metabolism  of  proteins  and  fat.  Its 
output  may  be  increased  by  the  ingestion  of  foods  which  contain  oxalic 
acid.     Such  foods  are  cabbage,  spinach,  apples,  grapes,  etc. 

Aromatic  Oxyacids  and  Derivatives. — Under  this  heading  may  be  men- 
tioned phenol,  />-cresol,  indoxyl,  scatoxyl,  indol  acetic  acid  and  homogen- 
tisic  acid.  These  substances  are  all  formed  from  the  aminoacids,  trypto- 
phan, tyrosin  and  phenylalanin.  Homogentisic  acid  is  apparently  formed 
as  a  result  of  abnormal  oxidation  of  the  last  two  amino-acids  men- 
tioned. It  occurs  in  alkaptonuria,  a  comparatively  rare  anomaly  of  metab- 
olism. In  this  condition  the  excretion  may  amount  to  as  much  as  16 
grams  per  day,  although  ordinarily  it  is  less,  i.  e,,  3  to  5  grams.  Intestinal 
putrefaction  (in  rare  instances,  putrefaction  elsewhere  in  the  body)  gives 
rise  to  the  formation  of  the  other  bodies  mentioned.  Phenol,  p-cresol,  and 
indoxyl  are  eliminated  in  the  urine  partly  in  combination  with  sulphuric 
acid,  constituting  the  ethereal  sulphates.  Indoxyl-potassium-sulphate,  or 
indican,  appears  to  depend  upon  the  amount  of  intestinal  putrefaction, 
and  to  be  an  excellent  index  of  it,  but  the  same  can  hardly  be  said  of  the 
ethereal  sulphates  as  a  whole,  indicating  that  in  part  they  have  another 
origin.  Under  normal  conditions  from  5  to  20  mg.  of  indican  are  excreted 
per  day,  but  in  conditions  showing  excessive  intestinal  putrefaction  as 
much  as  200  mg.  may  be  eliminated.  In  certain  of  these  cases  indol  acetic 
acid  is  excreted,  giving  rise  to  the  so-called  urorosein  reaction.  According 
to  the  recent  studies  of  Eolin  and  Denis  the  larger  part  of  the  phenols 
(phenol,  p-cresol,  etc.)  are  excreted  in  the  free  form.  The  daily  elimina- 
tion of  phenols  appears  to  average  about  300  mg.,  of  which  about  60  per 
cent  is  free  and  40  per  cent  conjugated. 

Sug^. — Sugar  appears  to  be  present  in  normal  urine  in  very  small 
amounts.  As  a  'result  of  the  recent  studies  of  Benedict,  this  subject  has 
attracted  considerable  interest.  I^onnal  urine  apparently  contains  from 
0.02  to  0.2  per  cent  of  sugar  with  an  average  of  about  0.07  per  cent.    Of 


500  VICTOK  C.  MYERS 

this  sugar  roughly  half  is  fermentable.  The  24  hr.  elimination  may  vary 
from  0.5  to  1.5  grams,  but  from  a  large  series  of  analyses  made  by  Croll 
on  hospital  cases  the  daily  average  would  appear  to  be  about  0.7  gram. 
Unless  the  carbohydrate  tolerance  is  definitely  disturbed,  larger  amounts 
do  not  appear  to  be  excreted.  Even  in  hyperthyroidism  comparatively 
normal  values  are  found. 


Inorganic  Constituents 

The  inorganic  constituents  of  the  urine  are  chiefly  the  sodium,  potas- 
sium, calcium,  magnesium  and  ammonium  salts  of  hydrochloric,  phos- 
phoric and  sulphuric  acids.  The  salts  of  sodium  and  potassium  are  elimi- 
nated almost  exclusively  in  the  urine,  but,  as  pointed  out  in  the  section 
on  feces,  much  more  calcium  and  magnesium  are  eliminated  by  the  intes- 
tine than  by  the  kidneys,  these  elements  being  largely  in  combination 
with  phosphoric  acid.  The  average  inorganic  solid  elimination  in  the 
urine  amounts  to  about  20  grams  daily,  sodium  chlorid  ordinarily  con- 
tributing considerably  more  than  half  of  the  total.  The  average  elimina- 
tion of  these  different  constituents  for  the  human  adult  may  be  given  as 
follows: 

Grams 

Sodium  as  iSTagO 6.0 

Potassium  as  KgO 3.0 

Calcium  as  CaO 0.3 

Magnesium  as  MgO 0.2 

Ammonium  as  NHg , 0.6 

Iron  as  Fe. . .  o 0.003 

Chlorids  as  CI 7.0 

Phosphates  as  P2O5. 2.5 

Sulphates  as  SO3 2.0 

Long  and  Gephart  have  made  fairly  complete  mineral  analyses  on 
the  composite  urines  of  six  healthy  adults.  They  foimd  that  tbey  could 
obtain  an  almost  exact  balance  between  acids  and  bases,  if  they  assumed 
that  four-fifths  of  the  phosphoric  acid  was  held  as  dihydrogen  phosphate 
and  one-fifth  as  monohydrogen  phosphate.  On  this  basis  they  suggested 
the  arbitrary  salt  combinations  given  in  tabular  form  on  the  next  page. 

Chlorids. — The  amount  of  chlorids,  chiefly  sodium  cblorid,  excroted 
per  day  is  dependent  upon  the  food  chlorids.  The  elimination  is  quite 
variable  but  ordinarily  falls  between  10  and  15  grams.  Some  )>eople 
ingest  very  large  amounts  of  salt  with  their  food.  Thi^  salt  is  absorbed 
and  passes  rapidly  through  the  kidneys  into  the  urine.  In  stai-vation  the 
sodium  chlorid  excretion  is  reduced  to  a  minimum.     The  same  conditions 


EXCRETIONS  501 

Grams 

Sodium  chlorid 13.00 

Potassium  chlorid 4.23 

Calcium   sulphate 0.52 

Magnesium  sulphate 0.61 

Ammonium  sulphate 1.52 

Ammonium  urate 0.58 

Potassium  urate 0.03 

Potassium   phenyl   sulphate 0.42 

Potassium  dihjdrogen  phosphate 2.56 

Potassium  monohydrogen  phosphate 0.86 

obtain  in  cases  of  carcinoma  of  the  stomach,  resulting  in  stenosis  of  the 
pylorus,  essentially  a  condition  of  starvation.  The  sodium  chlorid  elimi- 
nation is  decreased  by  those  conditions  wbick  favor  its  removal  from 
ihe  blood  through  other  channels,  e.  g.,  cases  of  diarrhea,  rapidly  formed 
transudates  and  exudates,  such  as  pleurisy  with  effusion.  It  may  be 
pointed  out  that  for  several  days  after  the  reabsorption  of  an  exudate, 
the  chlorid  excretion  may  be  greatly  increased,  and  is  here  a  favorable 
diagnostic  sign.  Diminished  chlorid  elimination  is  observed  dunng  the 
crises  of  acute  febrile  diseases,  especially  pneumonia  and  in  nephritis 
with  edema,  in  the  latter  case  because  of  the  relative  impermeability  of 
the  kidney  to  salts.  In  febrile  diseases  it  is  worthy  of  note  that  the  elimi- 
nation of  chlorids  progressively  decreases  as  the  febrile  process  approaches 
its  crisis,  and  tends  to  rise  to  its  original  level  during  convalescence.  It 
has  been  observed  that  in  pneumonia  there  is,  if  anything,  a  decreased 
chlorid  content  of  the  blood,  while  in  exceptional  cases  of  nephritis  with 
marked  edema,  the  chlorids  of  the  whole  blood  may  rise  from  the  normal 
of  0.45-0.50  per  cent  to  as  high  as  0.7  per  cent.  Such  cases  do  not  gen- 
erally show  marked  nitrogen  retention. 

Phosphates.- — Two  types  of  phosphates  are  present  in  nrine,  the  alJca- 
line  phosphateSj  salts  of  the  alkali  metals,  and  earthy  phosphates,  salts 
of  the  alkaline  earth  metals.  In  the  normally  acid  urine  the  larg-er  part 
of  the  phosphoric  acid  is  generally  present  as  Xa  or  KH2PO4,  the  dihy- 
drogen  phosphate.  The  urinary  excretion  of  phosphates  as  P2O5  amounts 
to  1  to  5  grams,  with  an  average  of  2.5  grams.  This  originates  to  a  small 
extent  in  the  setting  free  of  phosphoric  acid  in  protein  metabolism,  but 
to  a  greater  extent  in  the  phosphates  of  the  foods.  The  extent  to  which 
the  latter  control  the  phosphate  excretion  in  the  urine  depends  upon  the 
relative  abundance  of  alkali  and  alkali-earth  phosphates.  The  alkali- 
earth  phosphates  are  difficultly  absorbable  and  hence  are  in  gi*eat  part 
eliminated  directly  through  the  feces,  thus  contributing  but  little  to 
urinary  phosphate.  Ordinarily  about  two-thirds  of  the  phosphorus  is 
eliminated  in  the  urine,  but  a  diet  containing  a  very  large  amount  of 


502  VICTOR  C.  lyiYERS 

milk,  for  example,  will  increase  the  fecal  excretion.  The  alkali  phosphates 
are  absorbed  and  add  to  urinary  phosphate  to  a  large  extent,  hut  even 
these  may  be  converted  into  alkali-earth  phosphates  in  the  body  and  be 
in  part  excreted  into  the  intestine,  reapjx^aring  in  the  feces.  About 
1  to  4  per  cent  of  the  phosphorus  excreted  is  in  an  organic  combination 
of  unknown  nature.  The  phosphate  elimination  is  said  to  be  increased 
in  periostosis,  osteomalacia,  rickets  and  after  copious  water  drinking; 
and  decreased  in  acute  infectious  diseases,  pregnancy  and  diseases  of  the 
kidney.  Sherman  and  Pappenheimer  have  recently  shown  that  phos- 
phorus may  be  made  the  limiting  factor  in  experimental  rickets  in  rats, 
while  a  number  of  investigators  have  observed  a  retention  of  inorganic 
phosphorus  in  the  blood  in  nephritis.  The  retention  of  acid  phosphate, 
or  rather  the  inability  to  excrete  acid  phosphate,  is  probably  a  very  impor- 
tant factor  in  the  latter  condition.  At  times  a  turbidity  due  to  phos- 
phates may  be  observed.  This  is  sometimes  erroneously  interpreted  as 
indicating  an  increased  elimination  of  phosphates,  ^^phosphaturia."  It 
is  more  likely  due  to  a  condition  of  decreased  acidity  and  is  more  properly 
termed  "alkalinuria.''  This  precipitation  of  phosphates  may  also  be  due 
to  an  unusual  amount  of  calcium  which  would  form  one  of  the  less  soluble 
phosphate  combinations. 

Sulphates. — Sulphur  is  excreted  in  three  forms :  oxidized  or  inorganic 
sulphur,  e,  g.,  the  sulphates  of  sodium,  potassium,  calcium  and  magnesium; 
ethereal  sulphur,  e.  g,,  sulphates  of  phenol,  indoxyl,  scatoxyl,  cresol,  etc. ; 
neutral  sulphur,  e.  g.,  cystin,  cystein,  taurin,  hydrogen  sulphide,  etc. 
The  greater  part  of  the  sulphur  of  the  urine  is  present  in  the  oxidized  or 
inorganic  form,  averaging  rather  more  than  2.0  grams  calculated  as  SOg, 
this  as  a  rule  being  about  10  times  the  amount  of  ethereal  sulphates  ex- 
creted. The  ethereal  sulphates  normally  amount  to  0.20  gram  and  the 
neutral  sulphur  to  about  the  same  amount,  although  sometimes  being  more 
and  sometimes  less.  The  neutral  sulphur  elimination  is  relatively  unin- 
fluenced by  the  diet,  and  Folin  regards  it  as  being  analogous  to  the  crea- 
tinin.  An  idea  of  the  distribution  of  the  sulphur  on  a  high  and  on  a 
low  protein  diet  may  be  obtained  from  the  table  on  page  486.  The  inor- 
ganic sulphur  of  the  urine  arises  mainly  from  the  oxidation  of  the  sul- 
phur of  the  protein,  and  is  thus  increased  by  those  conditions  which  stimu- 
late protein  metabolism  such  as  acute  febrile  diseases,  and  decreased  when 
the  rate  of  metabolism  is  lowered.  The  ethereal  sulphates  of  the  urine 
are  increased  by  excessive  fonnation  and  absorption  from  the  intestine  of 
products  of  putrefaction,  e.  g.,  phenol,  indol,  skatol,  or  by  the  administra- 
tion of  similar  aromatic  bodies  such  as  phenol,  cresol,  resorcinol,  etc. 

Sodium  and  Potassium. — The  quantity  of  sodium  ordinarily  present 
in  the  urine  parallels  quite  closely  the  amount  of  chlorin.  The  excretion 
in  the  healthy  adult  may  be  given  as  4  to  8  grams  with  an  average  of 
about  6  grams  calculated  as  Xa^O.     The  proportion  of  'Nsi  to  K  is  fairly 


EXCKETIONS  503 

constantly  maintained  at  about  5  ;3.  It  is  well  known  that  foods  rich  in 
potassium,  such  as  meat  and  potatoes,  require  more  salt  than  other  foods. 
The  quantity  of  both  of  these  elements  excreted  depends  chiefly  upon  the 
food.  In  starv^ation  or  during  fever  the  potassium  of  the  urine  may  be  in 
excess  owing  to  a  destruction  of  the  body's  own  tissues. 

Calcium  and  Magnesium. — Since  the  larger  part  of  the  calcium  and 
magnesium  eliminated  are  excreted  in  the  feces  it  is  always  necessary  to 
have  data  on  the  fecal  excretion  of  these  elements  to  make  satisfactory  de- 
ductions (see  discussion  on  page  511).  Under  difFei'ent  conditions  of  diet 
the  calcium  excretion  in  the  urine  may  vary  from  0.1  to  0.5  gram  calcu- 
lated as  CaO,  and  the  magnesium  from  0.1  to  0.3  gram  calculated  as  MgO 
depending  upon  the  diet ;  sometimes  the  calcium  is  in  excess  in  the  urine 
and  sometimes  the  magnesium.  In  a  series  of  25  healthy  adults  Xelson 
and  Burns  found  the  calcium  in  excess  in  17  and  the  magnesium  in  8. 
The  figures  for  the  CaO  ranged  from  0.13  to  0.49  gram  and  for  the  MgO 
from  0.12  to  0.30.  In  this  connection  they  state  that  either  calcium  or 
magnesium  may  be  excreted  by  way  of  the  urine  in  the  larger  amount, 
in  the  normal  individual.  Whichever  element  predominates  does  so  con- 
stantly, or  ver)'  nearly  so,  and  seems  to  be  independent  of  the  character 
of  the  food  ingested.  The  excretion  of  calcium  and  magnesium  does  not 
necessarily  run  parallel  pathologically,  since  there  may  be  a  retention 
of  magnesium  in  certain  bone  disordei-s  accompanied  by  a  loss  of  calcium ; 
for  example,  osteomalacia.  Very  little  is  known,  however,  about  the 
pathological  excretion  of  these  elements.  The  lime  salts  absorbed  are  in 
great  part  excreted  again  into  the  intestine,  and  the  quantity  in  the  urine 
is  therefore  no  measure  of  their  absorption.  The  introduction  of  readily 
soluble  lime  salts  or  the  addition  of  hydrochloric  acid  to  the  food  may 
therefore  cause  an  increase  in  the  quantity  of  lime  in  the  urine,  while 
the  reverse  takes  place  on  the  addition  of  alkali  phosphate  to  the  food. 
In  other  words,  the  balance  between  the  acid-  and  base-forming  elements 
in  the  foods  has  a  very  important  bearing  upon  the  excretory  path  of  these 
elements  and  phosphorus. 

Iron. — Iron  exists  in  the  urine  only  in  very  small  amount  (1  to  5  mg. 
per  day)  and  that  in  organic  form.  It  is  largely  eliminated  by  the  intes- 
tine. 

Feces 

It  has  long  been  the  common  notion  that  feces  are  composed  of  the 
residues  of  undigested  food.  In  health,  however,  this  is  far  from  the 
truth.  It  is  easy  to  comprehend  that  the  nitrogenous  waste  products '  of 
the  urine  are  derived  from  the  catabolism  of  protein  in  the  body,  but 
since  the  intestinal  canal  is  a  long  tube  open  at  both  ends  through  w^hich 
undigested  material  may  pass,  it  has  been  difficult  to  appreciate  that 


504  VICTOR  C.  MYERS 

under  normal  conditions  the  feces  are  composed  largely  of  intestinal 
secretions  and  excretions,  together  with  bacteria,  cellular  material  from 
the  intestinal  walls  and  food  residues.  Fui-themiore  as  Mendel  (a)  and  his 
coworkers  have  shown,  the  feces  is  the  normal  path  for  the  elimination  of 
a  number  of  foreign  inorganic  elements,  sucli  as  strontium,  barium,  etc. 
As  a  proof  that  feces  are  a  true  secretion,  it  has  been  shown  by  F.  Voit 
that  the  material  secreted  in  an  isolated  loop  of  the  intestine  of  a  dog 
is  of  similar  composition,  and  contains  the  same  amount  of  nitrogen  as 
the  feces  of  the  nonnal  intestine  through  which  food  is  passing.  Espe- 
cially significant  are  the  observations  of  ^[osenjthal(a),  who  also  worked 
with  isolated  intestinal  loops,  and  estimated  that  the  succus  entericus  con- 
tained nitrogen  equivalent  to  35  per  cent  of  the  nitrogen  ingested,  and  300 
to  400  per  cent  of  the  nitrogen  of  the  feces.  Nitrogen  equivalent  to  at  least 
25  per  cent  of  that  of  the  intake  must  therefore  have  been  reabsorbed. 
Prausnitz  has  pointed  out  that  the  nitrogen  content  of  the  feces  of  the 
pame  indi\'idual  on  a  meat  and  on  a  rice  diet  are  practically  identical, 
indicatins:  the  metabolic  origin  of  the  nitrogen.  He  defines  normal  feces 
as  those  resulting  from  the  eating  of  any  food  that  is  completely  digested 
and  absorbed.  Such  foods  as  milk,  cheese,  rice,  eggs,  meat,  raacarojii  and 
white  bread  are  largely  available  for  the  use  cf  the  organism  and  conse- 
quently yield  a  comparatively  small  amount  of  feces.  On  the  other  hand, 
the  cellulose  containing  vegetables  do  not  possess  this  availability  and 
therefore  yield  a  much  more  copious  fecal  output.  Cabbage  is  an  excel- 
lent illustration  of  such  a  vegetable.  It  is  logical  to  expect  that  on  a  diet 
whose  constituents  are  not  entirely  available,  not  only  would  the  amount 
of  feces  be  increased  by  the  undigested  cellulose,  but  also  the  nitrogen 
content  would  be  increased  because  of  the  large  amount  of  digestive  juices 
secreted,  the  large  volume  of  food  and  the  accompanying  increased  peri- 
stalsis. Although  the  exact  composition  of  a  larae  part  of  the  organic 
material  eliminated  in  the  feces  is  unknown,  still  it  is  now  recognized  that 
bacterial  substance  fonns  a  considerable  part  of  this  material. 

The  fact  that  about  one-third  of  the  dry  matter  of  nonnal  human  feces 
consists  of  bacteria,  and  at  least  one-half  of  the  nitrogen  of  the  feces  is 
bacterial  in  its  origin,  serves  to  emphasize  the  importance  of  bacteria  in 
the  intestinal  canal,  though  experimental  evidence  would  indicate  that 
the  presence  of  this  large  number  of  bacteria  is  a  normal  and  even  useful 
condition.  ^lacXeal,  Latzer  and  Kerr,  who  have  devoted  considerable 
attention  to  the  bacterial  content  of  the  feces,  find  that  in  normal  subjects 
the  bacterial  dry  substance  varies  between  1.8  and  9.2  grams  with  an 
average  of  5.3  grams  per  day,  while  the  bacterial  nitrogen  ranges  between 
0.2  and  1.0  gram  with  an  average  of  0.6  gram,  this  latter  figure  constitut- 
ing 40.3  per  cent  of  the  fecal  nitrogen.  Of  the  fecal  bacteria  they  find 
that  80.7  per  cent  are  Gram  negative  (45.0  per  cent  B.  coli  type),  17.0 


EXCRETIONS  505 

per  cent  Gram  positive  and  2.3  per  cent  free  spores.  ^Fattill  and  nawk(a), 
who  x?mployed  the  MacN'eal  method  slightly  modified  (no  ether  extrac- 
tion used),  obtained  slightly  higher  results  oa  two  subjects  who  were 
followed  iur  several  weeks.  "Ihey  found  that  the  bacterial  nitrogen  aver- 
aged 5*i.l)  per  cent  of  the  fecal  nitrogen  and  the  bacterial  dry  "substance 
(S.27  grams.  Under  normal  conditions  the  bacteria  probably  derive  their 
sustenance  in  considerable  part  from  the  intestinal  secretions  and  excre- 
tions, but  pathologically  they  may  decompose  appreciable  amounts  of  par- 
tially digested  protein  and  carbohydrate. 

In  nurslings  the  bacterial  flora  is  relatively  simple,  though  later  in 
life  the  number  of  these  bacterial  forms  becomes  very  large.  The  dominant 
organism  in  nurslings  is  B.  hifidus  {B,  acidopliUus  of  More  is  also 
present),  but  this  is  ultimately  replaced  by  B.  coll  and  B,  lactis 
acrogenes.  Other  organisms  which  may  be  observed  are  coccal  forms, 
B,  ivelchii,  and  in  certain  cases,  B.  putrificus  (Herter(df)).  These  last  two 
organisms  Ilerter  is  inclined  to  associate  with  conditions  of  excessive  putre- 
faction in  the  intestines.  MacXeal  has  pointed  out,  however,  that  B. 
welchii  can  generally  be  detected  in  normal  stools.  In  early  life  the  prod- 
ucts of  intestinal  decomposition  are  very  small  in.  amount,  and,  as  would 
be  expected,  the  number  of  putrefactive  bacteria  are  few.  One  finds, 
however,  in  middle  life  a  large  number  of  persons  in  w^hom  the  putre- 
factive conditions  in  the  intestine  are  distinctly  more  active  than  was  the 
case  earlier  in  life.  Apparently  the  most  important  factors  in  bringing 
about  this  strongly  proteolyzing  type  of  bacterial  flora  are  the  consumption 
of  an  overabundance  of  protein  food,  combined  with  inadequacy  in  the 
digestive  juices,  delayed  absoi*ption,  and  insufficient  motility  in  the  ali- 
mentary canal.  Very  little  decomposition  takes  place  in  the  large  intes- 
tines under  the  action  of  B.  coll,  however,  if  the  absorption  in  the  small 
intestine  has  been  good.  Rettger  and  his  coworkers  have  recently  pointed 
out  that  the  daily  administration  of  150-300  grams  of  lactose  or  dextrin 
to  adults  will,  with  few  exceptions,  bring  about  a  marked  change  in  the 
bacterial  flora  in  which  the  usual  mixed  t^^pes  of  bacteria  give  way  to 
B,  acidophilus,  which  is  a  normal  intestinal  organism,  but  which  is  pi*es- 
ent  in  the  intestine  after  early  infancy  in  relatively  small  numbers  only. 
This  method  would  appear  to  possess  interesting  possibilities  of  thera- 
peutic usefulness. 

Amount. — Upon  the  ordinary  mixed  diet,  the  daily  fecal  excretion  of 
the  adult  male  averages  from  100  to  150  grams,  with  a  solid  content  vary- 
ing between  20  and  40  grams.  Upon  a  vegetable  diet  the  fecal  output 
will  be  much  greater,  reaching  350  grams  with  a  solid  content  of  75 
grams,  and  even  more.  This  being  the  case,  data  on  variations  in  the 
daily  excretion  are  of  little  practical  significance,  except  where  the  com- 
position of  the  diet  is  accurately  known.  Lesions  of  the  digestive  tract, 
a  defective  absorptive  function,  or  increased  peristalsis,  as  well  as  admix- 


500  VICTOR  C.  MYERS 

ture  of  mucus,  pus,  blood  and  pathological  products  of  the  intestinal  wall 
may  cause  the  total  amount  of  feces  to  be  markedly  increased. 

C(ytisUtencij, — The  form  and  consistency  of  the  feces  is  dependent,  in 
large  measure,  upon  the  nature  of  the  diet.  Under  normal  conditions  the 
consistency  may  vary  from  a  thin,  pasty  composition  to  a  fii-mly  formed 
stool.  Feces  which  are  exceedingly  thin  and  watery  generally  have  a  path- 
ological significance. 

Color. — The  fecal  pigment  of  the  normal  adult  is  hydrobiliruhin,  also 
called  stercobilin.  It  has  its  origin  in  the  bilirubin  of  the  bile,  being 
formed  by  the  reducing  action  of  certain  bacteria.  Hydrobilinibin  is 
probably  identical  with  the  urobilin  of  the  urine.  This  pigment  is  pres- 
ent in  both  the  urine  and  feces,  partly  in  the  form  of  its  chromogen, 
urobilinogen.  This  is  transformed  to  urobilin  under  the  action  of  light, 
j^ormally  hydrobilinibin  appears  to  be  largely  reabsorbed  and  converted 
to  bilirubin.  In  pernicious  anemia  the  destruction  of  red  cells  is  so  rapid 
that  it  cannot  be  reabsorbed,  thus  leading  to  a  marked  excretion  of  the 
reduced  pigment  in  the  stool,  a  very  valuable  point  in  the  differential 
diagnosis  of  primary  and  secondary  anemia.  (It  is  not  increased  in  sec- 
ondary anemia.)  In  certain  liver  diseases  there  is  sometimes  a  breakdown 
in  the  ability  to  reconvert  urobilin  to  bilirubin,  which  leads  to  the  appear- 
ance of  the  pigment  in  the  urine  in  abnomial  amounts.  Xeither  bilirubin 
nor  biliverdin  occur  noiTually  in  the  feces  of  adults,  although  bilirubin 
sometimes  occurs  in  the  stools  of  nursing  infants. 

The  diet  is  the  most  important  factor  in  determining  the  color  of  the 
feces.  On  a  mixed  diet  the  stools  may  vary  in  color  from  light  to  dark 
brown,  on  an  exclusive  meat  diet  the  stools  are  brownish  black,  while  on 
a  milk  diet  they  are  invariably  light  colored.  Cocoa  produces  reddish 
brown  feces,  while  with  certain  berries  the  feces  may  be  almost  black. 
Pathologically,  absence  of  bile,  or  any  condition  producing  a  large  amount 
of  fat,  gives  clay  colored  stools;  blood  from  the  upper  part  of  the  ali- 
mentary tract  yields  "tar  feces." 

Odor. — The  odor  of  nonnal  feces  is  generally  stated  to  be  due  to  skatol 
and  indol.  However,  these  aromatic  putrefactive  substances  are  generally 
found  in  such  small  amounts  as  to  be  an  insufficient  explanation  on  this 
point.  Hydrogen  sulphid  and  methylmercaptan  probably  play  a  certain 
part  in  the  disagreeable  character  of  the  odor.  The  intensity  of  the  odor 
depends  to  a  large  extent  upon  the  diet,  being  very  marked  in  stools  from  a 
meat  diet,  much  less  marked  in  stools  from  a  vegetable  diety  and  often 
hardly  detectable  on  stools  from  a  milk  diet.  The  stool  of  the  infant  is 
ordinarily  quite  odorless,  and  any  decided  odor  may  generally  be  traced 
to  some  pathological  source. 

A  simple  division  of  fecal  material  may  be  based  upon  the  separation 
afforded  by  the  customary  procedures,  viz.,  the  estimation  of  the  total 
nitrogen,  ethereal  extract,  carbohydrate  residues  and  ash.     The  results 


EXCKETIONS  607 

obtained  with  these  methods  have  yielded  data  of  great  scientific  impor- 
tance, though  the  time  required  and  the  nature  of  the  results  render 
them  of  comparatively  little  value  diagnostically. 

An  idea  of  the  approximate  composition  of  feces  in  the  normal  human 
adult  may  he  obtained  from  the  tabular  data  below.  Except  for  the 
moisture  cr>ntent,  the  percentage  figures  are  on  a  dry  basis. 

Grams  Per  Cent 

Moist  feces 120  . , 

Air  dry  feces 30 

Moisture  content 75 

Nitrogen 1.8  6 

Ether  extract 6.0  20 

Carbohydrate 1.0  3    • 

Ash 4.5  15 

Nitrogenous  Substances. — Three  sources  are  usually  considered  as 
contributinir  to  the  nitrogenous  material  excreted  in  the  feces;  food  resi- 
dues, residues  of  the  digestive  juices  and  cellular  material  from  the 
intestinal  wall,  and  bacteria  and  their  products.  The  quantity  of  this 
nitrogen  nonnally  amounts  to  from  one  to  two  grams  and  from  four  to 
eight  per  cent  of  the  dry  feces.  As  already  pointed  out  0.5  to  0.8  gram 
of  nitrogen  is  daily  eliminated  in  the  fonii  of  bacteria.  This  constitutes 
just  about  half  of  the  fecal  nitrogen  and  corresponds  almost  exactly  with 
what  is  ordinarily  spoken  of  as  the  ^^metabolic  nitrogen."  Upon  a  meat 
diet  the  food  residues  represent  almost  nothing  under  normal  conditions, 
i.  e.,  the  muscle  protein  is  practically  100  per  cent  utilized,  and  further- 
more the  fecal  nitrogen  is  almost  wholly  "metabolic"  in  origin.  In  the 
case  of  vegetable  proteins  it  has  been  a  matter  of  common  observation 
that  the  utilization  was  not  so  good  as  with  animal  proteins.  This  in 
part  at  least  is  explained  by  the  inaccessibility  of  certain  of  the  vegetable 
proteins  to  the  digestive  juices,  for  as  i^Iendel  and  Fine  have  shown,  the 
proteins  of  the  wheat,  and  probably  also  of  the  barley  and  corn,  are  as 
well  utilized  as  meat,  when  taken  in  pure  form  or  freed  from  extraneous 
cellular  substance.  With  legrnnes  the  utilization  does  not  appear  to  bo 
quite  so  good.  In  order  to  calculate  the  digestibility  of  various  proteins 
and  make  allowance  for  the  "metabolic  nitrogen"  Mendel  and  Fine  pro- 
pose the  fletennination  of  the  volume  and  nitrogen  of  feces  resulting  from 
the  material  under  investigation,  with  the  subsequent  determination  of 
the  fecal  nitrogen  resulting  from  a  nitrogen-free  diet  to  which  has  been 
i«dded  an  amount  of  indigestible  non-nitrogenous  matter  that  will  yield 
approximately  the  same  volume  of  feces  as  in  the  first  instance.  The 
excess  of  fecal  nitrogen  of  the  first  test  over  the  second  is  presumably  due 
to  the  undigested  or  unabsorbed  nitrogenous  matter  of  the  food  material. 


508  VICTOR  C.  MYERS 

With  regard  to  the  elimination  of  fecal  nitrogen  under  pathological 
conditions,  observations  show  that  it  is  increased  in  biliary  obstruction, 
intestinal  fermentative  dyspepsia,  and  diarrhea ;  and  decreased  in  chronic 
constipation. 

A  gi'eat  variety  of  substances  may  be  formed  by  bacterial  action  upon 
protein  or  its  cleavage  products.  Among  such  may  be  mentioned  indol, 
skatol,  phenol,  indol  acetic  acid,  various  oxyacids,  in  certain  instances, 
putrescin  and  cadaverin,  etc.  That  intoxication  may  result  from  poisonous 
products  formed  by  bacterial  action  can  hardly  be  questioned,  though 
just  what  the  substances  are  that  exert  this  action  cannot  be  stated  at 
the  present  time.  ^luch  attention  has  been  devoted  to  the  products  of 
bacterial  action  on  tryptophan,  viz.,  indol  acetic  acid  (urorosein  of 
urine),  skatol  and  indol.  Myers  and  Fine  found  comparatively  largt) 
amounts  of  skatol  and  indol  in  the  stools  of  pellagra  patients.  In  many 
of  the  patients  the  stools  were  rather  soft.  Ordinarily  skatol  appears 
to  be  observed  in  the  feces  much  less  frequently  than  indol,. but  the  reverse 
was  true  in  these  cases.  In  the  case  showing  the  most  severe  putrefaction, 
the  skatol  of  the  feces  averaged  51  mg.  and  the  indol  21  mg.  per  day. 
The  indican  of  the  urine  was  much  lower  in  this  case  than  in  several  other 
subjects  who  excreted  much  smaller  amounts  of  skatol  and  indol  in  the 
feces.  It  seems  questionable  whether  the  skatol  and  indol  in  the  amounts 
absorbed  in  this  way  have  any  toxic  properties.  The  presence  of  large 
amounts  cf  indican  in  the  urine,  however,  is  excellent  evidence  of  in- 
creased intestinal  putrefaction. 

Ethereal  Extract. — The  bodies  which  go  to  make  up  this  ethereal 
extract  are  the  neutral  fats,  free  fatty  acids  (and  fatty  acids  in  the  fonn 
of  soaps  when  an  acidified  solvent  has  been  employed),  and  coprostcrol 
(stercorin  of  Flint)  formed  from  cholesterol  by  the  action  of  reducing 
bacteria,  flyers  and  Wardell  found  the  coprosterol  (and  cholesterol)  of 
dry  feces  to  vary  between  0.5  and  1.5  per  cent,  the  high  figures  being 
found  in  soft  stools.  The  ethereal  extract  ordinarily  fcims  from  12  to 
25  per  cent  of  the  dry  weight  of  the  feces.  The  utilization  of  fat  varies 
under  normal  conditions  from  90  to  05  per  cent,  depending  upon  the 
source  of  food.  The  higher  fats  such  as  stearin  are  much  less  readily 
assimilated.  In  biliary  obstruction  as  much  as  70  grams  of  fat  may  be 
eliminated  in  the  feces,  forming  50  per  cent  of  the  drv  weight  of  the 
material.  In  various  conditions  associated  with  defective  fat  digestion 
(pancreatic  disease)  or  defective  fat  absoi*ption  increased  amounts  may 
be  eliminated,  while  in  chronic  constipation  the  amount  may  be  decreased. 
In  both  biliary  obstruction  and  pancreatic  disease  the  fat  utilization  has 
leen  found  to  be  as  low  as  25  per  cent. 

Carbohydrate  Residues, — Normally  feces  may  yield  on  hydrolysis 
reducing  substances  equivalent  to  from  one-half  to  two  grams  of  glucose 
or  from  two  to  six  per  cent  of  the  dry  weight  of  the  feces.    Although  the 


EXCRETIONS  50a 

utilization  of  carbohydrate  has  generally  been  given  as  about  08  per  cent, 
it  is  evident  from  tliese  figures  that  on  a  diet  of  »500  to  400  grams  carbo- 
hydrate it  is  above  DJ)  per  cent.  As  Langworthy  and  Denel  have  recently 
pointed  out,  contrary  to  the  general  assumption,  even  raw  starch  may  be 
quite  well  utilized.  Ordinarily  starch  digestion  does  not  seem  to  be  inter- 
fered with,  though  the  amount  of  carbohydrate  eliminated  in  the  severer 
catarrhal  conditions  of  the  intestine  may  be  slightly  increased.  One- 
question  to  be  asked  with  regard  to  all  carbohydrate  material  is,  are  the 
enz\ines  of  the  alimentary  canal  capable  of  hydrolyzing  it  ?  As  Mendel 
and  certain  of  his  pupils  have  pointed  out,  there  appear  to  be  no  enzymes 
in  the  digestive  tract  capable  of  attacking  certain  of  the  more  complex  car- 
bohydrates, such  as  agar  agar,  Iceland  moss,  inulin,  certain  galactans,  etc. 

Ash. — The  inorganic  constituents  of  the  feces  are  derived  partly  from 
the  intestinal  secretions  and  partly  from  the  food.  The  proportion  which 
comes  from  the  food  varies  with  the  nature  of  the  diet.  A  purely  meat 
diet  results  in  a  lowering  of  the  ash  content  of  the  feces,  while  with  a 
inilk  diet  the  ash  is  increased,  owing  to  the  presence  of  unabsorbed  lime. 
On  an  ordinary  mixed  diet  the  ash  of  the  feces  generally  falls  between 
10  and  15  per  cent  of  the  dry  weight,  but  on  a  milk  diet  values  of  25  to 
35  per  cent  are  found,  about  40  per  cent  of  wliich  is  due  to  calcium. 
PathologicaHy,  Cammidge  has  occasionally  observed  cases  of  chronic 
colitis  in  which  as  much  as  45  to  50  per  cent  of  the  dry  weight  of  the 
feces  consisted  of  inorganic  ash. 

A  general  idea  of  the  composition  of  human  feces  may  be  obtained 
from  the  table  on  the  next  page  taken  from  Myers  and  Fine,  giving  the 
fecal  analyses  of  a  series  of  pellagra  patients.  Except  for  Case  5  (a  male) 
the  patients  were  all  rather  small  women.  It  is  not  believed  that  the 
findings  differ  very  materially  from  what  would  be  found  in  other  hospital 
cases  on  similar  diets,  and  with  similar  fecal  movements.  The  cases  have 
been  divided  into  two  groups,  the  first  group  having  well  fonued  stools, 
and  the  second  group  soft  or  diarrheal  stools.  The  diet  in  all  cases  w^as 
lactovegetarian,  which  probably  explains  the  rather  high  ash  figures  ob- 
tained. Estimations  of  iron  and  sodium  were  not  made.  The  figures 
recorded  in  the  literature  for  the  daily  excretion  of  sodium  (as  Xa^O) 
in  the  feces  amount  to  0.25  to  0.-35  gram,  and  for  iron  (as  FeO) 
to  25  to  40  mg.  (The  daily  excretion  of  iron  in  the  urine  varies  from 
1  to  5  mg.)  An  idea  of  the  comparative  importance  of  the  intestines 
and  kidneys  as  paths  for  the  elimination  of  various  elements  may  be 
obtained  from  the  table  on  page  511.  The  figures  ai'e  computed  from  the 
previous  table  and  urinary  data  for  the  same  period. 

An  inspection  of  the  table  shows  that  in  the  first  group  of  cases  the 
total  nitrogen  and  total  sulphur  parallel  each  other  very  closely,  as  prob- 
ably might  be  expected  from  their  common  origin  (protein).  With  diar- 
rhea, sulphur  does  not  appear  to  be  quite  as  well  absorbed  as  the  nitrogen. 


510 


VICTOK  C.  MY-ERS 


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4 

EXCRETIONS 


511 


Comparative  Importance  of  the  Intestink  a.xd  Kidneys  as  Excretoky  Ciiaxxels 


Case 

Percentage  Output  of  Material  Eliminated  in  Feces 
of  Total  Output  of  Both  Urine  and  Feces 

H/J 

N 

S 

CI 

P 

Ca 

Mg   1    K 

1.     M.  F.    (b)      

7 
4 
6 
6 
8 

13 

7 

6 

14 

10 

10 

9 
7 

10 
15 
10 

3 
2 
2 

t 

33 
43 
28 
40 
35 

90 
92 
89 
88 
89 

76 
83 
69 
66 
65 

23 

2.  M.   L 

3.  M.  F.   (a)    

18 

4.  C.    T 

5.  J.    A 

IS 

20 

Averao-es    

6 

10 

3 

36 

90 

72 

18 

6.  E.   C 

7.  A.  N.   

8.  M.  T 

9.  M.   McH.    (a)     

7 
6 
7 

14 
20 
13 
33 
17 
32 

18 
10 
12 
8 
22 
14 
21 
11 
21 

19 
10 
15 
12 
29 
18 
26 
15 
26 

8 
7 
5 

13 
9 
4 

18 
7 

16 

35 
23 
27 
31 
35 
44 
33 
30 
42 

80 
90 
85 
85 
94 
93 
92 
81 
92 

89 

46 
59 
54 
60 
74 
81 
84 
77 
77 

68 

28 
28 
11 
34 

10.  R.  N 

11.  L.   G 

12.  M.   McH.    (b)     

24 
30 
29 

13.  M.  S 

14.  B.  B '. .. 

24 
38 

Averages    

16 

15 

19 

9 

33 

27 

Although  normally  very  little  chlorid  is  eliminated  by  the  intestine,  the 
amount  found  in  the  stools  may  be  considerably  increased  in  diarrhea. 
About  one-third  of  the  total  phosphorus  output  of  the  intestine  aud 
kidneys  is  found  in  the  stools.  The  percentage  output  in  the  feces  of 
both  calcium  and  magnesium  is  high,  due  probably  to  the  lactovegetarian 
diet,  which  resulted  in  a  poor  absorption  of  compounds  of  these  elements. 
On  a  mixed  diet  about  60  per  cent  of  both  calcium  and  magnesium  are 
ordinarily  eliminated  in  the  feces  of  adults,  although  on  milk  diets  the 
stools  of  infants  may  contain  considerably  more  than  90  per  cent  of 
these  elements.  As  might  be  anticipated  from  our  knowledge  of  potassium 
salts,  a  very  appreciable  amount  of  this  element  is  eliminated  in  the 
feces,  and  diarrhea  considerably  accentuates  this  elimination.  Although 
diarrhea  very  definitely  reduces  the  absorption  of  nitrogen,  sulphur, 
chlorin  and  p(^tassium,  it  appears  to  be  almost  'without  influence  on  the 
phosphorus,  calcium  and  magnesium. 

It  is  evident,  therefore,  that  calcium,  magnesium  and  iron  are  nor- 
mally eliminated  chiefly  by  the  intestine.  Failure  of  absorption  is  par- 
tially responsible  for  this,  but  in  part  these  elements  are  secreted  into  the 
intestines,  as  are  such  similar  elements  as  strontium  and  barium  (Mendel). 
The  elimination  of  calcium  and  phosphorus  are  interrelated  both  as  to 
total  excretion  and  path  of  elimination.  An  increased  ingestion  of  either 
causes  an  increased  elimination  of  the  other  at  the  expense  of  the  body's 
store,  if  necessary.  Proportionate  increase  in  the  intake  of  both  increases 
the  fecal  excretion.  Marked  deviation  in  the  balance  of  calcium  and 
phosphorus  partially  diverts  the  elimination  of  the  more  abundant  through 


512  VICTOR  C.  MYERS 

(he  kidney.    The  excretion  of  magnesium  and  calcium  are  likewise  inter- 
related. 

Sweat 

Next  to  the  kidneys,  the  skin  is,  in  man,  the  most  important  channel 
for  the  elimination  of  water.  The  volume  eliminated  varies  widely  under 
(litferent  physiological  and  pathological  conditions.  Obviously  the  elimi- 
nation in  warm  w^eat her  is  much  greater  than  in  cold  weather,  also  during 
muscular  activity  than  during  rest.  The  specific  gravity  varies  between 
1.001  and  1.015,  ordinarily  amounting  to  about  one-half  the  latter  figure. 
The  solids  range  from  about  0.4  to  2.0  per  cent.  The  reaction  may  be  acid, 
neutral  or  alkaline  to  litmus,  although  under  normal  conditions  it  is  most 
often  acid.    Protein  is  generally  present  in  traces. 

The  skin  excretes,  qualitatively,  practically  the  same  substances  as 
occur  in  the  urine,  namely,  urea,  ammonia,  uric  acid,  amino-acids,  crea- 
tinin,  chlorids,  phosphates  and  sulphates.  Probably  for  this  reason  it 
has  been  more  or  less  generally  accepted  that  the  skin  and  kidneys  can 
act,  to  a  certain  extent,  vicariously.  At  one  time  the  use  of  sweat-baths 
in  the  treatment  of  nephritis  was  common.  The  quantity  of  substances 
excreted  by  the  skin,  however-,  is  quite  insignificant  in  comparison  to  that 
excreted  by  the  kidney.  In  addition  to  their  power  to  excrete  water,  the 
sweat  glands  do  appear  to  possess  the  power  of  excreting  salt,  the  quautity 
of  sodium  chlorid  amounting  to  from  0.2  to  0.5  per  cent. 

A  variety  of  methods  have  been  employed  to  collect  sweat.  Probably 
the  most  satisfactory  procedure  is  to  place  the  patient  in  st  rubber  bag 
during  the  sweating  period.  Sweat  obtained  in  this  way  is  a  cloudy, 
nearly  colorless  liquid,  w^iich  settles  or  filters  nearly  or  perfectly  clear. 
In  the  comparatively  recent  experiments  of  Riggs,  and  Plaggemeyer  and 
Marshall  this  was  the  method  employed.  In  his  work  on  the  cutaneous 
excretion  of  nitrogen,  where  an  attempt  was  made  to  determine  th.e 
twenty-four  hour  excretion,  Benedict  extracted  the  nitrogen  from  specially 
prepared  undei'wear. 

An  idea  of  the  composition  of  sweat  obtained  from  normal  subjects 
and  nephritic  patients  may  be  obtained  from  the  table  on  the  next  page 
compiled  from  the  observ^ations  of  Riggs.  The  sweat  was  obtained  by 
placing  the  subject  without  clothing  in  a  rubber  bag  which  enclosed  the 
entire  body  except  the  head.  Sweating  was  induced  by  covering  with  a 
pack  of  hot  blankets  for  thirty  to  forty-five  minutes. 

The  observations  on  the  nephritic  patients  are  not  especially  signifi- 
cant. It  is  of  interest,  however,  that  in  the  first  two  cases  where  the 
volume  of  sweat  is  large  the  percentage  of  nitrogen  is  low  and  the  chlo- 
rids high,  whereas  in  the  last  two  cases  where  the  volume  is  small,  the 
reverse  is  true. 


EXCKETIO^rS 


51S 


COMPOSITIOX  OF    TIUilAN    SwtLiT 


Specimen  and  Subject 


1.  Normal    

2.  Normal     

3.  Normal     

4.  Normal     

5.  Normal    

6.  Normal     

7-16.     Nephritic    on    rcgulai 

diet    

17-23.     Nephritic    

24-26.     Nephritic    

27-29.     Nephritic   


Quan- 

tity 

Total 

c.c. 

% 

216 

0.074 

117 

0.077 

246 

0.050 

«6 
170 

0.126 
0.085 

140 

0.083 

324 

0.064 

221 

0.077 

90 

0.215 

77 

0.158 

Nitrogen 


Ammonia 


0.006 
0.0C7 
0.007 
0.007 
0.006 
0.006 


L'rea 


% 
0.035 
0.049 
0.026 
0.060 
0.040 
0.040 


0.054 
0.054 

6.  lie 


Urea 
Plus  Am- 
monia 
Nitrogen 
Terms  of 
Total  N 

% 
57 
73 
66 
60 
58 
55 

82 
69 

65 


Total 
Solids 


0.49 
0.51 
0.30 
0.59 
0.56 
0.55 

0.52 
0.65 
0.24 
0.43 


Sodium 
Chlorid 


0.3C 
0.34 
0.25 
0.36 
0.33 
0.35 

0.46 
0.53 
0.12 
0.15 


The  total  nitrogen  content  of  sweat  appears  to  vary  from  0.05  to  0.20 
per  cent,  from  50  to  80  per  cent  being  in  the  form  of  urea  and  ammonia. 
According  to  the  obsei-vations  of  Benedict  (a)  the  average  daily  loss  of 
nitrogen  in  the  perspiration  when  the  subject  perfonns  no  muscular  work 
amounts  to  0.07  gram,  but  during  hard  muscular  work  as  much  as  0.2 
gram  may  be  excreted  in  a  single  hour. 

From  the  data  of  both  Riggs  and  Plaggemeyer  and  Marshall  the  urea 
<H  content  of  sweat  appears  to  amount  in  round  numbers  to  0.1  per  cent. 
As  the  latter  workers  have  pointed  out,  the  relationship  between  the  differ- 
ent forms  of  nitrogen  in  sweat  and  urine  are  entirely  different.  The  con- 
centration of  urea  in  sweat  is  from  three  to  ten  times  as  high  as  that  of 
the  blood  but  only  one-tenth  the  concentration  in  the  urine. 

Uric  acid  occurs  in  sweat  in  much  smaller  amounts  than  in  either  blood 
or  urine,  the  concentration  being  about  one-twentieth  that  in  blood  and 
one-five-hundredth  that  in  urine.  If  creatinin  is  present  it  exists  in  very 
small  amounts. 

The  gi-eater  part  of  the  total  solids  is  made  up  of  sodium  chlorid, 
although  according  to  the  observations  of  Riggs  sufficient  potassium  is 
nresent  to  combine  with  twenty  per  cent  of  the  chlorin.  For  example, 
with  a  ^solid  content  of  0.5  per  cent  one  might  expect  a  salt  content  of 
0.35  per  cent.  The  salt  excreted  in  the  sweat  may  readily  amount  under 
certain  conditions  to  two  or  three  gTams  per  day,  a  quantity  ten  times 
that  normally  present  in  the  feces.    Phosphates  are  present  only  in  traces. 

A  diastatic  ferment  is  present  in  the  sweat  in  appreciable  amount. 
Such  dyes  as  phenolsulphonephthalein  are  not  excreted  by  the  skin  nor  does 
the  injection  of  phlorhizin  result  in  the  excretion  of  sugar  by  the  sweat 
glands. 


SECTION  V 


Normal  Processes  of  Energy  Metabolism 

John  R,  Murlin 

Indirect  Calorimetry — Methods  of  Pleasuring  the  Respiratory  Exchange  by 
Means  of  a  Respiration  Chamber — Methods  for  Measuring  the  Respira- 
tory Exchange  by  Direct  Connection  with  the  Respiratory  Passages — 
Methods  of  Calculating  the  Heat  Production  from  the  Respiratory  Ex- 
change— The  Xon-protein  Respiratory  Quotient — Direct  Calorimetry — 
The  Heat  of  Combustion — Animal  Calorimetry — Basic  Principles  of 
Energy  Metabolism — The  Energy  of  Muscular  Work  Is  Definitely  Re- 
lated to  the  Potential  Energy  of  the  Food — The  Energy  Metabolism  Is 
Determined  in  Part  by  the  Environing  Temperature — The  Indigestion 
of  Food  Increases  the  Metabolism — Basal  Metabolism — Energ)-  Metab- 
olism of  Growth — Energy  ^letabolism  of  Pregnancy — Energy  Metab- 
olism of  the  Xewborn  Infant — Energy  Metabolism  from  Two  Weeks  to 
One  Year  of  Age — Energy  ^Metabolism  of  Children  up  to  Puberty — 
— Energy  Metabolism  of  Old  Age. 


Normal  Processes  of  Energy 
Metabolism 


JOHN  E.  MUELIN 

ROCHESTER 

It  is  a  familiar  fact  that  the  temperature  of  what  we  call  "warm- 
blooded^' animals  is  not  only  several  degrees  higher  than  the  average  tem- 
perature of  the  atmosphere,  but  it  is  held  constantly  at  this  level  despite 
fluctuations  of  the  environing  temperature.  So-called  "cold-blooded^'  ani- 
mals likewise  produce  heat,  the  difference  being  that  in  these  the  body 
temperature  is  not  regulated  but  is  dependent  upon  the  external  temper- 
ature. All  animals  therefore  are  transformers  of  energy.  In  fact  experi- 
ence and  theory  are  in  accord  in  regarding  the  production  of  heat  as  a  necesr 
sary  consequence  of  the  phenomena  of  life;  it  is  a  sign,  indeed,  of  vital 
activity. 

There  are  two  general  methods  of  measuring  the  production  of  heat: 
(1)  by  determining  the  intensity  of  the  chemical  processes  (combustion) 
by  which  heat  is  liberated  in  the  organism ;  and  (2)  by  registering  directly 
the  heat  disengaged  by  the  organism  in  a  calorimeter.  The  first  is  known 
as  the  indirect  or  chemical  method;  the  second,  the  direct  or  physical 
method. 

A.    Indirect  Calorimetry 

The  indirect  or  chemical  method  depends  upon  the  successful  measure- 
ment of  the  respiratory  exchange.  We  must,  therefore,  consider  at 
some  length  the  technology  of  this  subject.  In  the  meantime  it  may 
be  stated  that  the  indirect  method  of  calorimetry  offers  certain  ad- 
vantages over  the  direct  method.  When  the  latter  subject  is  con- 
sidered (page  567)  it  will  be  evident  that  in  order  to  measure  all  of  the 
heat  discharged  from  the  animal  body  by  the  several  routes  of  escape  a 
rather  complicated  apparatus  is  necessary.  In  time  this  may  be  simplified, 
but  at  present  an  accurate  calorimeter  is  far  more  complex  and  far  more 
costly  both  in  initial  cost  and  for  operation  than  a  respiration  machine. 
Secondly,  the  indirect  method  is  more  accurate  as  matters  now  stand. 
Krogh(c)  finds  that  he  can  measure  oxygen  absorption  with  his  micro- 
respiration  apparatus  to  an  accuracy  of  2  cu.nmi.  of  Oo,  equivalent  to  10 

515 


^.>- 


516  JOHN  K.  MUELIN 

milligi-am-calories  in  ten  hours,  while  the  highest  accuracy  attainable  by 
Bohr  and  Ilasselbalch  with  their  egg  calorimeter  was  100  milligram-calo- 
ries. The  percentage  difference  is  not  so  great  as  this  in  applying  the  two 
methods  simultaneously  to  the  study  of  the  human  organism;  but  one 
comes  very  soon  to  rely  upon  the  indirect  measurement  more  than  the 
direct  (see  page  580).  Furthermore,  and  in  the  third  place  the  two  meth- 
ods agree  very  closely  in  the  best  forms  of  respiration  calorimeters.  This 
being  true  and  the  indirect  method  being  both  simpler  and  more  reliable, 
greater  space  will  be  given  to  its  description  and  to  the  methods  of  calcu- 
lating energy  production  from  the  fundamental  data,  than  for  the  direct 
method. 

I.    Methods  of  Measuring  the  Respiratory  Exchange 
by  Means  of  a  Respiration  Chamber 

The  methods  of  measuring  respiratory  metabolism  are  of  two  general 
kinds:  (a)  one  requiring  a  chamber  in  which  the  subject  is  confined,  and 
(b)  a  method  so  devised  that  the  respiratory  passages  are  connected  di- 
rectly with  the  measuring  apparatus. 

Two  general  types  of  ventilation  also  have  been  used,  one  known  as  the 
open-circuit  and  the  other  as  the  closed-circuit  type.  The  classical  instance 
of  the  first  type  is  the  apparatus  of  Pettenkofer  first  described  in  1863  and 
later  improved  by  C.  Voit.  The  classical  instance  of  the  closed-circuit  type 
is  the  Regnault-Eeiset  apparatus  first  described  in  1849.  Only  the  more 
important  constructions  of  each  type  will  be  described  here. 

1.  Open-circuit  Tjrpe  of  Apparatus. — a.  Pette^ihofer  Apparatus. — 
The  original  apparatus  of  Pettenkofer  consisted  of  a  chamber  containing 
12.7  cubic  meters  which  was  ventilated  by  means  of  air  pumps  drawing 
air  from  the  outside.  The  air  was  aspirated  through  the  chamber  and  at 
the  point  of  exit  samples  were  measured  after  having  been  passed  through 
pumice  stone  saturated  with  sulphuric  acid  thence  through  barium  hydrate 
for  the  absorption  of  the  carbon  dioxid.  In  the  earliest  experiments  per- 
formed with  the  apparatus  by  Pettenkofer  the  efficiency  of  the  absorption 
system  was  checked  by  burning  candles  in  the  apparatus  and  an  error  of 
1.96  per  cent  was  found  as  the  average  for  a  considerable  number  of  tests. 
The  error  on  the  water  absorption  was  somewhat  higher,  varying  from  2.5 
to  3.5  per  cent. 

This  apparatus  was  used  exclusively  with  the  human  subject.  For 
obtaining  the  oxygen  absorption  Pettenkofer  and  Voit(c)  employed  the  fol- 
lowing method :  Adding  to  the  original  weight  of  the  subject  the  amount 
of  food  consumed  and  the  amount  of  water  drunk  a  sum  was  obtained  which 
was  subtracted  from  the  final  weight  of  the  subject  plus  all  of  the  excreta 
(urine,  feces,  carbon  dioxid  and  water  vapor).  The  difference  between 
these  two  sums  was  taken  as  the  oxygen  absorption. 


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518  JOHN  R  MUKLm 

In  the  modified  form  of  apparatus  devised  by  Yoit(d)  for  experiments 
on  small  animals  the  suction  pumps  were  replaced  by  a  largo  meter  driven 
by  a  water  wheel  which  served  at  once  to  aspirate  the  air  through  the  cham- 
ber and  to  measure  its  volume.  The  chamber  devised  by  Voit  was  of  small 
capacity  containing  only  64  liters.  Larger  chambers,  however,  were  used 
as,  for  example,  the  chamber  in  the  accompanying  figure  which  had  a  ca- 
pacity of  340  liters. 

The  construction  of  the  small  suction  pumps  also  was  somewhat  modi- 
fied in  the  Voit  construction  and  a  very  useful  type  of  valve  with  mercury 
seal  known  as  the  Voit  valve  was  employed  to  give  direction  to  the  air 
sample.  (See  figure  1.)  With  this  type  of  apparatus  in  five  control  ex- 
periments in  which  pure  olein  was  burned  in  the  form  of  a  candle  or  tal- 
low dip,  an  average  error  of  1.75  per  cent  was  found  for  the  CO2,  and  for 
the  absorption  of  water  an  error  which  varied  from  1.4  to  5.5  per  cent. 

\Volpert(a)  working  under  the  direction  of  Rubner  also  made  some 
improvements  on  the  Pettenkofer  type  of  apparatus.  His  chamber 
measured  1.5  x  2.5  x  2  meters  with  a  cubic  capacity  of  7.5  cubic 
meters.  The  measuring  drum  was  driven  by  means  of  a  water  motor. 
The  apparatus  differed  otherwise  in  only  minor  details  from  the  Voit 
construction,  but  Rubner(y)  succeeded  in  measuring  the  water  vapor 
with  a  much  greater  degree  of  accuracy. 

b.  The  Apparatus  of  Sonden  and  Tigerstedt. — This  apparatus  erected 
at  Stockholm  and  first  described  in  1895  was  so  constructed  as  to  accommo- 
date a  number  of  individuals  employed  as  subjects  at  the  same  time.  The 
chamber  consisted  of  a  room  measuring  5x5x4  meters  and  had  a  total 
capacity  of  approximately  100  cubic  meters.  The  walls  were  sealed  with 
sheet  metal  carefully  soldered  together  and  the  room  was  ventilated  through 
a  zinc  pipe  measuring  14  cm.  in  diameter  which  was  carried  up  above 
the  roof  of  the  room  and  cappecl  with  a  ventilator  containing  a  valve  to 
guard  against  aspiration  of  air  from  the  room  by  action  of  the  wind.  The 
room  was  heated  by  steam  and  the  air  was  kept  stirred  by  means  of  an 
electric  fan.  Ventilation  was  accomplished  by  means  of  pumps  gauged 
to  three  different  speeds  which  could  be  adapted  to  the  numbei'  of  indi- 
viduals serving  as  subjects.  Samples  of  air  were  withdrawn  from  the 
exit  tube  near  its  mouth  and  were  analyzed  by  means  of  the  Son  den-Pet  ter- 
son  apparatus.  Check  experiments  with  burning  candles  or  }>etroleura 
gave  an  average  error  of  1.10  per  cent  on  the  CO2.  In  other  series  of  ex- 
periments performed  later  by  Rosenberg  the  error  was  reduced  to  1  pei 
cent.  This  apparatus  and  a  later  one  on  the  same  principle  at  ITelsingfors 
( Tigerstedt  (^))  have  been  used  especially  for  the  study  of  metabolism  in 
school  children. 

c.  The  Apparatus  of  Ativater  and  Rosa, — This  apparatus  constnicted 
with  the  aid  of  the  U.  S.  government  in  the  chemical  laborator^^  at  Wesley- 
an  University,  Middletown,  Conn.,  was  first  described  in  1897.     It  con- 


KOEMAL  PROCESSES  OF  ENERGY  METABOLISM     519 

sisted  of  a  chamber  2.15  x  1.22  x  1.92  meters  or  a  cubic  capacity  of  5.03 
cubic  meters.  It  wa3  ventilated  by  means  of  a  so-called  Blakeslee  pump  of 
a  reciprocating  type.  By  means  of  a  toothed  wheel  containing  100  teeth, 
the  firat  and  fiftieth  of  which  were  longer  than  the  others,  samples  of  air 
could  be  diverted  from  the  main  stream  at  each  fiftieth  stroke  of  the  pump. 
These  samples  were  collected  in  pans  for  analysis. 

The  apparatus  was  not  long  used  in  this  form.  Realization  of  the 
necessity  for  accurate  determination  of  the  oxygen  absorption  led  to  its 
modification  to  the  closed-circuit  type  as  will  be  described  later. 

The  apparatus  was  at  once  a  respiration  chamber  and  a  calorimeter  for 
direct  measurement  of  the  heat.  The  method  of  heat  measurement  will 
be  described  in  a  later  section. 

d.  Apparatus  of  Jaquet. — This  apparatus  in  its  original  form  has  a 
cubic  capacity  of  1393  liters.  The  subject  can  either  sit  or  lie  down  during 
the  observation.  It  is  ventilated  by  means  of  a  bellows  driven  by  a  water 
motor,  the  air  being  withdrawn  from  one  end  through  an  exit  tube  and 
being  replaced  by  pure  air  from  the  outside  which  enters  at  the  other  end. 
The  air  is  passed  through  a  gas 'meter  after  withdrawal  from  the  apparatus. 
Samples  are  aspirated  from  the  exit  tube  by  means  of  a  mercury  pipette, 
the  leveling  bulb  being  lowered  by  means  of  a  pulley  connected  with  the 
axle  of  the  measuring  meter  so  that  the  rate  of  sampling  is  proportional 
to  the  rate  of  ventilation. 

The  air  analyses  for  COg  and  O2  are  accomplished  by  means  of  the 
Petterson  apparatus. 

Precaution  against  change  of  composition  of  air  in  the  apparatus  is 
taken  by  analysis  of  the  air  just  before  the  beginning  and  just  at  the  end 
of  an  observation  period. 

By  burning  alcohol  in  the  appai'atus  an  average  error  of  1.8  per  cent 
was  attained.  An  experimental  period  could  be  prolonged  with  this  ap- 
j)aratus  for  some  12  to  13  hours. 

e.  Apparatus  of  E.  Grafe(h). — This  is  a  modification  of  the  Jaquet 
type  of  apparatus  so  constructed  as  to  accommodate  a  man  in  a  standing, 
sitting  or  lying  position.  The  respiration  chamber  consists  of  a  rectangu- 
lar base  bordered  by  a  groove  into  which  the  superstructure  of  the  chamber 
is  made  to  fit  air-tight  by  means  of  a  liquid  seal.  The  whole  upper  part  of 
the  chamber  is  suspended  from  the  ceiling  of  the  room  by  means  of  pulleys 
and  a  counterpoised  weight.  Entrance  to  the  apparatus  is  gained  by  rais- 
ing one  end  of  the  superstructure.  The  rectangular  section  of  the  ap- 
paratus measures  0.9  meter  at  the  head  and  foot  ends  and  2  meters  in 
length.  In  the  vertical  section  one  end  is  higher  than  the  other,  measuring 
1.7  meters  at  the  head  end  and  0.75  meter  at  the  foot  end.  The  frame 
is  constructed  of  wood  covered  with  sheet  metal  painted  with  an  oil  paint. 

Ventilation  of  this  apparatus  is  accomplished  in  exactly  the  same  man- 
ner as  in  the  original  Jaquet  construction,  air  being  drawn  through  and 


520 


JOHX  R  MURLI]tT 


measured  simultaneously  by  means  of  a  gas  meter  driven  by  water  power. 
Samples  taken  by  the  aliquot  method  of  Jaquefc  are  analyzed  for  oxygen 
and  COo  by  means  of  the  Petterson  analyser. 

The  apparatus  used  by  Krogh  and  Lindhard  at  Copenliagen  is  of  the 
Jaquet-CJrafe  type  (Fig.  2). 

f.  Apparatus  of  JIaldane{a). — A  convenient  form  of  open  circuit  type 
of  apparatus  devised  for  observations  on  small  animals  is  that  of  Haldane 
described  in  1892.  The  respiration  chamber  (Figure  3)  consists  of  a  large 


Fig.  2.  Diagram  of  the  Jaquet-Grafe  respiration  apparatus  used  by  Krogh  and 
Lindhard.  The  floor  is  made  from  a  single  sheet  of  galvanized  iron  with  the  edges 
bent  down  into  a  U-shaped  rectangular  groove  (1)  which  is  filled  with  water.  As 
shown  at  (2)  one  end  can  be  lifted  to  let  in  the  subject  and  put  in  the  apparatus; 
(3)  small  tubes  introducing  wires,  etc.,  for  the  working  of  the  ergometer:  (4  and  5) 
ventilating  tubes  for  use  with  a  meter;  (6)  inlet  for  outside  air;  (7)  side  tubes 
drawing  air  from  points  50  cm.  from  the  outlet;  (9  and  10)  fans  for  mixing  the  air; 
<11)  wet  and  dry  bulb  thermometers;  (12)  bottle  of  water  keeping  water  level  in 
the  meter;  ( 1.3)  hand  sampling  apparatus;  (14)  automatic  sampling  apparatus;  (15) 
tube  leading  from  outlet  to  the  automatic  sampling  apparatus;  (16)  thermometer  in 
the  meter. 


bottle  of  16  liters  capacity.  Air  is  aspirated  through  the  bottle  by  means 
of  an  ordinary  laboratory  water  suction  pump.  The  ingoing  air  is  passed 
over  sulphuric  aeid  in  pumice  stone  and  another  bottle  containing  soda 
lime.  The  outgoing  air  is  likewise  passed  through  three  absorbers,  the  first 
containing  sulphuric  acid,  the  second  soda  lime  and  the  third  sulphuric 
acid.  The  gain  in  weight  of  the  first  gives  the  amount  of  water  vapor 
exhaled  by  the  animal.  The  gain  in  weight  of  the  second  two  gives  the 
amount  of  carbon  dioxid  exhaled.  After  passing  the  absorbers  the  air  is 
again  saturated  with  moisture  and  measured  by  a  gas  meter. 

The  apparatus  is  of  such  a  size  that  the  chamber  with  the  contained 
animal  can  be  weighed.     Loss  in  weight  of  the  animal  during  an  experi- 


KORMAL  PROCESSES  OF  ENERGY  METABOLISM     521 


ment  less  the  gain  in  weight  of  the  absorbers  gives  the  amount  of  oxygen 
absorbed. 

2.  Closed  Circuit  Type  of  Apparatus. — In  most  of  the  open-circuit 
types  of  apparatus  thus  far  described  the  determination  of  oxygen  is  in- 
direct, being  based  upon  the  loss  of  body  weight  of  the  subject.  The  absorp- 
tion of  oxygen  can  bo  detennined  directly,  however,  provided  the  subject  Ls 
enclosed  in  an  air-tight  system  of  known  capacity.  The  simplest  system 
of  this  sort  consists  of  a  respiration  chamber  only  of  largo  enough  capacity 
to  supply  oxygen  and  permit  respiration  of  ordinary  atmospheric  air  with- 
out discomfort  for  at  least  an  hour.  By  analysis  of  a  sample  of  air  at  the 
beginning  and  the  end  of  an  obseiTation  it  is  possible  to  learn  from  the 
changed  composition  the  amount  of  oxygen  absorbed  and  the  amount  of 
CO2  given  off. 


Fig.  3.  Haldane  respiration  apparatus.  Ch,  chamber ;  1  and  2  absorbers  for 
ingoing  air;  3,  4,  and  5,  absorbers  for  outgoing  air;  M,  meter;  J,  safety  bottle;  P, 
air  pump. 

A  more  physiological  arrangement,  however,  is  to  provide  for  the  ab- 
sorption of  the  carbon  dioxid  approximately  as  rapidly  as  it  is  produced 
and  its  replacement  by  oxygen.  The  observations  can  then  be  pi'olonged 
for  many  hours. 

a.  The  Apparatus  of  RegnauU  and  Reiset, — This  is  the  original  closed- 
circuit  apparatus.  The  respiration  chamber  consists  of  a  glass  bell  of  45 
liters  capacity  (A,  Fig.  4).  The  bell  is  fitted  by  an  air-tight  seal  into  a 
metal  base  which  serA^es  at  the  same  time  as  the  base  for  the  surround- 
ing water  jacket.  Entrance  to  the  chamber  is  gained  by  means  of  a  circu- 
lar opening  in  the  base.  The  top  or  handle  of  the  bell  is  perforated  by 
several  tubes  one  of  which  connects  with  a  mercury  manometer  (a,  b,  c) 
for  recording  the  pressure  inside  the  chamber.  A  second  connects  with  a 
sampling  apparatus  d'.  Two  others  connect  with  the  CO2  absorbers  C  and 
C,  and  a  fifth  with  the  oxygen  supply  (the  flasks  N,  W  and  N").  The 
CO2  absorbers  have  a  capacity  each  of  about  three  liters.  The  absorbing 
fluid  is  an  assayed  solution  of  KOH.  Movement  of  air  from  the  chamber 
to  the  absorbers  is  accomplished  by  alternately  raising  and  lowering  the 
absorbers.    For  example,  when  C  is  raised  as  in  the  figure  the  fluid  runs 


522 


JOHN  R  mukli:n' 


from  C  into  C,  thereby  aspirating  the  air  into  C  and  returning  air  from 
C  to  the  respiration  chamber.  By  thus  absorbing  the  COg  produced  by 
the  subject  the  volume  of  the  contained  air  is  reduced  and  its  place  is 
taken  by  oxygen  driven  from  the  flask  N  by  water  pressure.  The  experi- 
ment is  continued  until  all  the  oxygen  contained  in  the  three  flasks  is  used 
up.  The  last  300  or  400  c.c.  of  oxygen  is  driven  over  under  pressure  and 
the  experiment  is  continued  until  the  atmospheric  pressure  is  again 
reached.  At  this  moment  samples  of  the  chamber  air  are  drawn  off  for 
analysis. 

The  CO2  is  discharged  from  the  KOH  by  weak  sulphuric  acid  and  is 
again  caught  in  a  KOH  absorber  to  be  weighed.    It  could  not  be  obtained 


Fig.  4.  Respiration  apparatus  of  Regnault  and  Reiset.  A,  chamber  for  animal; 
B,  water  jacket;  C,  carbon  dioxid  absorbers;  a,  6,  c,  manometer  for  recording  pressure 
inside  respiration  chamber;  N,  N\  A'",  flasks  containing  oxygen;  T,  T\  thermometers. 


by  direct  weighing  of  the  absorbers  because  they  contain  some  water  ex- 
haled from  the  animal  as  well  as  COj.  To^the  amount  of  CO2  contained 
in  the  KOH  is  added  the  residual  amount  found  in  the  chamber  air  by 
analysis  at  the  end  of  the  observation. 

The  oxygen  absorbed  is  found  by  measurement  of  the  contents  of  the 
flasks  corrected  by  analysis  of  the  chamber  air. 

b.  TJie  Apparatus  of  Iloppe-Seyler^c). — Similar  in  principle  to  that 
of  the  original  construction  of  Regiiault  and  Reiset  this  apparatus  con- 
sists of  a  horizontal  cylinder  two  meters  in  length,  1.66  meters  in  diameter 
and  a  total  capacity  of  4.480  cubic  meters.  It  is,  therefore,  large  enough 
for  observation  on  the  human  subject. 

The  respiration  chamber  rests  on  the  ground  floor  of  the  laboratory, 


FORMAL  PROCESSES  OF  ENERGY  MEtABOLIS:i[     523 

the  driving  mechanism,  absorbers  and  gasometei*s  being  set  up  in  the 
cellar  immediately  below  the  respiration  chamber  (Fig.  5).  The  air 
of  the  chamber  is  cooled  by  means  of  a  stream  of  water  passing  through 
a  grid  of  pipe  placed  near  the  ceiling  of  the  chamber.  Besides  the  main 
ventilating  tubes  which  connect  with  the  COg  absorbers  (b)  other  tubes 
penetrate  the  walls  of  the  apparatus  for  recording  the  intemal  pressure,  for 
admitting  oxygen  and  for  withdi*awing  a  sample  of  air  foj-  analysis.  The 
CO2  absorbers  are  alternately  raised  and  lowered  by  means  of  a  walking 


j«^£^ 


Fig.  6.  Respiration  apparatus  of  Hoppe-Seyler.  A,  respiration  chamber;  5, 
apparatus  for  raising  and  lowering  carbon  dioxid  absorbers;  C,  engine;  i>,  gasometer 
filled  with  oxygen;   G,  meter  for  measuring  sample. 


beam  operated  by  a  gas  motor.  Air  is  thereby  alternately  withdrawn  and 
returned  to  the  chamber  after  absoi-ption  of  its  carbon  dioxid. 

Oxygen  is  admitted  from  the  gasometer  D  through  a  gas  meter  G  after 
passing  first  through  a  water  fiask  to  pi'event  evaporation  of  water  from 
the  meter. 

The  carbon  dioxid  absorbed  is  determined  exactly  as  in  the  Regnault- 
Reiset  method  by  discharging  the  COo  from  the  KOH  and  collecting  it 
again  and  w^eighing.  This  amount  obviously  must  be  corrected  by  analysis 
of  the  air  residual  in  the  chamber  at  the  end  of  an  observation. 

Oxygen  is  determined  by  reading  the  gas  meter  and  correcting  the 


524 


JOHX  E.  mueli:n- 


amount  so  indicated  by  the  residual  analysis.     The  quality  of  the  oxygen 
supplied  is  likewise  controlled  by  analysis. 

c.  Apparatus  of  Atwaler  and  Benedict (d), — These  authors  introduced 
the  use  of  an  eccentric  blower  (Fig.  6)  for  driving  the  air  through  the  ab- 
sorption system  and  back  to  the  respiration  chamber.  The  original  cham- 
ber described  on  page  518  for  the  open-circuit  apparatus  was  adapted 
to  the  new  type  of  ventilation  shown  in  Fig.  6.  In  the  upper  part  of  the  fig- 
ure the  respiration  chamber  is  shown  and  below  it  is  the  blower  and  ab- 
sorbing or  purifying  system.  Air  from  the  chamber  containing  nitrogen, 
carbon  dioxid,  water  vapor  and  a  somewhat  diminished  percentage  of 
oxygen  passes  through  the  blower  and  enters  the  absorption  system.  Here 
it  is  forced  through  sulphuric  acid  to  remove  the  water  vapor  and  through 
a  specially  prepared  soda  lime  which  takes  out  the  carbon  dioxid;  the 

soda  lime,  however,  con- 
tains water  some  of  which 
is  taken  up  by  the  dry 
air.  A  second  sulphuric 
acid  absorber  to  catch 
^his  water  is  therefore 
necessary  and  the  total 
CO2  absorption  is  found 
by  the  gain  in  weight  of 
these  two  vessels.  The 
air  is  now  freed  of  car- 
bon dioxid  and  water, 
but  is  still  deficient  in 
oxygen.  The  latter  in 
requisite  amount  is  ad- 
mitted from  a  cylinder  of 
compressed  oxygen  through  an  opening  in  the  ventilating  pipe  (see  Fig. 
6)  and  the  air  now  restored  to  its  original  composition  re-enters  the  respi- 
ration chamber. 

The  respiration  chamber  of  the  original  construction  continued  to  be 
used  as  a  calorimeter.  In  later  patterns  of  this  respiration  calorimeter 
w^hich  have  been  constructed  at  the  IN'utrition  Laboratory  of  the  Carnegie 
Institution  at  Boston  (Benedict  and  Carpenter  (a)),  at  Cora  ell  Medical 
College  (Williams,  H.  B.)  and  at  the  U.  S.  Depai-tment  of  Agriculture 
(Langworthy  and  Milner)  some  slight  modifications  of  the  original  plan 
have  been  made  and  these  will  be  described  here  so  far  as  the  an-angements 
for  ventilation  and  determination  of  the  respiratory  exchange  ai'e  con- 
cerned as  if  belonging  to  the  original  construction  at  Middletown. 

The  metal  walls  of  the  chamber  and  the  ventilating  pipes  which  con- 
sist of  metal  or  heavy  rubber  confine  the  air  to  a  definite  volume  and  to 
allow  for  expansion  or  contraction  of  the  air  volume  as  the  result  of  pres- 


Fig.  6.  Diagram  of  the  system  of  ventilation  in 
the  closed-circuit  apparatus  of  Atwater  and  Benedict, 
llie  direction  of  the  air  is  indicated  by  arrows. 


iS^ORMAL  PROCESSES  OF  ENERGY  :METAB0LISM     525 

sure  and  temperature  changes  a  compensating  device  in  the  form  of  a 
spirometer  is  inserted  (see  Figs.  7  and  8). 

The  approximate  amount  of  water  vapor  coming  from  the  subject's 
hod  J  and  the  amount  of  carhon  dioxid  exhaled  from  his  lungs  is  found 
by  direct  weighing  of  the  absorbers.  Likewise  weighing  of  the  oxygen 
cylinder  gives  within  a  small  margin  the  amaunt  of  oxygen  absorbed  by 
the  subject.  These  amounts  would  be  absolutely  correct  if  there  were  no 
change  in  barometric  pressure  or  temperature  of  the  confined  air,  and  if 
the  composition  of  the  air  at  the  end  of  an  observation  period  were  exactly 
the  same  as  at  the  beginning. 

Barometric  pressure  and  temperature  are  readily  determined  from  ac- 
curate instruments  and  corresponding  corrections  in  the  volume  of  the 
contained  air  are  readily  made.  For  detecting  alterations  in  the  composi- 
tion of  the  air  resulting  from  inefficiency  of  an  absorber  or  from  unusual 
production  of  CO2  or  water  vapor,  known  volumes  of  the  circulating  cur- 
rent are  diverted  from  the  main  pipe  and  are  made  to  pass  through  a 
smaller  channel  over  sulphuric  acid  and  soda  lime  and  sulphuric  acid  again 
(exactly  as  in  the  main  circuit)  contained  in  U  tubes  which  can  be  weighed 
to  a  high  accuracy  on  a  sensitive  balance  (Fig.  8). 

As  an  illustration  of  a  compact  form  of  this  apparatus  constructed  for 
determination  of  the  respiratory  exchange  alone  (without  direct  measure- 
ment of  the  heat)  either  in  laboratory  animals  or  in  infants,  the  design 
of  Benedict  and  Talbot  may  be  described. 

This  apparatus  was  originally  described  by  the  authors  in  a  preliminary 
publication  in  1912.  Later  it  was  somewhat  modified  and  was  employed 
in  most  of  their  obsei-vations  on  the  infant  in  the  form  shown  in  Fig,  7. 
In  this  form  it  was  capable  of  determining  the  oxygen  directly,  exactly  on 
the  same  principle  as  that  described  above  for  the  respiration  calorimeter. 

The  chamber  C,  in  which  the  infant  reposes,  is  provided  with  a  water 
jacket,  W.  W.  for  temperature  control.  The  air  leaves  the  chamber  (Fig. 
7)  near  the  right  hand  end  at  O,  and  is  drawn  by  the  rotary  blower  over  a 
wet  and  dry  bulb  psychrometer,  Z,  which  gives  the  amount  of  moisture  in 
the  air  of  the  chamber.  A  can,  i^T,  filled  with  dry  cotton  batting  is  also 
placed  in  the  air-current  between  the  blower  and  the  chamber  to  act  as  a 
muffler.  After  leaving  the  exhaust  side  of  the  blower,  P,  the^air  is  forced 
through  an  empty  glass  bottle,  A,  which  serves  as  a  trap  should  any  back- 
pressure take  place  and  sulphuric  acid  be  forced  back  from  the  water-ab- 
sorbing vessels,  B  and  C.  These  latter  vessels  are  of  peculiar  construction. 
They  were  designed  by  Williams  for  the  small  respiration  calorimeter  at 
Cornell  Medical  College.  The  air  passes  along  a  pipe  to  a  2-way  valve,  V, 
where  it  may  be  deflected  through  either  of  the  soda  lime  bottles  Dj  or  D2 
in  which  the  carbon  dioxid  is  absorbed.  Since  the  reagent  must  be  some- 
what moist  to  facilitate  the  absorption  it  gives  up  water-vapor  to  the  dry 
air-current,  which  must  in  time  be  absorbed  by  sulphuric  acid  in  the  Wil- 


526 


JOHN  R  MUKLIN 


Hams  bottles  Ei  or  Eg.  The  air  next  passes  through  the  2-way  valve,  V2, 
and  enters  a  small  can,  F,  which  contains  dry  sodium  bicarbonate,  where 
the  unweighable  and  nearly  imperceptible  sulphuric  acid  odors  are  effec- 
tually removed.  The  air  then  returns  to  the  chamber  tli rough  the  by-pass 
J,  or,  if  it  is  desired  to  moisten  the  air,  the  current  can  bo  deflected  by 
closing  the  valve,  R,  in  the  bypass,  J",  so  as  to  pass  all  of  the  air  through 
distilled  water  in  the  Williams  bottle  K.  The  air  is  now  free  from  carbon 
dioxid  and  contains  the  water  vapor  added  in  passing  through  K,  but  is 
still  deficient  in  oxygen.  This  deficiency  is  made  up  by  admitting  oxygen 
from  the  pressure  cylinder  L.  The  air  thus  enters  the  respiration  chamber 
I  somewhat  moist  and  with  approximately  normal  percentage  of  oxygen. 


g^— -y 


(ml 


cj T^,l\\ 


Fig.  7.    Diagram  of  the  respiration  apparatus  used  by  Benedict  and  Talbot  in 
their  study  of  the  gaseous  metabolism  of  infants.     Description  in  the  text. 


Either  series  of  absorbers  may  be  used  as  desired,  for  if  the  air  cuiTcnt 
has  been  passing  through  the  series  D^  and  E^,  for  a  given  experimental 
peri(Kl,  the  air  can  be  instantly  deflected  through  the  series  Dj,  and  Eo  by 
turning  the  valves  V^  and  Vo.  These  valves  are  connected  by  a  long  rod  so 
that  they  may  be  thrown  simultaneously  by  one  movement  of  the  hand. 

Since  the  air-current  is  entirely  closed  a  small  spirometer  S  is  attached 
at  the  upper  right  hand  corner  of  the  respiration  chamber,  thus  providing 
for  an  expansion  or  contraction  of  the  air.  A  thermometer,  Tj ,  in  the  cover 
of  the  chamber  and  a  second  thermometer,  Tg,  in  the  outgoing  air  serve 
to  indicate  the  temperature  changes  while  the  manometer,  ls\,  sho^vn  be- 
low the  spirometer  indicates  the  pressure  of  the  air  in  the  chamber. 

By  noting  the  increase  in  weight  of  the  absorbers  Dj  and  Ej  or  D2  and 
E2  the  amount  of  CO2  absorbed  is  known.    It  is  possible  that  the  amount 


X0R:V[AL  processes  of  energy  metabolism     527 

of  water  vajx>r  given  up  by  Di  oi'  D.^,  to  the  dry  air  paaaing  through  it  may 
be  actunlly  more  than  the  amount  of  carbon  dioxid  absorbed,  or  that  tlie 
bottle  ])i  or  Do  may  l>e  losing  weight;  on  the  contrary,  the  water  vajwr 
given  up  is  inmiediately  absorlx'd  by  E,^and  hence  the  algebraic  sum  of  the 
diffcjonce  in  weight  of  the  two  bottles  gives  the  weight  of  the  carbon  dioxid 
absorbed.  Usually  both  bottles  are  weighed  on  a  balance  at  the  same  time. 
The  loss  in  weight  of  the  cylinder,  L,  gives  the  amount  of  oxygen  absorbed 
by  the  subject,  corrections  being  made  for  any  variation  in  temperature 
and  barometric  pri'essure.  Corrections  for  changes  in  composition  ,of  air 
inside  the  chamber  may  be  made  by  withdrawing  samples  through  a  by-pass 
not  shown  in  the  figure. 

The  infant  is  placed  inside  a  wire  crib  suppoi-ted  at  one  end  upon  a 
stout  spiral  spring,  U,  and  at  the  other  end  upon  a  knife  edge,  G ;  tliis 
mode  of  suspension  affords  a  means  of  recording  the  muscular  activity  of 
the  infant.  Alongside  the  spring,  IJ,  is  a  pneumograph,  .II,  the  distention 
or  contraction  of  which  compresses  the  air  inside  of  the  pneumograph 
tube,  thus  transmitting  to  a  delicate  tambour  outside  a  record  of  the  light- 
est motion  of  the  cage. 

The  respiration  chamber  is  constructed  of  galvanized  iron  or  copper, 
and  is  77  cm.  long,  25  cm.  deep,  and  37  cm.  mde.  To  insure  temperature 
control-  the  whole  respiration  chamber  is  surrounded  by  a  water  jacket 
consisting  of  a  second  shell  of  galvanized  iron  or  copper  with  a  space  of 
5  cm.  between  the  two  walls.  The  water  jacket  which  is  filled  with  water 
to  within  a  few  centimeters  of  the  top  acts  also  as  a  seal  when  the  cover  is 
placed  upon  the  apparatus.  In  the  cover  are  a  window  securely  fastened 
and  an  opening  for  the  air  thermometer. 

The  psychrometer  is  essential  for  indicating  the  degree  of  moisture  in- 
side* the  respiration  chamber.  This  is  of  value  not  only  for  the  comfort 
of  the  infant,  but  also  for  computing  the  amount  of  oxygen  inside  the  cham- 
ber at  the  end  of  the  experimental  period.  Experiments  carried  out  with  a 
very  delicate  instrument  have  shown  that  the  depression  of  the  wet-bulb 
thermometer  can  be  measured  with  great  accuracy  and  the  amount  of  water 
vapor  in  the  air  computed  with  an  exactness  sufficient  for  all  practical  pur- 
poses. The  two  thermometers  are  graduated  to  0.1°  C.  but  are  capable 
of  being  read  with  a  lens  to  .02°  C.  It  is  necessary  to  make  sure  that 
the  cloth  around  the  wet  bulb  thermometer  is  kept  thoroughly  drenched 
with  distilled  water,  also  that  the  capillarity  of  the  fiber  is  good  as  otber- 
wise  the  cloth  may  become  partially  dried  and  inaccurate  results  obtained. 
Prior  to  each  experiment  the  wet  bulb  is  drenched  by  using  an  elongated 
medicine  dropper  filled  with  distilled  water. 

The  blower,  P,  is  connected  with  a  leather  belt  to  a  small  electric  motor 
and  can  be  provided  with  a  safely  clutch  to  prevent  reversing  the  wheel 
through  carelessness,  and  the  drawing  over  of  sulphuric  acid  from  the  water 
absorbers.     The  safety  trap,  A,  is  an  additional  security  against  this  mis- 


528  JOHN  R  MUKLIN 

hap.  The  blower  used  with  this  apparatus  gives  a  ventilation  of  about  35 
liters  of  air  per  minute  when  rotating  at  a^peed  of  270  revolutions  p.  m. 
Experiment  with  an  alcohol  flame  shows  that  this  rate  of  ventilation  does 
not  produce  a  draft  which  would  l>e  perceptible  by  the  infant.  The  fact 
that  the  relative  humidity  does  not  become  unduly  low,  even  without  use 
of  the  water  bottle,  is  proof  that  the  infant  is  sojourning  in  an  atmos- 
phere approximately  normal. 

To  remove  the  moisture  coming  from  the  lung  and  skin  of  the  infant, 
and  any  additional  moisture  from  water  bottle  K,  one  larger-sized  Williams 
bottle  B  is  usually  sufficient.  However,  a  second  bottle  C  removes  the  last 
traces  of  water  vapor.  To  facilitate  the  handling  of  these  bottles  in  weigh- 
ing and  to  prevent  breakage,  they  are  usually  enclosed  in  a  small  wire 
basket  with  a  handle  by  means  of  which  they  may  be  suspended  directly 
from  a  hook  on  the  arm  of  the  balance. 

The  Williams  bottles  as  well  as  the  soda  lime  bottles  are  fitted  with  short 
lengths  of  rubber  tubing  of  good  quality  to  which  are  attached  respectively 
male  and  female  parts  of  ordinary  garden  hose  couplings  of  standard  % 
inch  size ;  with  a  standard  rubber  hose  gasket,  the  couplings  are  made  air- 
tight by  a  single  twist  of  the  hand. 

For  infants  weighing  not  less  than  3  to  5  kgm.  the  soda  lime  container 
holding  in  the  neighborhood  of  2  kgm.  soda  lime  is  capable  of  absorbing 
all  the  carbon  dioxid.  This  amount  of  soda  lime  will  take  up  as  much  as 
75  gm..  CO2  without  renewal. 

The  direct  determination  of  oxygen  may  be  made  either  by  weighing 
the  small  cylinders  of  gas  L,  and  noting  its  loss  in  weight  during  the  ex- 
periment, or  by  passing  the  gas.  under  reduced  pressure,  through  a  delicate 
and  accurate  gas  meter.  With  oxygen  made  from  liquid  air  a  corrective 
for  argon  has  usually  to  be  made  amounting  to  about  1  per  cent.  The  vol- 
ume of  air  inside  the  respiration  chamber  is  about  75  liters.  Correction 
for  temperature  change  is  therefore  necessary  in  order  to  determine  the 
actual  volume  of  air  at  the  end  of  every  experimental  period.  Two  care- 
fully calibrated  mercury  thermometers,  one  in  the  cover  of  the  chamber, 
the  other  the  dry  bulb  themiometer  of  the  psychrometer,  are  used  to  record 
such  changes.  While  the  two  thermometers  barely  read  alike,  their  fluctu- 
ations are  usually  parallel.  The  average  of  the  readings  of  the  two  is  taken 
as  representing  the  average  temperature  of  the  air  in  the  chamber. 

It  is  impoi-tant  that  the  respiration  chamber  shall  not  be  subjected  to 
sudden  fluctuations  of  temperature  during  the  experimental  periods.  The 
water-jacket  serves  to  damp  any  changes  in  the  room  temperature,  and  by 
supplying  either  heat  or  cold  to  maintain  the  chamber  at  a  temperature 
either  above  or  below  that  of  the  room.  During  cold  weather  a  mercury 
thermo-regulator  placed  in  the  w^ater  and  connected  with  a  small  burner 
placed  underneath,  secures  a  constant  temperature  which  may  be  regulated 


KORAIAL  PKOCESSES  OF  ENERGY  2IETAB0LISM     529 


at  any  desired  level.    In  the  excessively  warm  days  of  summer,  it  is  neces- 
sary to  place  ice  in  the  tank. 

An  apparatus  devised  by  the  writer,  and  constructed  simultaneously 
with  the  last  for  use  in  Bellevne  Hospital,  Xew  York,  follows  the  same 
general  principles  as  that  just  described,  but  employs  as  a  means  of  con- 
trolling the  temperature  the  electrically  regulated  incubator  of  Freas. 


Fig.  8.     Respiration  incubator    (Miirlin). 

For  this  reason  it  has  been  called  a  ^^respiration  incubator,"  and  can 
be  used  as  an  incubator  for  premature  infants  independently  of  its  features 
as  a  respiration  machine  (Murlin(^)). 

d.  Appamius  far  Very  Small  Animals. — ^With  very  small  animals,  their 
eggs  or  larval  stages  it  is  not  necessary  to  circulate  the  air  through  absorb- 
ers. The  absorption  of  oxygen  can  be  recorded  by  a  change  of  pressure  and 
the  carbon  dioxid  can  be  readily  absorbcnl  by  means  of  a  suitable  solution 
of  alkali.    Several  forms  of  apparatus  constructed  on  these  principles  have 


530 


JOHN  R  MUKLIN 


been  invented.     Some  of  them  should  be  described  briefly  under  the  head- 
ing of  closed-circuit  apparatus.   ^ 

An  original  form  described  by  Thunberg  was  a  gas-analysis  apparatus 
of  the  Petterson  type  for  the  determination  of  very  small  i>ercentages  of 
CO2  in  which  the  animals  to  be  experimented  on  could  be  introduced  into 
the  gas-measuring  pipette.  Any  change  in  volume  with  the  animal  in  the 
confined  space  would  he  due  to  the  difference  between  O^j  and  CO2  given 


Fig.  9.  Micro-respiration  apparatus  of  Winterstein.  5  and  0,  duplicate  air 
chambers.  The  small  animal  is  placed  in  chamber  6  and  chamber  5  is  used  as  control, 
the  two  chambers  being  connected  by  a  sensitive  oil  manometer.  The  absorption  of 
oxygen  from  chamber  6  is  measured  by  the  pressure  of  mercury  necessary  to  restore 
the  balance  on  the  oil  manometer. 


off.  This  volume  having  been  noted  the  air  could  then  be  driven  over  into 
potash  bulb  and  the  COg  absorbed.  Changes  in  volume  this  time  would 
give  the  CO2  produced  by  the  animal  and  the  oxygen  could  be  found  by 
adding  the  difference-volume  first  noted. 

Winterstein  (a)  improved  upon  this  apparatus  by  employing  the  prin-' 
ciple  of  the  compensating  vessel  fii*st  introduced  into  gas  analysis  by  Petter- 
son and  connecting  the  two  vessels  (the  animal  chamber  and  compensating 
chamber)  by  means  of  a  very  sensitive  graduated  manometer  containing  a 
drop  of  kerosene.  The  oil-drop  being  set  at  zero,  the  level  of  the  mercury  in 
the  U-tube  manometer  at  the  left  which  is  graduated  in  cubic  millimeters  is 


:N'0RMAL  processes  of  energy  metabolism     531 

read.  By  absorption  of  oxygen  from  the  animal  cliaml)er  the  oil-drop  is 
shifted  toward  that  chamber  and  whenever  a  reading  is  taken  a  drop  is 
brc>ng;ht  back  to  the  zero  mark  by  means  of  the  pressnre  screw  on  the  mer- 
cury colnmn.  The  volume  of  mercury  moved  upward  then  is  ctpial  to  the 
volume  of  oxygen  absorbed  when  corrected  from  the  original  temperature 
and  barometric  pressure  to  0°  and  760  mm.  The  carlx)n  dioxid  is  absorbed 
as  rapidly  as  produced  by  a  drop  of  caustic  soda  placed  in  the  bottom  of  the 
aninifvl  chamber,  the  animal  of  course  being  protected  from  contact  with 
the  solution.  The  production  of  carbon  dioxid  can  be  determined  if,  in 
a  control  period,  a  small  amount  of  water  is  used  instead  of  the  alkali. 
The  pressure  change  will  then  indicate  the  difference  between  the  volume 
of  oxygen  absorbed  and  the  carbon  dioxid  given  off.  If  the  oxygen  absorp- 
tion is  determined  just  before  and  just  after  this  under  conditions  other- 
wise the  same,  the  volume  of  carbon  dioxid  will  be  found  by  substracting 
the  difference-volume  from  the  volume  of  oxygen.  The  respiratory  quotient 
is  then  available. 

It  is  obviously  necessary  to  keep  the  two  chambers  in  the  same  water  or 
oil  bath  in  which  the  liquid  is  sufficiently  stirred  so  that  the  two  chambers 
shall  be  of  exactly  the  same  temperature. 

The  micro-respiration  appaiatus  of  Krogh  follows  very  similar  prin- 
ciples. With  it  Krogh  was  able  to  follow  the  oxygen  absorption  of  a  single 
insect  egg  weighing  about  2  mgin.  in  ten-hour  periods  from  immediately 
after  it  was  laid  until  the  hatching  of  the  larva  (Krogh(6)). 

11.     Methods  for  Measuring  the   Respiratory   Exchange 
by  Direct  Connection  with  the  Repiratory  Passaj^es 

The  first  obsei-vations  upon  the  respiratory  exchange  of  man  made  by 
Lavoisier  provided  for  the  direct  examination  of  the  expired  air.  A  copper 
mask  was  used  fitting  tightly  over  the  subject's  face  and  by  some  means 
not  clearly  understood  the  inspired  air  was  separated  from  the  expired  air, 
which  was  passed  into  alkali,  thereby  removing  the  carbon  dioxid.  Many 
different  modifications  of  the  original  method  of  Lavoisier  have  been  de- 
vised. Those  which  employ  means  to  separate  the  inspired  air  from  the 
expired  air  and  provide  for  the  collection  or  automatic  analysis  of  the  latter 
should  be  described  under  the  rubric  of  "open  circuit''  or  air-current  types 
of  apparatus.  Other  methods  employ  some  form  of  "closed  circuit"  ap- 
paratus. 

1.  Open  Circuit  Instruments,  a.  Mouihr-pieces,  Nose-pieces,  Masks, — 
For  connection  of  the  apparatus  to  the  respiratory  passages  of  the  subject 
a  rubber  mouth-piece  originally  constructed  by  Denayrouse  for  the  use  of 
divers  has  been  widely  employed.  It  consists  of  a  wide  rubber  disc  which 
fits  in  between  the  lips  and  the  teeth  of  the  subject.  In  the  middle  of  this 
disc  is  a  2  cm.  opening  leading  into  a  rubber  tube  of  the  same  size.     On 


532 


JOHN  R  MURLIN 


the  two  sides  of  the  opening  are  thick  rubber  projections  which  may  bo 
held  between  the  teeth.    Sometimes  the  mouth-piece  is  supplemented  by  a 

band  of  rubber  tied 
around  the  head  and 
pressing  ag-ainst  the 
lips  from  the  outside. 
In  the  use  of  this  device 
the  nose  must  of  course 
be  closed  by  some  form 
of  clip  or  clamp  (Reg- 
nard)  (Fig.  10). 

Glass  nose-pieces 
have  been  described  by 
Tissot  and  these  have 
been  improved  by  Car- 
penter (a).  A  pneu- 
matic nose-piece  de- 
scribed by  F.  G.  Bene- 
dict(^)  (Fig.  11)  is 
mucli  to  be  preferred  to 
the  all-glass  construc- 
tion. They  can  be  made 
very  secure  by  inflation 
of  the  pneumatic  por- 
tion particularly  if  the 
outer  rubber  which  fits 
against  the  nose  is  cov- 
ered with  mucilage. 
Many  subjects,  how- 
ever, find  the  nose- 
pieces  quite  uncomfort- 
able and  prefer  the 
mouth-piece  described 
above.  Benedict  him- 
self has  recently  recom- 
mended the  mouth- 
piece with  a  clinical 
respiration  apparatus  in  preference  to  the  nose-piece  (Benedict  and  Col- 
lins). When  nose-j)ieces  are  used  the  mouth  should  be  sealed  shut  with  an 
adhesive  tape. 

Various  types  of  masks  have  also  been  used  from  the  crude  copper  mask 
covering  the  entire  face  employed  by  Lavoisier,  to  the  modern  so-called  half 
mask  employed  in  mine  rescue  work.  The  gas  masks^  perfected  from  force 
of  necessity  during  the  recent  war,  have  also  found  a  useful  field  in  con- 


Fig.  10.  ]Mouth-piece  of  Denayrouse  with  nose 
clip  attached.  (1)  brass  tube  connecting  to  apparatus; 
(2)  collar  supporting  stand  (3)  which  in  turn  sup- 
ports nose  piece;  (4)  brass  collar;  (5)  frame  of  nose- 
piece  with  adjusting  screw  for  regulating  pressure  on 
nose;  (6)  nose  pads;  (7)  rubber  of  mouth-piece  which 
fits  in  between  teeth  and  lips;  (8)  opening  from  mouth- 
pit'ce  into  brass  tube:  (0)  rubber  lugs  which  may  be 
grasped  between  the  teeth;  (10)  rubber  tube  continuous 
with  mouth-piece;  (11)  strap  for  holding  mouth-piece 
firmly  in  place. 


NORMAL  PEOCESSES  OF  ENERGY  METABOLISM     533 


nection  with  respiration  experiments.  A  form  of  mask  described  by  Bohr 
consi.sts  of  a  funnel-shaped  piece  of  tin  plate  coated  on  the  edges  with 
a  substance  used  by  dentists,  known  on  the  market  as  Stent's  compound. 
This  substance  softens  at  a  temperature  a  little  above  the  body  temperature 
and  may,  therefore,  be  molded  to  fit  the  face  of  each  subject.  The  mask 
can  1)6  made  perfectly  air  tight  by  covering  the  molded  surface  with  vase- 
line or  lanolin  and  binding  it  securely  to  the  face  (Krogh(c)). 

The  half  mask  employed  by  Eoothby  is  made  of  rubber  on  a  flexible 
wire  frame  so  that  it  may  be  bent  to  conform  to  the  shape  of  the  nose,  cheeks 
and  chin.  It  is  bordered  by  a  pneumatic  cushion.  Boothby  finds  that  it 
is  much  safer  not  to  inflate  this  cushion  for  the  air-valve  tends  to  leak,  thus 
altering  the  pressure  against  the  face  and  causing  leakage.  He  recom- 
mends the  use  of  tapes  fastened  to  a  towel 
which  lies  upon  the  pillow  under  the  neck  of 
the  subject.  The  tapes  may  be  drawn  for- 
ward and  tied  about  the  mask  transversely 
and  obliquely  in  such  a  way  as  to  apply  the 
pressure  just  w^here  it  is  most  needed. 
(Boothby  and  Sandiford.)  (Fig.  12.) 

Kendry,  Carpenter  and  Emmes  liave  showTi 
that  the  oxygen  consumption  is  pi'actically 
identical  with  the  different  types  of  breathing 
appliances  adapted  to  the  subject. 

b.  Valves. — Universally  the  separation  of 
inspired  air  from  expired  air  is  accomplished 
by  some  type  of  valve.  One  of  the  simplest 
is  the  well  known  fluid  valve  of  ^^iiller  de- 
scribed in  1859  (Tigerstedt(/)).  Formerly 
they  were  much  used  filled  either  with  water 
or    mercury;     but    they    offer    considerable 

resistance  to  the  air  and  have  now  been  very  generally  displaced  by 
valves  of  lighter  construction.  One  form  which  has  been  widely  used 
is  the  valve  of  Loven  consisting  of  two  round  brass  boxes  each  enclos- 
iii,G:  a  thin  membrane  of  gold-beater's  skin  or  condom  rubber  (Fig.  13). 
Small  circular  apertures  suitably  spaced  and  arranged  in  a  circle  round 
the  peripheral  attachment  of  the  membrane  serve  for  passage  of  air.  The 
mechanics  of  this  valve  will  be  evident  from  the  figure.  Another  favorite 
form  is  the  metal  valve  of  Thiry  used  by  Tissot  (Fig.  14).  Boothby 
prefers  the  so-called  flutter  valve  used  in  the  most  recent  form  of  British 
and  American  ai-my  gas  masks.  He  has  devised  a  metal  housing  for  the 
rubber  flutter  and  finds  the  valve  in  this  foi-m  perfectly  competent.  In 
case  of  doubt  regarding  the  competency  of  a  valve  Boothby  recommends 
the  use  of  two  valves  one  after  the  other  in  the  inlet  or  outlet  tubing 
(Boothby  and  Sandiford). 


Fig,  11.  Pneumatic  nose- 
piece  of  Benedict,  a,  glass 
tube  to  which  is  fastened  a 
rubber  finger-cot,  6,  whicli  is 
drawn  over  a  rubber  stopper, 

c.  A    capillary  rubber   tube, 

d,  serves  for  dilating  the  cot 
6;  the  clamp  c  closes  d  after 
b  is  inflated. 


534 


JOHN  K.  MUELIjS" 


Fig.  12.    The  half  mask  as  used  by  Boothhy. 

c.  Cofleding  Apparatus.— The  expired  air  can  be  collected  either  in 
a  spirometer  ( Speck (&),  Tissot),  in  a  bag  (RegTiard,  Douglas,  C.  G.),  or 


Fig.  13.     Air  valve  of  Loven. 

it  may  be  measured  by  means  of  a  gas  meter  and  simultaneously  sampled 
for  analysis  (Geppert(a)). 

In  the  original  spirometer  method  of  Speck  the  inspired  air  was  drawn 
from  one  spirometer  and  the  expired  air  forced  into  another  so  that  the 
difference  in  volume  of  inspired  and  expired  air  could  be  recorded  and  the 


KORMAL  PKOCESSES  OF  ENERGY  METABOLISM     535 

inspired  air  could  also  be  readily  measured  at  the  same  temperature  and 
pressure  preliminary  to  analysis.  The  bell  of  each  spirometer  was  counter- 
poised and  provision  was  made  by  mechanical  means  for  compensating 
the  increase  or  decrease  in  weight  of  the  bell  according  as  it  was  lifted 
from  or  depressed  into  the  water  jacket.  The  Tissot  method  as  used  in  the 
PVench  laboratories  has  been  fully  doscrilx^d  by  Carpenter  (a).  The  spi- 
rometers are  of  special  design  and  used  principally  in  two  sizes,  one  of  50 
liters  and  another  of  200  liter  capacity.  The  height  of  the  bell  in  the 
former  is  60  cm.  and  the  diameter  33 ;  while  in  the  200  liter  instrument 
the  bell  is  73  cm.  high  and  65  in  diameter  (Fig.  15).  Air  is  admitted 
to  the  bell  through  a  tube  which  terminates  at  the  bottom  of  the  spirom- 
eter in  a  3-way  stop-cock,  A.  The  major  portion  of  the  weight  of  the 
spirometer  bell  is  counterpoised  by  the  weight  R.  The  automatic  adjust- 
ment of  the  counterpoise  for  the  spirometer  bell  is  accomplished  by  means 
of  a  water  siphon.    A  glass  cylinder,  C,  is  made  of  such  size  that  when 


Fig.  14.    Metal  air  valve  of  Thiry. 

filled  to  the  level  of  the  spirometer  the  w^eight  of  the  water  in  the  cylinder 
exactly  equals  the  increase  in  the  weight  of  the  spirometer  bell  due  to  its 
new  position.  When  the  bell  rises  or  falls  water  is  added  to  or  taken  from 
the  cylinder  C,  by  means  of  the  siphon  tube,  D.  Any  increase  or  decrease 
in  the  weight  of  the  bell  due  to  the  varying  displacements  of  the  volume 
of  water  by  the  mass  of  metal  in  the  spirometer  bell  is  thus  exactly  counter- 
poised by  a  like  increase  or  decrease  in  the  weight  of  water  in  the  cylinder. 
The  upright  position  of  the  counterpoised  cylinder,  C,  is  determined  and 
maintained  by  means  of  two  brass  rods  on  which  the  cylinder  travels.  This 
siphon  tube,  I),  is  so  arranged  that  it  does  not  touch  the  cylinder,  C,  at  any 
point. 

A  clinical  form  of  spirometer  or  gasometer  used  by  Boothby  differs 
from  the  original  form  of  Tissot  in  only  minor  features.  A  spirometer 
mounted  on  wheels  as  used  in  the  Mayo  clinic  is  illustrated  in  Fig.  16. 
The  counterpoise  of  the  bell  in  this  instrument  is  hung  over  ball  bearing 
wheels  by  means  of  steel  piano  wire.  The  main  weight  of  the  bell  is  bal- 
anced by  a  long  hollow  brass  tube  at  the  upper  end  of  wdiich  are  placed 
the  necessary  lead  Aveights  to  counterbalance  the  bell  exactly.  The  siphon 
arrangement  of  the  original  Tissot  spirometer  is  used,  but  instead  of  draw- 
ing water  from  the  gasometer  itself  to  the  counterposed  cylinder,  water  is 
drawn  from  a  special  receptacle.  ^ 


536 


JOHN  R,  UUllLm 


Fig.    15. 
eter    with 


liters.  A, 
connecting 
spirometer 


Tissot  Spirom- 
capacity  of  50 
three-way  valve 
air  in  bell  of 
with  outside 
air;  B,  tube  leading  to  in- 
side of  bell;  C,  counterpoise 
tube  compensating  for 
change  in  weight  of  bell; 
D,  siphon  tube  connecting 
C  with  water  in  tank;  E, 
flat  steel  band  supporting 
spirometer;  F\  wheel  over 
which  runs  E;  H,  rubber 
tube  connecting  siplion  tube 
with  supply  tube  J;  I, 
brancli  of  supply-water  tube 
leading  to  tank  at  L;  .1/, 
N,  overflow  tube  from  tank; 
O,  pointer;  P,  cock  for 
emptying  tank;  Q,  Q,  level- 
in<j  screws;  K,  lead  counter- 
poise; Z,  opening  for  gas 
sampling. 

to   counterbalance   the 
tubes. 


In  this  form  of  apparatus  the  scale  for  read- 
ing the  volume  of  expired  air  is  attached  to  the 
back  side  of  the  counterpoise  tube. 

In  carrying  out  an  ex[>erimeDt  by  the  Tissot 
method  the  valves  are  first  tested  for  tightness. 
Boothby  carries  out  this  test  by  filling  the  gas 
mask  with  water  and  letting  it  stand  for  a  time 
for  detection  of  leaks.  A  three-way  valve  at 
the  side  of  the  spirometer  permits  breathing 
from  the  subject  into  the  room  air  or  into  the 
spirometer  according  to  the  pioaition  of  the 
handle.  The  mask  is  attached  securely  to  the 
face  and  the  subject  breathes  for  a  time  into 
the  room  air  with  the  bell  at  its  lowest  posi- 
tion. The  subject  continues  to  breathe  into 
the  apparatus  for  a  definite  period  of  time,  the 
inspired  air  being  drawn  through  a  pipe  from 
outdoors.  The  valve  is  again  turned  at  the  end 
of  an  experiment.  The  temperature  of  the  air 
is  recorded  by  the  thermometer  in  the  top  of  the 
bell  and  a  reading  of  the  barometric  pressure 
is  taken. 

With  the  Boothby  apparatus  several  of  the 
lead  weights  are  slotted  so  that  they  may  be 
readily  removed.  When  all  the  weights  are  in 
place  the  bell  is  in  perfect  equilibrium  at  any 
point  of  its  course,  so  that  when  the  valve  is  open 
to  the  room  air  the  bell  will  not  change  its  posi- 
tion. When  one  or  more  of  the  lead  weights  are 
removed  so  that  the  bell  is  no  longer  perfectly 
counterpoised  it  will  gradually  drop.  For  the 
purpose  of  sampling  this  is  a  useful  arrange- 
ment for  the  weight  of  the  spirometer  sei'ves  to 
drive  expired  air  through  the  outlet  tube,  thus 
washing  out  room  air  from  the  main  tube  and 
the  sampling  connections.  While  the  subject  is 
breathing  into  the  apparatus  the  extra  weight 
of  about  300  gTams  should  be  placed  on  the 
counterpoise  so  as  to  induce  a  slight  ^negative 
pressure  toward  the  spirometer.  This  seiTes 
resistance   which   the   air   meets   in   the   various 


:N"0EMAL  processes  of  energy  metabolism     537 

In  the  original  hag  method  of  Regnard  the  subject  breathed  through  a 
Denayrouse  mouth-piece  and  a  pair  of  valves  into  a  rubber  sack  of  about 
200  liters  capacity.  At  the  end  of  an  obser\'ation  a  sample  of  about  150 
c.c.  of  air  was  withdrawn  for  analysis  and  the  balance  of  the  contents  was 
passed  slowly  through  a  series  of  absorbers  and  through  a  gas  meter.  In 
the  Douglas  method  as  originally  described  a  mica  or  rubber-flap  valve 
was  used  in  connection  with  a  mouth-piece  and  a  tube  of  20  inm, 
diameter  led  to  a  three-wav  valve  of  large  bore  which  was  connected  with 


Fig.  16.     Spirometer  of  Boothby  and  Sandiford  as  used  in  the  writer's  laboratory. 
Sampling  tubes  are  shown  on   shelf  above  the  wheels. 


a  wedge-shaped  reservoir  bag  made  of  rubber-lined  cloth  (Fig.  17).  This 
form  of  bag  is  more  impervious  than  rubber  and  therefore  more  reliable. 
The  shape  of  the  bag  permits  it  to  be  rolled  up  and  emptied  completely. 
The  expired  air  is  measured  at  the  end  of  an  observation  by  passing  it 
through  a  meter  and  a  sample  is  analyzed.  By  supporting  the  tube  and 
valves  on  a  light  framework  upon  the  head  and  resting  the  bag  on  an- 
other frame  placed  on  the  back  the  apparatus  is  made  adaptable  to  a  march- 
ing experiment. 

It  has  proved  especially  valuable  in  mountain  climbing  (Ilaldane, 
Henderson,  et  al.)  and  other  forms  of  open-air  exercises.  With  violent 
exercise  a  bag  holding  GO  liters  will  not  take  the  air  expired  during  one 


538 


JOHN  R  MURLIN 


minute;  but  Krogli  has  shown  that  experiments  of  even  much  shorter 
duration  are  sufficient  to  ^ve  perfectly  reliable  results. 

Tlie  method  of  Zuntz  and  Geppert  of  measuring  the  expired  air  as  it  is 
exhaled  and  collecting  at  the  same  time  a  continuous  aliquot  sample  for 
analysis  is  an  important  one  and  has  been  very  widely  used  in  Europe. 
The  subject  breathes  through  a  mouth-piece  attached  to  a  tee-tube  connect- 


Z-U^QAJ   ia/L 


Fig.  17.     Respiration  apparatus  of  Douglas.     The  mouth-piece  is  of  the  Denay- 
e  type.     The  bag  or  bellows  is  provided  with  straps  for  carrying  the  apparatus 


rouse    ,  ^ 
on  the  back. 


ing  two  valves  (made  of  rubber  and  glass  as  used  in  the  Zuntz  laboratory, 
Magnus-Levy (&))  which  separates  inspired  from  expired  air.  The  latter 
passes  at  once  through  a  moist  gas-meter.  The  continuous  sample  is  taken 
over  water  by  an  automatic  apparatus  and  is  then  immediately  analyzed  in 
a  special  analyzer  in  which  the  COo  is  absorbed  by  potash  and  the  oxygen 
by  phosphonis.  In  the  figure  (Fig.  18)  the  meter  is  shown  at  the  left  and 
the  special  air  analyzer  is  sho\vn  at  the  right.  The  expired  air  enters  the 
apparatus  at  P.  The  sample  is  drawn  through  the  narrow  tube,  L,  by  the 
lowering  of  the  water-tube,  H,  which  descends  at  a  rate  proportional  to  the 
ventilation  as  measured  by  the  meter.     As  the  tube,  H,  descends  water 


Is^OKMAL  PROCESSES  OF  ENERGY  METABOLISM     539 

flows  out  at  J  and  makes  room  for  air  in  the  two  burettes  (1)  which  fill 
from  L  at  K  and  K.  When  these  burettes  are  filled  and  contents  measured 
the  air  is  driven  over,  into  the  potash  bulbs  I,  after  which  it'is  drawn  back 
into  the  two  burettes  (2),  where  it  is  again  measured.  Thence  it  is  passed 
into  the  phosphorus  absorbers  II  and  is  finally  measured  for  shrinkage  due 
to  loss  of  oxygen  in  the  two  burettes  (3).  The  burette  (4)  is  a  ^'thermo- 
barometer"  for  recording  any  change  in  volume  of  the  air  contained  in  the 


Fig.  18.  Respiration  apparatus  of  Ziintz  and  Geppert.  The  recording  and  sam- 
pling apparatus  is  shown  at  the  left  and  the  air  analysis  apparatus  at  the  right. 
Air  enters  the  apparatus  from  the  lungs  of  the  subject  at  J\  a  sample  being  drawn 
automatically  through  a  tube  L,  and  being  passed  in  duplicate  successively  through 
the  burettes  numbered  1,  2  and  3.  Burette  4  is  for  control.  The  part  of  the  apparatus 
labeled  D,  E,  G  is  a  "thermo-barometer." 


burettes   due   to    alterations    of   temperature   and    pressure   during   an 
analysis. 

The  apparatus  R.  D.  E.  G.  is  another  thermo-barometer  for  recording 
similar  changes  in  the  volume  of  the  total  ventilation.  100  c.c.  dry  air 
at  760  nmi.  pressure  and  0°  have  been  stored  in  two  metal  boxes  one  of 
which  is  inserted  into  the  entrance  tube  of  the  gas  meter  at  P,  and  the  other 
into  the  exit  tube,  I'he  air  in  these  boxes  conmiunicates  with  the  burette 
E.  The  enclosed  volume  of  air  will  be  aifected  by  the  temperature  of  the 
air  entering  and  leaving  the  meter  and  by  the  atmospheric  pressure,  and 
the  volume  changes  can  be  read  off  on  the  burette  when  the  water  in  G  and 


540 


JOHX  K.  MURLIN 


E  has  been  brought  to  the  same  level  by  moving  G.  The  bui-ette  is  so 
divided  that,  if  a  volume  of  say  107.4  is  read  off  during  an  exi>eriment, 
the  volume  of  air  which  has  passed  through  the  meter  can  be  re{^luced  to 

normal  conditions  (0°  and 
760  imn.  dry  pressure)  by  mul- 
tiplication  with         '     .    This 

arrangement  is  certainly  not 
more  accurate  and  scarcely 
more  convenient  than  to  re- 
duce by  means  of  a  table  after 
reading  the  barometer  and  a 
thermometer  placed  in  the  exit 
tube  of  the  gas  meter. 

d.  Air  Analyzers. — ^With 
either  the  spirometer  method 
or  the  bag  method  of  collect^ 
ing  expired  air  or  with  the 
Jaquet  type  g  f  chamber 
an  absolutely  essential 
part  of  the  apparatus  is  a  re- 
liable device  for  detei'mining 
carbon  dioxid  and  oxygen  vol- 
umetricsally.  The  apparatus 
most  used  to-day  is  the  Hal- 
dane  analyzer.  This  appara- 
tus is  fully  described  by  Hal- 
dane  in  his  book  entitled 
"Methods  of  Air  Analysis." 
(Haldane(c).) 

In  a  general  way  the 
method  is  as  follows:  A 
sample  of  air  drawn  into  a 
10  c.c.  burette  is  accurately 
measured  under  the  atmos- 
phea-ic  pressure;  the  air  is 
then  passed  into  a  potash  bulb 
and  back  into  the  burette  until 
a  constant  reading  is  obtained;  the  difference  is  the  volume  of  CO2 
in  the  sample.  In  the  same  way  the  oxygen  is  absorbed  in  a  solution  of 
pyrogallol  in  strong  potash  and  the  difference  in  volume  obtaijied  repre- 
sents the  volume  of  oxygen  in  the  sample. 

As  used  by  Boothby  in  the  Mayo  clinic  the  apparatus  is  shown  in  Fig. 
19.    Full  details  for  manipulation  of  the  apparatus  and  for  calibration  of 


Fig.  19.  The  Haldane  air  analyser  as  used 
by  Boothby.  1.  Water-bath.  2.  Burette.  3.  Con- 
trol tube.  4.  Glazed  glass  back  of  water-bath. 
5.  Pressure  tubing  connecting  burette  and  its 
mercury  reservoir.  6.  Mercury  reservoir.  7. 
Ratchet  and  pinion.  8.  Burette  tap.  9.  Sampling 
tap.  10.  Sampling  connection.  14.  Potash  tap. 
15.  Level  marking  on  potash  pipette.  16.  Potash 
pipette.  17.  Potash  reservoir.  18.  Control  tube 
tap.  19.  Pyro  tap.  20.  Level  marking  on  pyro 
pipette.  21.  Pyro  pipette.  25.  Level  marking  on 
manometer  tube. 


KOR^iFAL  PROCESSES  OF  ENERGY  METABOLISM     541 

the  burette  are  given  in  Boothby  and  Sandiford^s  book  on  "Basal  Metabolic 
Rate  Determinations." 


ii- 

11 


Fig.  19-a.  Henderson  modification  of  Haldane  apparatus  (Bailey).  (1)  Burette 
graduated  in  hundredths  of  a  ex.;  (2)  four-way  stop  cock  at  top  of  burette;  (3)  con- 
trol tube  same  volume  as  burette;  (4  and  5)  glass  tubes  for  circulation  of  air  through 
water  jacket;  (6)  mercury  reservoir  for  varying  pressure  in  control  tube;  (9)  mer- 
cury reservoir  for  filling  and  emptying  burette;  (10  and  11)  cord  and  counter-weight 
for  suspending  mercury  reservoir;  (12t  potash  pipette;  (13,  14,  15)  tubing  and 
leveling  bulb  for  potash  pipette;  (16)  pyrogallol  pipette;  (17)  leveling  on  pyrogallol 
pipette;  (18  and  19)  leveling  marks  on  potash  pipette;  (20)  connection  to  sampling 
bottle. 


e.  Analysis  of  Outdoor  Air. — Haldane  working  with  the  portable 
form  of  his  apparatus  found  that  outside  air  contains  0.03  per  cent  of 
carbon  dioxid  and  20.03  per  cent  of  oxygen.  Benedict  using  the  Sonden 
apparatus  found  as  the  result  of  212  analyses  in  the  Back  Bay  district 


542 


JOHN  R.  MURLIN 


of  Boston  an  average  value  of  0.031  per  cent  for  carbon  dioxid  and  20.038 
per  cent  for  oxygen.  In  one  series  of  340  analyses  nearly  equally  divided 
among  18  Haldane  analyzers  of  the  type  described  in  Fig.  19  Boothby 
and  Sandiford  found  the  average  COo  in  the  air  taken  upon  the 
fire  escape  of  their  laboratory  in  the  middle  of  Rochester,  Minn.,  to  be 


Fig.  20.  The  air  analyser  of  Krogh.  This  apparatus  like  that  of  Zunlz  and 
Geppert  employs  separate  burettes  for  measurement  of  the  air  before  and  after 
absorption  of  CO2  and  oxygen.  The  air  is  moved  from  one  burette  to  another  by 
means  of  air  pressure.     For  details  of  operation  consult  the  original  article. 


0.03Y  per  cent  and  the  oxygen  20.930  per  cent.  In  a  second  series  of  343 
analyses  the  average  was  0.035  and  20.930  per  cent.  The  higher  percentage 
of  CO2  they  ascribe  to  the  fact  that  a  large  number  of  chimneys  in  the 
neighborhood  of  the  laboratory  gave  out  smoke  which  often  drifted  toward 
the  laboratory. 


NOKMAL  PKOCESSES  OF  ENERGY  METABOLISM     543 

Y.  Henderson  (Henderson  and  Morris)  has  devised  a  somewhat  simpler 
form  of  the  Haldane  apparatus  which  has  been  improved  in  certain  details 
by  Bailey  ^  at  the  N.  Y.  Post-Graduate  Hospital.  The  degree  of  accuracy 
necessary  for  ordinary  routine  analyses  for  the  determination  of  the  basal 
metabolism  in  the  hospital  is  easily  attainable  with  this  apparatus. 

Krogh  has  recently  described  an  apparatus  which  is  accurate  to  0.001 
per  cent.  He  finds  that  the  sources  of  en'or  wjiich  prevent  the  oxygen 
analyses  from  being  highly  accurate  in  the  Haldane  apparatus  are  inti- 
mately connected  with  the  presence  of  water  and  dirt  in  the  gas  burette. 
Water  must  of  course  be  pi-escnt  to  insure  the  saturation  of  the  gas  with 
water  vapor  and  dirt  accumulates  rapidly  from  the  contact  of  mercury 
with  the  i*ubber  tubing  and  with  oxygen.  Krogh  gets  rid  of  these  inter- 
fering factors  by  employing  three  separate  burettes  (Fig.  20,  1,  2,  3)  of 
which  one  ( 1 )  is  employed  exclusively  for  moving  the  air  to  and  from  the 
absorption  pipettes,  while  the  second  (2)  is  of  a  suitable  size  for  meas- 
uring the  air  before  and  after  the  absorption  of  COg,  and  the  third  (3) 
for  measuring  it  after  absorption  of  O.^.  The  water  vapor  necessary  for 
saturating  the  sample  air,  when  it  has  become  partially  dried  in  the  ab- 
sorption pipettes  will  be  supplied  by  the  first  burette  and  the  variations  in 
the  amount  of  water  present  has  no  influence  upon  the  accuracy  of  the 
measurements.  The  two  other  burettes  (2)  and  (3)  contain  just  enough 
water  to  insure  that  the  samples  remain  saturated. 

A  second  improvement  introduced  by  Krogh  in  this  appai*atus  is  that 
the  mercury  is  raised  and  lowered  in  the  burettes  not  by  raising  and  low^- 
ering  a  mercury  reservoir  but  by  means  of  air  pressure,  an  arrangement 
which  obviates  the  use  of  rubber  connections  between  the  burettes  and  the 
reservoirs  and  besides  facilitates  the  manipulation  considerablv  (Krogh 

id)). 

Still  another  apparatus  employing  the  open  circuit  method  is  deserving 
of  mention.  This  is  the  apparatus  of  Hanroit  and  Richet.  By  means  of 
air  valves  the  inspired  air  and  the  expired  air  are  separated,  both  being 
measured  by  meters.  In  addition  the  expired  air  is  measured  again  after 
absorption  of  the  carbon  dioxid  in  potash.  The  first  meter  gives  the  vol- 
ume of  the  inspired  air,  the  second  of  the  unchanged  expired  air,  and  the 
third  the  volume  of  the  expired  air  minus  the  volume  of  carbon  dioxid. 
The  volume  of  inspired  air  less  the  final  volume  of  expired  air  gives  the 
amount  of  oxygen  consumed.  The  method  as  carried  out  by  Hanriot  and 
Ttichet  does  not  seem  to  be  particularly  accurate;  but  Krogh  expresses 
the  opinion  that  the  method  has  great  possibilities  if  used  with  modern 
gas  meters  of  sufficient  size  and  placed  in  a  water  bath  where  the  volumes 
measured  would  be  subject  to  the  same  fluctuations.     Krogh  notes  that 

*  This  construction  of  the  apparatus  is  made  by  E.  Machlett  &  Son,  153  East  84th 
Street,  New  York  City. 


544  JOPIN  R.  MURLm 

the  volume  recorded  bj  a  meter  is  independent  of  the  rate  onlj  within 
certain  limits  corresponding  roughly  to  100  complete  revolutions  per  hour 
(Krogh(c)  ).  As  Benedict  has  shown  the  volumes  recorded  at  higher  rates 
than  this  are  smaller  than  the  actual  volumes,  but  if  the  high  rate  is  constant 
and  the  meter  is  calibrated  at  such  a  rate  it  is  quite  possible  to  record  vol- 
umes with  no  appreciable  error.  In  such  a  method  as  that  of  Ilanriot  and 
Richet  the  meter  employed  for  measuring  the  respiration  of  a  man  at  rest 
should  be  capable  of  measuring  correctly  not  less  than  12  meters  per 
revolution,  and  since  in  heavy  muscular  work  the  total  ventilation  may 
be  multiplied  tenfold  over  that  of  the  resting  rate  of  respiration  a  meter 
for  measuring  the  ventilation  of  the  lungs  would  need  to  have  a  capacity 
of  120  meters.  Krogh  has  recently  devised  a  spirometer  for  calibrating 
gas  meters  which  should  simplify  this  process  and  render  the  use  of  gas 
meters  much  more  reliable.  In  the  paper  describing  this,  apparatus  Krogh 
notes  that  in  wet  meters  with  a  constant  quantity  of  water  the  volume 
per  revolution  increases  with  increasing  rate  but  can  be  determined  with 
sufficient  accuracy.  Dry  gas  meters  he  finds  are  much  less  accurate  than 
wet  test  meters. 

2.  Closed  Circuit  Instruments. — There  are  two  well-known  forms 
of  respiration  apparatus  used  with  mouth-pieces  or  nose-pieces  and  con- 
structed on  the  closed-circuit  principle.  The  first  of  these  is  the  so-called 
Universal  respiration  apparatus  of  Benedict (ci)(e)  j  and  the  second  is  a 
modification  of  the  instrument  consti-ucted  by  Haldane  and  Douglas  de- 
vised by  Krogh  (a).  To  speak  of  the  second  form  first,  Krogh  has  so  de- 
vised his  instrument  that  it  may  be  used  continuously  for  a  considerable 
period  of  time  by  a  man  at  rest.  The  soda  lime  absorber  is  capable  of  re- 
taining 1000  liters  of  carbon  dioxid.  Oxygen  is  admitted  from  a  cylinder, 
being  passed  through  a  meter  which  records  electrically  by  closing  a  circuit 
each  time  the  meter  revolves  once  and  has,  therefore,  passed  a  certain  vol- 
ume of  oxygen.  A  recording  spirometer  gives  a  quantitative  record  of 
the  respiratory  movements.  Only  oxygen  absorption  is  determined  as  the 
apparatus  is  usually  employed,  but  carbon  dioxid  determinations  can  be 
made  by  drawing  samples  of  inspired  and  expired  air  from  certain  parts 
of  the  apparatus.  So  far  as  known  to  the  writer  this  form  of  apparatus 
has  never  been  used  in  the  United  States. 

The  apparatus  of  Benedict  on  the  other  hand  has  been  used  quite  ex- 
tensively. The  writer  has  made  almost  continuous  use  of  one  of  these 
over  a  period  of  nearly  twelve  years.  It  has  been  modified  and  improved 
from  time  to  time  and  is  used  to-day  as  shown  in  Fig.  21.  Attachment 
to  the  respiratory  passages  of  the  subject  is  effected  by  means  of  the 
Denayrouse  mouth-piece  or  the  rubber  nose-pieces  of  Benedict.  Quite  re- 
cently also  the  half  mask  of  Boothby  has  been  adapted  to  this  use  and  has 
given  much  satisfaction.  It  is  far  more  comfortable  than  either  the  mouth- 
piece or  the  nose-piece.     The  apparatus  is  constructed  with  three  trains 


ITOEMAL  PKOCESSES  OF  ENEKGY  METABOLIS]^!     545 

of  absorbers.  The  first  immediately  following  the  rotary  blower  consists 
of  two  Williams  bottles  containing  sulphuric  acid  which  wash  out  all  of 
the  water  from  the  expired  air  and  water  left  over  from  the  moistener 
bottle.  The  other  two  are  duplicate  trains  for  absorption  of  carbon  dioxid. 
Each  consists  of  two  soda  lime  bottles  and  a  Williams  bottle  containing 
sulphuric  acid.  By  thus  reducing  the  size  of  each  unit  a  vsmaller  and  much 
less  expensive  balance  can  be  employed  for  weighing  the  absorption  of 


Tig.  21.  The  Benedict  Universal  respiration  apparatus  as  emplojed  by  the  writer. 
The  spirometer  and  tubes  leading  to  the  face  mask  are  carried  on  a  separate  stand 
so  that  they  may  be  adjusted  to  a  subject  in  the  reclining,  sitting  or  standing  position. 
Oxygen  is  supplied  from  a  pressure  cylinder  and  is  measured  on  its  way  to  tlie 
spirometer  by  the  meter.  Two  sets  of  absorber.s  are  used  so  that  observations  may 
be  made  continuously  in  successive  periods. 


carbon  dioxid.  Oxygen  is  fed  into  the  circuit  from  a  high  pressure  tank 
through  a  reduction  valve  and  on  its  way  is  measured  by  a  Bohr  meter. 
The  spirometer  and  tubes  leading  to  the  subject  are  mounted  on  a  separate 
standard  so  that  the  height  of  the  mouth-piece  can  be  adjusted  for  a  sub- 
ject in  the  reclining,  sitting  or  standing  position.  The  same  apparatus, 
therefore,  can  be  used  for  basal  metabolism,  for  work  experiments^  or 
for  observations  on  the  influence  of  food. 

The  technique  as  worked  out  in  the  writer^s  laboratory  for  operation 
of  this  instrument  is  briefly  as  follows.    Let  us  suppose  a  basal  metabolism 


546  JOHN  R  MUKLIN 

is  to  be  determined.  The  subject  comes  to  the  laboratory  early  in  the 
morning  after  having  taken  a  very  light  breakfast  of  black  coffee  and 
toast,  or  no  breakfast  at  all.  For  half  an  hour  the  subject  is  required  to 
lie  perfectly  still  wearing  the  nose  clip  and  breathing  thi-ough  the  mouth- 
piece into  the  room  air  or  breathing  through  the  face  mask  into  the  room 
air.  He  thus  becomes  accustomed  to  all  the  sensations  incident  to  the 
experiment.  A  slight  pulsation  of  the  air  current  transmitted  from  the 
blower  is  felt  by  the  patient  unless  special  means  is  taken  to  muffle  it. 
Such  vibrations  may  become  very  annoying  to  the  subject. 

When  the  absorbers  have  been  weighed  and  the  patient  has  become 
sufficiently  composed  the  blower  is  staiied  and  the  apparatus  is  run  idle 
blowing  the  air  round  and  round  through  the  circuit  for  at  least  two  min- 
utes in  order  to  make  certain  that  any  carbon >diox id  left  over  from  a 
previous  observation  shall  have  been  completely  removed.  With  a  small 
weight  placed  upon  the  spirometer  this  preliminary  run  serves  also  to 
test  the  entire  circuit  for  tightness.  If  after  a  minute  or  two  the  spirom- 
eter holds  its  level  the  entire  circuit  is  air  tight  and  the  experiment 
may  proceed.    The  oxygen  meter  is  read  at  this  point. 

With  an  intelligent  subject  it  is  our  custom,  to  let  the  subject  turn  the 
valve  himself,  instructing  him  to  do  so  just  before  beginning  an  inspira- 
tion. With  a  subject  wholly  unaccustomed  to  the  apparatus  or  not  suffi- 
ciently intelligent  to  understand  what  is  meant  by  "respiratory  pause" 
the  observer  quickly  turns  the  valve  at  the  moment  of  respirator^'' 
rest  intei'vening  between  the  end  of  an  expiration  and  the  beginning  of  an 
inspiration.  In  either  case  the  second  hand  of  a  watch  is  read  at  the  in- 
stant the  valve  is  thrown.  If  the  air  current  is  passed  through  a  moisten- 
ing bottle  which  follows  the  acid  absorber  in  the  carbon  dioxid  train  the 
air  comes  to  the  subject  feeling  rather  soft  with  moisture,  and  also  feel- 
ing perhaps  a  little  cool  from  the  temperature  of  the  water.  These  are 
the  only  sensations  which  the  subject  should  experience,  when  the  valve 
is  thrown  connecting  him  with  the  circuit.  There  should  be  no  trace  of 
irritation  either  from  the  air  itself  or  from  the  apparatus  connecting 
with  his  face. 

AVith  a  little  experience  oxygen  can  be  fed  in  through  the  meter  at  ap- 
proximately the  rate  at  which  it  is  absorbed  by  the  subject.  This  method 
is  pi'eferable  in  the  writer's  opinion  to  the  intermittent  feeding  of  oxygen, 
providing  only  that  the  rate  of  flow  be  kept  low  enough  so  that  at  the  ter- 
mination of  the  observational  period  the  spirometer  shall  be  lower  than 
it  was  at  the  moment  the  valve  was  first  thrown.  It  is  far  more  important 
to  terminate  the  observation  correctly  with  reference  to  the  phase  of  i*es- 
piration  when  the  valve  is  thrown  than  it  is  to  terminate  the  observation 
on  the  second  by  the  watch.  The  obsei'ver,  therefore,  gives  his  entire  at- 
tention to  throwing  the  valve  and  only  notices  the  position  of  the  second 
Land  after  he  has  successfullv  thrown  the  valve.     The  blower  is  allowed 


Is^OEMAL  PKOCESSES  OF  ENEEGY  METABOLISM     547 


to  continue  running  for  two  or  three  minutes  until  the  spirometer  ceases 
to  fall  and  oxygen  is  then  admitted  until  the  spirometer  comes  hack  to  the 
original  level.     The  blower  continues  running  for  a  few  seconds  longer 
to    make    certain    that    this 
level  will  be  maintained,  the 
oxygen     now     having     been 
stopped,  whereupon  the  cur- 
rent  is  turned   oft'   stopping 
the    blower.       The    oxygen 
meter  is  now  read. 

If  a  second  obseryation 
is  to  follow  immediately  the 
valves  are  thrown  connecting 
wdth  the  second  set  of  ab- 
sorbers and  the  blower  im- 
mediately started.  As  soon 
as  it  is  certain  that  the  sec- 
ond train  of  absorbers  is  air 
tight  the  second  period  can 
be  started.  The  absorbers 
of  the  first  train  can  bo 
weighed  while  the  second 
period  is  running.  The  ba- 
rometer is  read  and  the 
temperature  of  the  water 
meter  measuring  the  oxygen 
is  recorded.  The  volume  of 
oxygen  is  then  reduced  to 
0°  and  760  mm.,  and  the 
carbon  dioxid  obtained  in 
grams  is  likewise  reduced  to 
the  standard  conditions. 
The  respiratory  quotient  is 
obtained  by  division  of  the 
volume  of  carbon  dioxid  by 
the  volume  of  oxygen. 

Kecently  several  forms 
of  so-called  portable  instni- 
ments    constructed    on    the 


Fig.  22.  Portable  respiration  apparatus  of 
Benedict  and  Collins.  A,  moiithpioce ;  //.  tube 
conducting  expired  air  to  bell  C;  /),  hair  dryer; 
E,  soda-lime  container;  F  and  G,  tubes  convey- 
ing air  current  to  mouthpiece  A;  IIU,  tank  in 
which  bell  C  floats;  J  and  K,  cord  and  pulley 
supporting  bell  C;  L,  counterpoise;  J/,  pointer  on 
counterpoise;  A',  thermometer;  O  and  P,  supports 
for  pulley  K.     a,  rubber  gasket;  6,  rubber  gasket; 

c,  c,  tubes  supporting  spirometer;  rf,  d,  lower 
part  of  frame  supporting  spirometer;  c  and  /, 
telescoping  tubes  supporting  mouthpiece  and 
tubing;  g,  g,  supporting  plates;  h,  h,  knolwt  fit- 
ting into  g,  g;  jk\  part  of  support  for  mouthpiece 
and  tubing;  wjw,  attachment  to  support  c,  c,  to 
tank  ////;  p,  circular  band  connecting  four  tubes, 

d,  d;  r,  r,  leveling  screws;  f,  sliding  ring;  u, 
knobs  for  support  of  apparatus  when  collapsed; 
ic,  sliding  ring.    • 


general  principle  of  the  uni- 
versal respiration  machine  of  Benedict  have  made  theii*  appearance.     The 
best  of  these  doubtless  is  the  one  described  by  Benedict  and  Collins.     It 
may  be  doubted,  however,  whether  it  is  wise  to  attempt  to  make  the  deter- 
mination of  basal  metabolism  a  bedside  or  office  procedure.     Special 


548  JOHi^  K.  MUKLIN 

laboratories  for  this  purpose  in  hospitals  or  elsewhere  will  continue  to 
give  more  accurate  results,  as  is  true  of  x-ray  and  electrocardiographic 
work  and  for  the  same  reasons. 


III.    Methods  of  Calculating  the  Heat  Production 
from  the  Respiratory  Exchange 

Historically  four  distinct  methods  (Le¥evre(g))  have  been  employed 
for  the  calculation  of  the  heat  production  from  the  chemical  changes  going 
on  in  the  body.  In  each  case  the  method  rests  upon  the  fact  established  by 
Lavoisier  that  the  products  of  respiration  are  the  products  of  combustion. 

1.  Calculation  from  Heats  of  Combustion  of  Carbon  and  Hydrogen. — 
This  method  possesses  only  historical  interest  to-day,  yet  it  should  be  pre- 
sented briefly  for  the  sake  of  the  underlying  principle  involved.  In  1783 
Lavoisier  published  a  celebrated  work  upon  the  respiratory  metabolism  and 
calorimetry  of  the  guinea  pig.  The  chamber  in  which  the  animal  was 
contained  was  traversed  by  a  current  of  air  from  which  the  carbon  dioxid 
was  absorbed  at  the  entrance  and  exit  in  potash  bottles.  The  gain  in 
weight  of  the  latter  less  the  gain  in  weight  of  the  former  gave  the  carbon 
dioxid  produced  by  the  animal.  In  ten  hours  a  guinea  pig  gave  olf  3.33 
gm.  of  carbon,  which  from  previous  experiments  Lavoisier  knew  was 
equivalent  in  heat  value  to  32G.76  g-m.  of  ice  melted  at  0°.  He  proved 
this  by  placing  the  pig  in  an  ice  calorimeter  and  found  341.08  g-m.  melted. 

In  1785  Lavoisier,  applying  his  work  to  the  human  subject  as  well 
as  to  the  animal,  established  the  fact  that  out  of  100  parts  of  oxygen  ab- 
sorbed, 81  parts  only  reappeared  as  carbonic  acid  gas;  and  he  concluded 
that  the  other  19  parts  were  combined  with  hydrogen  to  form  water  (Gavar- 
ret).  Eespiration  was  thus  seen  to  be  accompanied  by  double  combustion 
and  Lavoisier  proposed  by  quantitative  studies  of  the  respiration  to  deter- 
mine the  proportion  in  Avhich  oxygen  is  partitioned  between  carbon  and 
hydrogen  of  the  materials  in  the  blood  to  produce  carbonic  acid  gas,  water 
and  heat. 

But  this  is  not  all.  With  Seguin,  Lavoisier  (Lavoisier  and  S6guin(&)) 
made  a  series  of  experiments  upon  the  human  subject  and  dcmonsti-ated 
that  carbon  dioxid  is  produced  and  oxygen  is  absorbed  in  proportion  to  tlie 
mechanical  work  effected  by  the  organism.  ^'By  this  new  discovery 
Lavoisier  raised  the  theory  of  combustion  to  the  level  of  a  great  generaliza- 
tion and  revealed  for  the  first  time  the  essential  source  of  all  animal 
energy' '  ( LeFevr e (g)). 

A  method  devised  by  Dulong  consisted  simply  in  measuring  directly 
the  CO2  produced  and  indirectly  the  water  by  assigning  to  hydi-ogen  all 
the  oxygen  which  was  not  recovered  as  COg.  Since,  however,  it  is  not  cer- 
tain that  all  of  the  oxygen  which  escapes  combination  with  carbon  serves 


]S'OK.MAL  PKOCESSES  OF  ENERGY  METABOLISM     549 

only  for  the  formation  of  water,  Boussingault(6)  sought  to  establish  the 
exact  amount  of  hydrogen  burned  by  striking  an  exact  and  complete 
balance  of  materials  between  the  ingesta  and  the  ejecta  of  the  body. 

The  heat  of  combustion  of  carbon  and  hydrogen  having  already  been 
established  at  8.040  and  34.4G  kilo-calories  per  gram  resj^ectively,  Helm- 
holtz  calculated  by  Dulong's  method  that  a  man  of  82  kg.,  giving  off  in 
the  respiration  in  24  hours  878.4  gin.  COo  or  230.6  gm.  C  produced 
(239.6  X  8.04  =)  1,925  calories.  The  excess  of  oxygen  going  to  form 
water  combined  with  13.615  gm.  H  producing  (13.615X34.40=) 
469.172  calories.     The  total  heat  production  therefore  was  2395.55  Cal. 

Vierordt  by  a  method  entirely  analogous  to  that  of  Boussingault  cal- 
culated the  heat  production  from  the  known  metabolism  of  food  as  fol- 
lows: Taking  the  average  ration  of  the  adult  at  120  gin.  protein,  90  gm. 
fat  and  340  gm.  carbohydrate  and  leaving  out  of  account  the  hydrogen 
of  the  carbohydrate,  because  it  was  known  to  be  saturated  with  oxygen, 
there  were  in 


c 

H 

120  gm.  protein              64.18 

8.60 

90     "     fat                    70.32 

10.26 

340     "    carbohydrate  146.80 

Total         281,20 

18.86 

But  the  urine  and  feces  contained  unoxidized  carbon  and  hydrogen  de- 
tennined  at  29.8  gm.  for  the  former  and  6.3  gm.  for  the  lattei*.  The  net 
combustion,  therefore,  was  (281.20  —  29.8=)  251.4  gm.  C  and  (18.86 
—  6.3  =)  12.56  gm.  H,  and  the  heat  production 

251.4    X    8.04  =  2031.31  Cal. 
12.56  X  34.36  =    332.82     " 

Total         2364.13     " 

These  methods  of  calculating  the  heat  production  upon  the  heats  of 
combustion  of  hydrogen  and  carbon  contained  in  the  food  as  if  the  hydro- 
gen and  carbon  were  free  gases  are  now  knowTi  to  contain  an  error  of  at 
least  11  or  12  per  cent.  The  heat  of  combustion  of  formic  acid  (C02H2)> 
for  example,  is  not  equal  to  the  combustion  heat  value  of  C  and  Hg ;  for 
the  heat  value  of  Hg  is  683  Cal.  per  gram-mol  and  of  C  is  943  Cal.  per 
gram-mol;  whereas  that  of  COoHs  is  only  694  Cal.  ]>er  gi-am-mol.  The 
difference  between  the  combustion  heat  value  of  CO2H.2  and  the  sum  of 
the  values  for  C  and  H2  is  called  the  heat  of  formation. 

The  heat  production,  therefore,  must  be  based  upon  the  combustion 
of  the  organic  foodstuffs  themselves. 

2.  Calculation  from  the  Heats  of  Combustion  of  the  Organic  Food- 
stuffs.— Berthelot  and  Andre  determined  the  physiological  heat  value 
of  protein  (egg  albumin  coagulated  and  dried  at  100°  C.)  by  burning  in 


550  JOHN  R.  MURLIN 

the  calorimeter  and  deducting  the  quantity  of  heat  represented  by  the 
urea  formed  from  it.  The  bomb  value  of  the  protein  was  5.690  calories 
and  the  urea  833,  leaving  a  net  value  to  the  organism  of  4.857  calories  per 
gram.  The  average  values  for  eleven  different  food  proteins  was  found 
by  them  to  be  5.601  Cal.  and  the  net  value  after  deducting  the  urea  fonned 
was  4.750  Cal.  per  gram. 

In  the  conclusion  to  their  paper  Berthelot  and  Andre  state  that  the 
influence  of  the  intestinal  excretions  "cannot  modify  these  figures  very 
much  for  the  feces  in  man  form  a  very  small  fraction  of  the  weight  of  the 
food."  The  unabsorbed  residue  from  proteins  it  is  now  known,  however, 
constitute  as  much  as  10  to  15  per  cent  of  the  food;  hence  they  are  by  no 
means  negligible. 

The  exact  physiological  heat  values  of  these  organic  foodstuffs  was 
first  resolved  with  a  high  degTce  of  exactness  by  Kubner((i).  lie  proceeded 
from  the  known  fact  that  in  the  case  of  proteins,  iu*ea  is  not  the  only  nitro- 
genous waste  product  and  that  some  of  the  others  have  very  different  heat 
values  from  that  of  urea.  Besides  he  saw  the  necessity  of  deducting  the 
heat  value  of  the  feces  resulting  from  the  food  in  question.  An  example 
of  the  method  employed  by  Rubner  may  l)e  given  as  follows : 

Lean  meat  free  of  connective  tissue  >vas  taken  and  dried ;  it  was  then 
macerated  in  alcohol  to  insure  its  complete  dehydration.  After  drying 
again  and  evaporation  of  the  alcohol  it  was  macerated  once  more  in  ether. 
The  albumin  resulting  had  the  appearance  of  impier  mache  and  was  prac- 
tically free  of  salts.  When  this  material  was  powdered  and  burned  a 
bomb  heat  value  of  5.754  Cal.  per  gram  was  obtained. 

A  dog  was  fed  for  eight  days  with  116.8  grams  of  the  dried  and  puri- 
fied protein  daily.  The  urine  for  the  first  six  days  was  rejected,  and  that 
for  the  7th  and  8th  days  only  saved,  the  dried  residue  of  which  gave 
a  heat  value  of  2.706  calories  per  gi-am.  The  heat  value  of  urea  he  found 
to  be  only  2.523  Cal.  or  7  per  cent  less  than  that  of  the  whole  urine.  One 
gram  of  the  dned  matter  was  found  to  contain  0.414  gm.  of  N,  from  which 
it  was  found  that  1  gm.  of  IN"  in  the  urine  represented  6.690  calories. 

The  feces  contained  37,8  gm.  of  dry  matter  daily.  The  loss  by  non- 
absorption  therefore  was  3.24  per  cent.  Burned  in  the  calorimeter  this 
dry  matter  was  found  to  contain  5.722  calories  per  gTam.  When  the  ash 
was  deducted  it  was  found  to  have  a  heat  value  per  gram  of  6.852  calories, 
and  the  nitrogen  was  found  to  be  7.02  per  cent.  The  net  physiological 
beat  value  therefore  could  be  calculated  as  follows : 


Ingested  100  gm.  dry  protein  of  meat  575.40  Cal. 

^        ,    fUrinc— 109.450  Cal. 
Excreta|-p^.^ 


Feces—  18.540 


Total  -—  approx.  —  128.000 

Difference    —    —    447.400  or  4.47  Cal.  per  gram. 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM  551 

Making  furtlior  corrections  for  tlie  heat  of  im])ibition  and  of  solution  this 
figure  in  the  particular  experiment  cited  was  reduced  to  4.42  Cal.  which 
was  76.8  per  cent  of  the  gross  heat  value  of  the  protein  as  fed. 

Since  100  grams  of  the  dried  alhumin  of  meat  contained  16.50  gm. 
of  N  and  its  combustion  gave  a  heat  value  of  4.424  Cal.  per  gram  each 
gram  of  N  had  a  heat  value  of  20.66  Cal. 

With  unwashed  meat  the  value  came  out  25.08  calories  per  gram.  In 
the  same  research  Rubner(c?)  calculated  that  the  body  protein  of  a  starving 
rabbit  had  a  physiological  heat  value  of  3.842  Cal.  per  gram,  or  71.9 
per  cent  of  its  gross  heat  value,  or  again  24.04  calories  per  gram  of  IST. 

The  mean  physiological  heat  value  for  a  number  of  animal  proteins — 
paraglobulin  (4.371),  egg  albumin  (4.307),  casein  (4.404),  fibrin  (4.179) 
— was  found  to  be  4.21  Cal.  per  gram.  Conglutin  was  taken  as  a  type  of 
vegetable  protein  and  was  found  to  have  a  value  of  3.97  calories. 

Since  out  of  100  gTams  of  mixed  protein  in  human  food  about  60 
per  cent  is  taken  from  animal  sources  and  40  per  cent  from  vegetable,  Rub- 
ner  calculated  the  mean  value  for  food  protein  in  general  at  4.11  Cal. 
per  gi'am. 

Accepting  the  bomb  values  of  Stohmann  for  carbohydrates  and  con- 
sidering the  preponderance  of  starch  in  human  dietaries  Rubner  estimated 
the  physiological  heat  value  of  carbohydrates  in  general  (making  deduc- 
tion of  cellulose)  at  4.1  Cal.  per  gram.  For  fat  he  adopted  the  mean 
value  of  9.3  Cal. 

These  values — Proteins — 4.1  Cal. 
Fat    —    9.3     " 

C.  H.  —  4.1     "    have  become  standard  in  the  liter- 
ature of  metabolism  and  are  now  generally  used. 

Atwater  and  his  collaborators  in  this  country  have  adopted  a  some- 
what different  method  of  arriving  at  the  physiological  heat  value  of  the 
foodstuffs.  He  lays  down  the  principle  tliat  the  combustible  value  to  the 
body  is  found  by  subtracting  from  the  lieat  of  combustion  of  the  utUizahle 
food  the  heat  value  of  the  urine  corres|x>uding  to  the  food  in  question. 
The  average  utilization  (i.  e.,  ingestion  less  feces)  of  the  several  classes 
of  foods  he  gives  as  follows  (Atwater,  Benedict,  Smith  and  Bryant)  : 


Animal  Foods 
Cereals 
Legume^^  dry 
Sugar  and  Starch 
Legumes,  fresh 
Fruits 

The  fats  and  carbohydrates  being  completely  burned  in  the  body,  the  heat 
value  to  the  body  is  equal  to  the  total  calorimetric  value  of  the  portion  ab- 


Prot. 

Fat 

C.  H. 

97% 

95% 

98% 

85 

90 

98 

78 

90 

97 

, , 

, , 

98 

83 

90 

95 

85 

90 

90 

552  JOHJSr  K.  MUHLIN 

sorbed.  The  total  heat  value  of  the  urine  arising  from  the  incomplete 
oxidation  of  proteins,  its  heat  value  represents  that  fraction  of  the  j>o- 
tential  energy  of  the  proteins  absorbed  which  the  body  does  not  utilize. 
Utilization  thus  is  used  in  two  senses.  From  the  standpoint  of  absorp- 
tion it  is  that  part  of  the  food  which  exceeds  the  amount  excreted  through 
the  bowel.  From  the  standpoint  of  energj-  it  is  that  part  of  the  absorbed 
food  diminished  by  the  potential  energy-  of  the  bodies  excreted  in  the 
urine.  Comparing  the  method  of  Rubner  with  that  of  Atwater,  it  is  seen 
that  in  the  former  calorimetric  heat  value  equals  heat  of  the  specific  food 
ingested  less  the  heat  of  the  feces  less  heat  value  of  the  urine.  According 
to  Atwater  the  calorimetric  heat  value  equals  the  heat  value  of  the  utiliz- 
able  food  less  heat  value  of  the  urine. 

The  method  of  Eubner  is  more  direct  and  thermochemically  is  more 
correct;  but  it  is  impracticable  in  its  application  to  man  for  it  requires  the 
ingestion  of  a  perfectly  pure  (salt  free)  foodstuff.  The  method  of  Atwater 
is  open  to  the  objection  that  he  assumes  the  same  heat  value  for  the  pro- 
teins of  the  feces  as  for  the  corresponding  food  protein.  It  has  the  ad- 
vantage of  simplicity,  however,  in  that  it  employs  a  coefficient  of  utiliza- 
tion and  can  be  used  for  a  mixed  diet  both  in  animals  and  man. 

Woods  made  56  determinations  of  the  heat  value  of  the  urine  in  At- 
water^s  laboratory  and  found  an  average  value  per  gram  of  X  of  7.9  Cal. 
If  this  1  gi-am  of  1^  represents  6.25  gm.  of  protein  destroyed,  for  each 
gram  of  protein  absorbed  and  burned  there  is  a  loss  of  (7.9-7-6.25  =) 
1.25  Cal. 

The  heat  value  of  a  food  protein  may  then  be  found  by  the  follow- 
ing method.  Protein  of  meat  has  (table  above)  a  utilization  of  97  per  cent. 
Its  heat  value  is  5.65  Cal.  The  energ;\'  of  the  portion  utilized  is  5.65  X 
0.97=5.48  Cal.  per  gram.  But  from  this  value  must  bo  deducted 
the  heat  value  of  the  urine,  which  according  to  Wood's  deteiinination 
is  1.25  X  0.97  =  1.20  Cab  The  physiological  heat  value  of  meat  for  the 
human  subject,  therefore,  is  (5.48  —  1.20  Cal.  =)  4.28  or  in  round  num- 
bers 4.25  Cal. 

The  bomb  heat  value  of  cereal  protein  Atwater  found  to  bo  5.8  Cal. 
per  gTam ;  its  utilization  was  85  per  cent ;  therefore,  its  physiological  heat 
value  would  be  (5.8  X  0.85)  —  (1.25  X  0.85)  =  3.87  Cal.  per  gram. 
The  mean  physiological  heat  value  for  all  animal  proteins  was  given  by 
Atwater  at  4.27  Cal.  and  that  of  all  vegetable  proteins  at  3.74  Cal.  or 
4.05  Cal.  per  gram  for  food  proteins  generally.  It  is  now  Iniowii,  how- 
ever, that  the  utilization  of  cereal  protein  such  as  that  of  bread  is  more 
commonly  92  pen-  cent  rather  than  85  per  cent  as  found  by  Atwater.  This 
would  change  his  figure  for  vegetable  protein  from  3.74  to  3.98  Cal.  per 
gram,  and  if  the  percentage  of  animal  and  vegetable  proteins  in  the  diet 
be  placed  at  40  and  60  which  more  nearly  accords  with  practice  in  most 


ISrORMAL  PROCESSES  OF  ENERGY  METABOLISM     553 

countries  outside  of  the  United  States  tlie  mean  heat  value  to  the  body 

,^  ^       4.27X40  +  3.98X60         .,,,^^i       .  .  ,    .    ,, 
would  be:   -jrz =4.100  (JaJ.  which  is  the  average 

value  given  by  Rubner. 

The  physiological  heat  values  of  fat  and  carbohydrate  are  found  by  the 
Atwater  method  in  the  same  manner  except  that  no  ileduction  is  made  for 
the  urine.  The  average  utilizatign  in  the  human  subject  for  animal  fat 
being  95  per  cent  and  for  vegetable  fat  90  per  cent,  and  the  bomb  values 
being  9.5  Cal.  and  9.4  Cal.  res[X?ctively,  the  value  to  the  body  is  9.02  and 
8.46  Cal.  for  the  two  or  8.75  Cal.  for  food  fats  in  general.  For  carbohy- 
drates the  factors  are  4.2  Cal.  per  gram  bomb  value,  and  98  per  cent  utili- 
zation.   Therefore,  the  value  to  the  Iwdy  is  4.1  Cal. 

Both  Rubner  and  Atwater  have  justified  the  heat  values  of  the  several 
foodstuffs  to  the  body  by  direct  calori metric  experiments  upon  the  dog  and 
man  respectively.  Rubner(/)  hit  u]x>n  a  very  clever  method  of  confinning 
his  heat  values  with  the  aid  of  his  calorimeter.  In  one  experiment  he  fed 
a  dog  a  large  amount  of  protein  and  a  small  amount  of  fat;  in  another 
just  the  reverse.    The  metabolism  was  as  follows: 

1st  Exp.  X  elim.  10.09  gm. 

C.  of  fat  oxidized  9.06     " 

Total  Calories  379.50  Cal. 

2nd  Exp.  X.  elim.  2.95  gm. 

C.  of  fat  19.12    " 

Total  Calories  311.0     Cal. 

Let  x  be  the  heat  value  of  a  gram  of  nitrogen  and  y  the  heat  vakie  of  a  gram 

of  C  from  fat.    Then,  10.09x  +    9.06y -=  379.5  *'CaL 

2.95x  +  19.12y  =  311.0     " 

From  which  x  =  26.70  Cal. 

y  =  12.15     " 

Kow  1  gram  of  X  corresponds  to  6.49  grams  pure  protein  of  meat — 

26.70 
hence    1  gm.  =      '      =  4.05  Cal.     One  gram  C  corresponds  to  1.3  gm. 

12  15 
pure  fat;  hence  1  gm.  =--^Cal.  =  9.31  Cal. 

x.o 

Atwater  in  a  series  of  27  studies  on  human  subjects,  14  of  which  "were 
carried  out  in  the  calorimeter  devised  by  Rosa,  found  a  difference  between 
the  direct  measurement  of  heat  eliminated  and  the  theoretical  heat  produc- 
tion as  calculated  from  his  factors  of  less  than  1  per  cent,  which  may  be 
taken  as  satisfactory  proof  that  these  values  for  the  human  subject  are 
substantially  correct.  ^ 

"  The  only  difference  of  any  consenjuenee  between   Riibner's   and  Atwater*s  values 
applies  to   fat.     Modern  antlioritioa  who   have  been   most  under  the  influence  of  the 


554 


JOHN  K.  MURLIlsr 


The  method  of  Alimentary  Calonmetry  consists  then  simply  of  findino" 
tho  average  daily  ingestion  in  terms  of  protein,  fat  and  carbohydrate  and 
multiplying  by  the  standard  physiological  heat  values.  Thus  Gautier(6) 
gives  the  average  dietary  of  a  middle  class  Parisian  as  102  grams  protein, 
5G  gi-ams  fat  and  400  gi-ams  carbohydrate.  His  average  energy  utilization, 
therefore,  would  be:  102  X  -4.1  +  56  X  9.0  +  400  X  4.1  =  2562  Calor- 
ies. If  a  person  on  this  diet  were  in  equilibrium  of  nitrogen  and  weight, 
his  energy  production  would  be  equal  to  this  sum;  otherwise  not.  Besides, 
weight  is  not  a  satisfactory  criterion  of  energy  equilibrium  and  the  utiliza- 
tion when  tho  diet  is  made  up  of  different  articles  will  vary  considerably. 
All  we  are  justified  in  saying,  therefore,  is  that  an  average  regimen  of  this 
sort  represents  such  and  such  an  energy  value  to  the  body.  Some  persons 
w^ould  gain  in  weight  on  it ;  others  would  lose.  Another  example  is  the  fol- 
lowing taken  from  the  nutritional  surveys  of  Army  Camps  in  the  United 
States  made  by  the  Medical  Department  of  the  Army  in  1918  (Murlin  and 

Miller). 

TABLE  1 

Nutrients  and  Exebgt  Consumed  in  Training  Camps  of  U.  S.  Army 


Food  per  Man  per  Day 

Consumed 

Distr.  of  Fuel 

Value 

Nutrients 

Supplied 

Wasted 

Consumed 

Averages 
427  messes 

Proteins  gra. . . 

Fat  gm 

Carbohydrate   . 
Fuel  Value,  Cal. 

131 
134 

516      • 
3899 

9 

11 

31 

266 

122 
123 

485 
3633 

14% 

31% 

55% 

100% 

The  "Fuel  value  consumed''  in  this  and  similar  tables  gives  the  energy 
value  to  the  body  of  the  food  consumed  and  not  the  amount  of  energy  re- 
leased by  the  body.  Upon  the  diet  of  the  Army  Camps  in  1018,  tbe  aver- 
age recruit  gained  nearly  six  pounds  in  weight  during  a  period  of  five 
months  training,  showing  that  the  energy  content  of  the  food  was  consid- 
erably more  than  sufficient  to  sustain  the  muscular  activity  of  hard  train- 
ing and  to  maintain  body  weight.  ^ 

The  admd  heat  pt^oduction  in  any  given  case  can  be  computed  from  the 
physiological  heat  values  just  discussed  provided  the  output  of  carbon  and 
nitrogen  can  be  determined,  and  provided  it  be  assumed  that  all  of  the 
carbohydrate  fed  is  burned  before  fat  burns.     This  method  of  calculation 

German  school  of  metabolism  have  adopted  Rubner's  values  of  9.3;  while  French  au- 
thorities like  Gautier  and  LeFevre  have  accepted  the  work  of  Atwater  as  equally  con- 
clusive with  that  of  Rubner  and  have  adopted  a  mean  value  between  the  two  authorities 
of  9.0  Cal.  per  gram.  Since  tlie  methods  of  calculating  the  actual  lieat  production  by 
use  of  these  values  have  been  largely  superseded  by  the  method  of  thermal  quotients 
to  b«/  described  in  tl.e  next  section,  tlie  controversy  over  these  values  has  subsided. 

^  Hecruits  fed  in  this  way  for  several  months  have  almost  certainly  a  liigher  basai 
metabolism  (see  page  GOT)  than  civilians  of  tlie  same  initial  weight  and  age,  and  it 
is  not  yet  certain  that  the  benefit  from  the  standpoint  of  muscular  efficiency  is  com- 
mensurate witli  the  cost  in  superfluous  metabolism.  This  is  a  problem  whicli  requires 
caieful  study  by  the  army  itself. 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     555 

was  first  applied  by  Rubner  to  the  results  obtained  by  Voit  and  Petten- 
koft'er  on  a  fasting  man  (  Lusk(/i) ).  These  observers  had  found  that  their 
subject,  weighing  71.00  kgm.,  gave  off  in  the  respiration  and  in  the  urine 
207.11  gm.  carbon  and  in  the  urine  11.33  gm.  nitrogen.  Deducting  from 
the  t(jtal  carbon  the  carbon  (3.28  times  the  2s)  belonging  to  protein  the  re- 
mainder was  calculated  as  carbon  of  fat  and  it  was  learned  tliat  the  man  had 
burned  70.81  gm.  protein  and  22.1  gm.  fat.  Rubner  applied  his  physio- 
logical heat  values  for  a  gi-am  of  N  in  starvation  (2-4.08  Cal.)  and  for  a 
gram  of  carbon  in  fat  (12.3  Cal.)  and  learned  that  the  total  energy  pro- 
duction of  the  man  in  twenty-four  hours  was : 

11.33  gm.  N  X  24.98  =  283  Cal. 

166.95  gm.  C  of  fat  x  12.3  =  2091  Cal. 


Total     2374  Cal. 

When  the  food  contains  only  fat  and  pi*otein  exactly  the  same  method 
is  used  for  calculating  the  heat  production,  except  that  the  heat  value  of 
nitrogen  in  the  urine  has  a  different  value  (see  page  552).  When  the 
food  contains  carbohydrate  any  gain  or  loss  of  C  to  the  body  may  be  esti- 
mated as  fat,  it  being  assumed  that  the  amount  of  glycogen  in  the  tissues 
is  the  same  at  the  end  of  an  experiment  as  at  the  beginning.  It  will  be 
seen  later  that  Rubner,  employing  this  method  of  calculation  in  experi- 
ments on  the  dogs  whose  heat  production  was  measured  simultaneously  in 
a  calorimeter,  found  perfect  agi*eement  between  the  heat  as  calculated  and 
as  measured,  thereby  proving  the  essential  correctness  of  the  method.  At- 
water's  method  of  calculation  in  similar  experiments  on  human  subjects 
was  different,  but  proved  to  be  equally  correct. 

3.  The  Method  of  Thermal  Quotients  of  Oo  and  OOg. — ^When  an  or- 
ganic foodstuff  is  burned  in  the  animal  body  a  definite  amount  of  oxygeji 
is  absorbed  and  a  definite  amount  of  CO2  is  formed  and  eliminated.  If  the 
heat  formed  by  such  a  combustion  is  known  the  heat  value  of  a  gTam 
of  oxygen  absorbed  or  of  a  gram  of  COg  eliminated  may  be  expressed  as 
a  simple  quotient  of  heat  divided  by  the  weight  of  the  gas.  Since  the 
measurement  of  the  respiratory  gases  by  volume  is  an  easy  matter  the 
thermal  quotient  can  be  expressed  also  in  relation  to  a  liter  of  gas  at  0^  C. 
and  760  ram.  of  pressure  or  at  any  other  desired  temperature. 

a.  Calculation  of  Thermal  Quotients. — If  we  suppose  that  protein 
burns  only  to  the  stage  of  urea  the  thermal  quotient  for  this  foodstuff 
may  be  calculated  from  the  following  equation : 

CrzHno^^'isSOas  +  17  0^=-  63  COo  +  37  HoO  +  0  COX2H4  +  H^SO^ 
Albumin  Urea 

According  to  this  equation  1.612  gm.  of  protein  yielding  7.810  Cal.  of  heat 
would  consume  77  molecules  of  O2  weighing  (77  X  32  =)  2.464  gm.  and 


556 


SOK^  R  MITHLIN 


63  CO2  weighing  (63  X  44  =)  2.772  gin.  For  oxygen  the  thermal  quo- 
tient would  be  (7.810-^2.464  =)  3.19  Cal,  per  gi-am  and  for  CO2 
(7  810-7-2.772  =)  2.82  Cal.  per  gm.  Or,  on  the  basis  of  volume  at 
0°  and  760, 

4.54  Cal.  per  liter  of  Og 
and  5.44  Cal.  per  liter  of  COg 

For  fat  the  thermal  quotient  may  be  calculated  from  the  following 
equation:    CstHio  A  +  80  O,  -  57  CO2  +  52  H.O 
Triolein 

From  this  it  follows  that  0.884  gm.  of  this  particular  fat  yielding 
8.423  Cal.  would  require  80  molecules  of  O2  weighing  (80  x  32  ==)  2.560 
gms.  and  57  molecules  of  CO2  weighing  (57x44=)  2.508  gms.  One 
gi-am  of  O2  therefore  has  a  heat  value  of  (8.423-^2.560  =)  3.29  Cal. 
and  one  gi-am  of  COg  (8.423-^-2.508  =)  3.35  Cal.  or,  on  the  basis  of 
volume  at  0°  and  760, 

4.70  Cal.  per  liter  of  Og 
and  6.58  Cal.  per  liter  of  CO2 

For  carbohydrate  the  equation  is:  CtjHioOg  +  6  O2  =  6  COg  + 
5II2O  and  the  thermal  quotients  are :    5.09  Cal.  per  liter  of  O2 

and     5.09  Cal.  per  liter  of  COg 
The  results  may  be  summarized  as  in  the  table  below. 

TABLE  2 

THER3IAL   QUOTIELNTS    {  LefIiVRE  (  gr )  ) 


Cal.  per  Gram 

Ca].  per  Liter 
at  0"  and  760  mm. 

at  18**  C. 

Gms.  Oj  Con- 

sumed  per 

Gram  of 

0, 

CO, 

0, 

CO, 

0, 

CO, 

Foodstuffs 
Burned 

Proteins 

Fats   

3.19 
3.29 
3.56 

2.82 
3.35 
2.59 

4.54 
4.70 
5.09 

5.44 
6.58 
5.09 

4.261 
4.410 
4.776 

6.104 
6.174 
4.776 

1.524 
2.896 

Carbohydrates. 

1.185 

To  estimate  the  mean  thermal  quotient  for  a  mixed  diet  the  method  is  a 
simple  one.  For  example,  take  the  mean  food  consumption  of  the  average 
soldier  in  the  training  camps  (p.  554)  namely,  122  gm.  protein,  123  gm. 
fat  and  485  gm.  carbohydrate.  The  amount  of  oxygen  required  for  the 
combustion  of  these  quantities  of  the  several  foodstuffs  would  be : 


122  gm.  Protein  x  1.524 


123  g-m.  Fat 
485  gm.  C.  H. 


185.9  gm.  O5 

X  2.896  =  356.2     "  " 

X  1.185  =  574.7     "  " 

Total         1116.8     "  " 


FORMAL  PROCESSES  OF  ENERGY  METABOLISM     557 

^Multiplying  each  of  these  quantities  of  oxygen  by  the  respective  thermal 
quotients  (see  table  above)  for  the  different  foodstuffs: 

185.9  gm.  O2  X  3.19  =  593.1  Cal. 
356.2  "   "  X  3.29  -=  1172.0  " 


j;>74.7 
Sums    1116^ 


X  3.56  =  2046.0 


3811.1 


From  this  calculaticm  1  gm.  02  =  3.41  calories. 

For  a  liter  of  oxygen  at  18°  C.  the  mean  thermal  quotient  would  bo 
4.60^  Cal.  (nearly). 

Laulanie(a)  conducted  experiments  on  small  animals  at  or  near  this 
temperature  by  means  of  a  small  calorimeter  and  computed  the  oxygen  ab- 
sorbed by  analysis  of  the  air  of  the  chamber  after  a  short  period  of  con- 
finement. The  average  value  of  the  thermal  quotient  found  by  him  was 
4.71  Cal.  per  liter  as  calculated  from  the  metabolism  and  4.75  Cal.  as 
measured  by  the  calorimeter. 

Atwater  and  Benedict (c)  in  a  series  of  12  experiments  on  mixed 
diets  found  as  an  average  a  heat  production  for  24  hours  of  2238  calories 
and  an  oxygen  absorption  of  652.1  gm.  The  mean  thermal  quotient  in 
this  series  was  3.4:i  Cal.  per  gi^am^  which  agrees  very  well  with  the  the- 
oretical value  based  upon  a  mixed  diet  At  18°  C.  the  heat  value  per 
liter  of  O2  would  be  4.61  Cal. 


TABLE  3 
Thermal  Quotient  of  0,  Based  Upon  Experiments  on  Man  (At>vater  and  Benedict) 


Exp.  No. 

Heat  Measured 

Weight  of  Oa 

Thermal  Quotient 

Cal. 

Absorbed  Gms. 

Cal.  per  Gm.  0, 

1 

2379 

708.0 

3.36 

2 

2279 

681.2 

3.34 

3 

2085 

603.2 

3.45 

4 

2403 

689.0 

3.48 

5 

2287 

664.8 

3.44 

6 

2309 

658.1 

3.50 

7 

2151 

628.5 

3.42 

8 

2193 

630.2 

3.47 

9 

2176 

659.7 

3.30 

10 

2244 

647.5 

3.46 

11 

2272 

65G.0 

3.46 

12 

2079 

600.6 

3.46 

Mean 

2238 

652.1 

3.43 

The  gieatest  deviation  frojn  the  mean  is  represented  by  experiment 
No.  9  where  it  is  only  3.9  per  cent. 

Ill  the  case  of  a  man  on  a  lacto-vegetarjan  diet  containing  39  gm.  pro- 
tein, 25  gm.  fat  and  265  gm,  carbohydrate  Atwater  and  Benedict  found 
that  1800  Cal.  of  heat  were  eliminated  and  that  the  absorption  of  oxygen 
>The  weight  of  a  liter  of  oxygen  at  18°  C.  is  1.341  gm.;  that  of  CO,  is  1.804  gm. 


658 


JOHN  R  MURLIN 


footed  up  528  grams.  The  thermal  quotient  therefore  was  3.41  Cal.  as 
against  a  theoretical  value  of  3.45  calculated  from  the  composition  of  the 
diet.  The  error  involved  in  the  use  of  a  thermal  quotient  of  3.43  Cal.  per 
gram  for  vegetarian  as  well  as  mixed  diet  would  not  be  in  excess  of  0.5 
per  cent. 

The  values  thus  far  discussed  were  obtained  upon  the  resting  subject. 
Would  they  apply  equally  to  a  subject  engaged  in  heavy  muscular  work 
where  oxygen  is  utilized  not  merely  for  production  of  heat  by  combustion 
but  also  for  the  transformation  of  the  food^s  potential  energy  into  mechan- 
ical work?  Lefevre(5')  has  calculated  the  thermal  quotients  for  many  of 
the  work  experiments  found  in  At  water's  publications  and  has  grouped 
them  as  given  in  the  table  below.  The  amount  of  work  reckoned  on  the 
basis  of  24  hours  was  from  120,000  to  190,000  kilogrammeters. 

TABLE  4 
Thermal  Quotients  of  O,  During  Muscular  Work  (Atwater  and  Benedict) 


Experiment 

Heat  Measured 
Cal. 

Oxygen  Absorbed 
Gms. 

Thermal  Quotient 
Cal.  per  Gm.  0, 

Mean  of  3  exp.  on  fat-rich  diet 
Mean  of  3  exp.  on  CH  rich  diet 
Mean  of  8  exp.  on  fat-rich  diet 
Mean  of  8  exp.  on  CH  rich  diet 

3570 
3099 
5128 
5142 

1053.5 
1081.6 
1512.7 
1465.6 

3.39 
3.42 
3.39 
3.50 

Mean    

4385 

1278.5 

3.425 

It  appears  that  the  mechanical  equivalent  of  oxygen  when  expressed 
as  heat  is  the  same  as  the  pure  combustion  equivalent.  This  is  a  very  sig- 
nificant fact  for  it  means  that  the  liberation  of  energy  from  combustible 
substances  is  a  constant  function  of  the  oxygen  absorbed  whetlier  that  en- 
ergy take  the  form  at  once  of  free  heat  or  pass  first  through  the  form  of 
mechanical  work. 

It  is  clear  that  if  the  oxygen  absorption  of  a  subject  is  known  the 
amount  of  energv'  liberated  in  the  body  (not  necessarily  the  amount  of 
heat)  can  be  found  with  a  high  degree  of  accuracy  by  simply  multiplying 
the  number  of  grams  of  oxygen  by  3.43  Cal.  or  the  number  of  liters  at  0° 
and  700  by  4.00  Cal.  or  the  number  at  18°  C.  by  4.60  Cal. 

b.  Thermal  Quotient  of  Carbon  Dioxid, — Results  not  nearly  so  con- 
stant are  obtainetl  when  the  carbon  dioxid  elimination  is  employed  as  the 
basis  of  computing  the  heat  production.  For  example,  when  tristearin  is 
completely  oxidized  the  thei-mal  quotient  of  COg  is  3.35  Cal.  ])er  gi-am. 
When  glucose  is  completely  oxidized  it  is  only  2.59  Cal.  per  gram  (Table 
2).  Besides,  it  is  possible  to  have  COg  produced  in  largo  excess  when  glu- 
cose is  transfonned  into  fat,  and  when  the  heat  production  is  very  low.  Un- 
der these  circumstances  the  thei-mal  quotient  of  CO^  is  given  by  Lefevre  at 
0,3  Cal.  per  gram.    Finally,  if  fat  is  ever  converted  to  glucose  in  the  body 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     559 

(and  the  possibility  of  this  reaction  lias  never  been  disproveil)  the  pro- 
duction of  carbon  dioxid  in  proportion  to  the  amount  of  heat  disengaged 
would  be  very  small  and  the  thermal  quotient  would  be  correspondingly 
high.  Lefevre(^)  has  brought  together  results  from  Atwater  and  Bene- 
dict's work  to  show  that  the  weight  of  COg  produced  for  each  100  Cal.  of 
heat  eliminated  from  the  human  body  is  very  variable.  The  results  are 
given  in  the  table  below. 

TABLE  5  5, 

Variation  in  Heat  Equivalent  of  CO,  (AT^VATER  and  Benedict) 


Condition 

Heat  Measured 
per  24  Hrs.,  Cal, 

Weight  of  GO,  Elimi- 
nated in  2-i  Hrs.,  Gm. 

CO,  in  Gm.  per  100 
Cal.  of  Heat 

Inanition   

2346 
2287 
2272 
3420 
5205 
5178 

C98.0 

823.5 

846.7 

'       1158.0 

1657.0 

1884.0 

29.8 

Restinor  

36.0 

Restin"^  

37.2 

Moderate  work    

Severe  work   

Severe  work  

33.9 
31.8 
36.4 

Even  in  experiments  of  long  duration  it  is  evident  that  the  calculation 
'of  heat  production  upon  the  basis  of  the  carbon  dioxid  contains  an  inherent 
error  of  as  much  as  25  per  cent.  In  experiments  of  short  duration  the 
error  would  be  even  greater.  In  fact,  of  the  series  of  experiments  from 
which  the  figures  given  above  were  obtained  many  were  performed  in  two 
hour  periods  so  that  it  is  possible  to  follow  the  heat  as  measured  and  the 
CO2  from  period  to  period.  In  spite  of  a  perfectly  uniform  heat  elimina- 
tion the  COo  elimination  varies  at  times  as  much  as  40  per  cent. 

c.  The  Respiratory  Quotient  and  Its  Significance, — Even  thougli  the 
value  of  the  oxygen  absorption  in  terms  of  heat  may  be  fairly  constant, 
so  that  for  long  periods  the  calculation  of  the  energ;^'  production  may 
proceed  upon  this  basis  with  involvement  of  very  slight  error,  the  re- 
quirements of  short  experiments  are  more  rigorous.  For  it  is  quite  pos- 
sible that  an  observation  of,  say,  only  15  minutes  duration  made  perchance 
soon  after  a  meal  would  coincide  with  maximum  absorption  of  carbohy- 
drate; while  another  made  some  hours  later  might  very  well  coincide  with 
the  maximum  absorption  and  combustion  of  fat.  Two  such  periods  could 
not  be  concordant  if  the  averag-e  thermal  quotient  for  oxygen  were  used. 
The  respiratory  quotient,  how^ever,  enables  us  to  know  what  kind  of  food 
is  being  oxidized  at  any  given  time,  or  at  least  what  possible  combinations 
of  combustion  there  may  be. 

If  a  sample  of  pure  food,  e.  g.,  cane  sugar,  be  placed  in  a  bomb  vnth 
oxygen  and  ignited,  it  is  possible  to  learn  the  amount  of  combustion  by 
analyzing  the  gases  before  and  after  firing.  In  the  case  of  pure  carbo- 
hydrate it  would  be  found  that  just  as  much  oxygen  by  weight  has  disap- 
peared as  is  contained  in  the  carbon  dioxid  formed.  Or,  since  equal  vol- 
umes of  all  gases  contain  the  same  number  of  molecules  at  the  same  pres- 


560  JOHN  R  MURLIiSr 

sure  and  temperature,  it  would  be  found  upon  reduction  to  standard  con- 
ditions that  the  volume  of  COg  proiluced  had  just  replaced  the  volume 
of  O2  consumed. 

The  same  method  may  be  employed,  in  fact  has  been  re]>eatedly  em- 
ployed, especially  by  the  French  students  of  respiratory  metabolism,  to 
examine  the  quality  of  combustion  in  the  human  body.  For  example, 
Weiss  sealed  a  child  up  in  a  closed  box  containing  pure  air,  and  at  the 
end  of  an  hour  drew  off  samples  for  analysis.  The  box  had  a  capacity 
of  60  liters  and  in  this  amount  of  atmospheric  air  the  child  could  subsist 
for  several  hours.  Comparing  then  the  composition  of  the  air  at  the  end 
of  an  hour  with  the  composition  at -the  beginning  it  was  found  that,  in 
certain  instances,  the  carbon  dioxid  produced  had  exactly  replaced  the  oxy- 
gen utilized  by  the  child.  The  observer  correctly  inferred  tJiat  carbo- 
hydrate had  been  the  source  of  the  energy  liberated  by  the  combustion; 
for  in  carbohydrate  there  is  nothing  to  unite  with  oxygen  except  carbon, 
the  hydrogen  present  being  already  cared  for  by  the  intramolecular  oxygen. 
In  this  instance  the  relation  by  volume  of  the  carbon  dioxid  produced  to 
oxygen  absorbed  would  be  1.0.  This  relationship  in  metabolism  is  the 
respiratory  quotient. 

The  actual  chemical  reactions  involved  in  the  combustion  of  the  sev- 
eral organic  foodstuffs  will  now  be  given  and  the  respiratory  quotients 
typical  of  each  deduced  therefrom. 

Glucose,  the  normal  sugar  of  the  blood  is  oxidized  thus: 
CgHiaOo  +  6  O2  =  6  CO2  +  6  H2O 

The  relation  of  CO2  by  volume  to  the  O2  is      ^    =  1.0,  or  the  rela- 

D    vy2 

6    O 

tion  by  weight  of  the  O2  in  COo  to  O2  absorbed  is      ^  =  1.0. 

6  U2 

The  respiratory  quotient  is  unity.     When  a  simple  fat  like  palmitine, 

C3H5(Ci6Hyi02)3  is  burned,  conditions  are  as  follows:    The  fat  may  be 

written  thus:     CgiHogOo  and  its  cojnbustion  w^ould  proceed  according  to 

the  equation : 

CsiHosOe  +  72.5  O2  =  51  COo  +  49  H2O 

51 

The  relation  of  CO2  by  volume  to  the  Oo  is  -p—-    =  0.703,  which  is 

the  respiratory  quotient.  With  a  simpler  fat  such  as  the  butyrate :  CgHj 
(C4Hj02)3.,  the  relationship  would  be  quite  different,  owing  to  the  rela- 
tively larger  quantity  of  O2  already  present  in  the  molecule.  Thus: 
C15H20O2  -f  I8.50J  =  I5CO2+  IBHoO.     The  respiratory  quotient 

15 

would  be   --—  =  0.81.     Food  fats  are  for  the  most  part  composed  of 
18.5 

the  glycerides  of  palmitic,  stearic,  and  oleic  acids,  an  average  composition 

on  the  percentage  basis  being  76.5  per  cent  C;  11.9  per  cent  H;  and  11.6 


KORMAL  PROCESSES  OF  ENERGY  METABOLISM     561 

per  cent  O.  One  hundred  g-rams  of  such  fat  would  require  288.6  gm. 
O2  in  addition  to  that  ah-eady  present  in  the  molecule  for  complete  con- 
version to  COo  and  HgO.    There  would  be  produced  280.5  gm.  CO2.    The 

relationship  of    —^    is    ^7^^    and  this  divided  by    — ,  the  molecular 
O2  2  00.0  o2 

c 
weight,  or  multiplied  by  -—  w^ould  give  the  respiratory  quotient  ==  O.TO6. 

A  slightly  simpler  calculation,  as  noted  above,  is  to  determine  the  weight  of 

O2  necessary  to  form  CO2,  (in  this  case  204.0  giamsj   and  divide  this 

204.0 
directly  by  the  weight  of  total  O2  required;  thus:  -^^^  =  0.706. 

The  respiratory  quotient  of  all  food  fats  is  in  the  neighborhood  of 
0.71.  The  same  is  true  also  of  body  fat.  Hence  whether  pure  body  fat 
or  pure  food  fat  were  being  buraed,  the  R.  Q.  would  be  approximately  0.71. 
As  a  matter  of  fact,  this  quotient  is  probably  never  actually  produced 
under  normal  conditions;  for  there  is  always  some  protein  being  de- 
stroyed, and,  since  under  the  conditions  of  high  fat  combustion,  whether 
from  starvation  or  excessive  fat  ingestion  this  small  amount  of  protein 
is  readily  oxidized,  there  is  a  mixed  quotient  contributed  in  small  part 
by  the  oxidation  of  protein  and  in  large  part  by  the  oxidation  of  fat.  On 
the  assumption  that  the  protein  quotum  of  energy  production  is  15  per. 
cent  and  the  other  85  per  cent  is  from  fat,  Magnus-Levy  estimates  that 
the  actual  respiratory  quotient  should  be  0.722,  while  if  the  remaining 
85  per  cent  is  produced  from  carbohydrate,  the  quotient  should  be  0.971. 

The  respiratory  quotient  of  proteins  will,  of  cx>urse,  depend  upon  the 
exact  formula  employed ;  but  since  all  proteins  arc  made  up  of  amino  acids, 
the  exact  relationship  can  best  be  appreciated  by  starting  with  a  single 
amino  acid.  If  alanin  is  given  to  an  animal,  it  will  be  oxidized  after  deam- 
ination,  as  follows : 

CH3 .  CHXH2 .  COOH  +  HOH  =  CH3 .  CHOH .  COOH  +  NH3 
CH3.CHOH.COOH  +  3O2  ==  3CO2  +  3HoO 

The  respiratory  quotient  of  this  reaction  would  be  1.0  since  the  volume 
of  O2  is  just  equal  to  the  volume  of  COg  produced.  But  the  j^Hs  is  not 
yet  disposed  of.  It  cannot  remain  in  the  body  as  NH3  and  it  cannot  he 
eliminated  as  a  gas,  for  the  lungs  are  not  permeable  to  NH3  even  if  it 
could  be  carried  in  the  blood  as  gas.  Actually,  the  NIE3  will  unite  with 
the  CO2  to  form  ammonium  carbonate,  thus : 

2  ]^H3  +  CO2  +  ir^O  -  (XH,)2  CO3 

Later,  this  is  converted  to  urea,  thus: 

-    NIIA  KHo\ 

CO3  — 21L>0=  CO 

]SrH4/  NHo/ 


562  JOHN  R.  MURLIN 

The  net  result  would  be  that  for  each  two  molecules  of  alanin,  yielding 
2  molecules  of  ^H3,  one  molecule  of  CO^  would  fail  to  appear  in  the  ex- 
pired air,  hut  would  be  eliminated  as  urea  or  water.  Hence,  for  6  mole- 
cules of  O2  absorbed,  only  5  would  come  back  as  COg  and  the  true  R.  Q. 
of  alanin  would  be  5/6  =  0.833,  If  all  proteins  w^re  made  up  of  amino 
acids  as  simply  as  this,  the  R.  Q.  for  their  combustion  would  be  as  easily 
computed.  The  respiratory  quotient  of  glycocoll  would  be  0.75;  that  of 
leucin  would  be  0.73.  But  that  of  lysin  containing  two  NH2  groups  and 
requiring,  therefore,  one  molecule  of  COg  for  elimination  of  the  N  as 
urea  for  each  single  molecule  of  the  substance,  would  be  only  0.71.  The 
more  diamine  acids  contained  in  a  protein,  therefore,  and  the  more  leucin, 
the  lower  would  be  the  respiratory  quotient.  With  gelatin,  which  con- 
tains a  high  percentage  of  glycocoll,  one  might  expect  a  somewhat  higher 
quotient  than  with  casein  which  contains  no  glycocoll  and  a  much  larger 
amount  of  leucin.  Taking  an  example  of  a  highly  synthetized  protein  such 
as  1-leucyl-triglycyl-l-leucyl-triglycyi-l-leucyl-octoglycyl-glycin,  which  was 
put  together  by  E.  Fischer  and  whose  exact  chemical  structure  is  there- 
fore known,  we  find  that  45  molecules  of  Og  would  be  necessary  to  produce 
complete  combustion ;  that  0  molecules  of  CO2  would  be  needed  to  remove 
the  NH2  in  the  form  of  (Nir4)2C03 ;  and  that  when  this  ammonium  car- 
bonate breaks  dowTi  by  dehydration  to  form  urea,  none  of  the  carbon  would 
return  to  the  respiration  and  none  of  the  oxygen  would  be  available  for 
combustion.     The  R.  Q.  therefore  would  be  0.81. 

Taking  the  elementary  analysis  of  protein  of  the  human  body  and 
adopting  the  percentages  used  by  !Magnus-Levy  we  get  the  following  com- 
position after  making  allowances  for  the  elements  which  would  appear 
in  the  urine  and  the  feces:  C,  38.6  per  cent;  H,  4.24  per  cent;  O,  9.24 
per  cent.  For  the  combustion  of  100  grams  of  such  protein,  127.6  gm. 
O2  in  addition  to  that  already  present  in  the  molecule  would  be  needed 
and  141.5  gm.  CO2  would  be  formed.  Taking  the  ratio  of  the  oxygen  in 
CO2  (102.9  gm.)  to  the  total  oxygen  required,  the  quotient  is  0.807  or 

by  the  long-er  calculation        ''   ^ —       ^  X-t=  0.807.     The  respiratory 

127.6  gm.  CO2      11 

quotient  of  a  complete  protein  such  as  is  ordinarily  used  in  rebuilding 

the  human  tissues,  but  which,  because  it  is  not  needed  for  this  purpose,  is 

oxidized  as  completely  as  it  is  possible  to  oxidize  protein  in  the  body,  is 

thus  approximately  the  same  as  that  for  alanin.     We  may  think  of  this 

amino  acid  as  representing  the  type  of  fuel  available  when  protein  is 

burned. 

Laulanie(c)   in  1898  gave  a  very  simple  method  of  calculating  the 

thermal  quotient  for  oxygen  from  the  respiratory  quotient.     This  method 

is  strictly  applicable  however  only  under  conditions  where  the  metabolism 

of  protein  is  entirely  negligible,  or  is  calculated  independently  and  suitable 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     563 

deduction  made  from  the  total  oxygen  absorbed.     The  method  follows: 

Let  a  be  any  R.  Q.  less  than  1.0.     Then  Vol.  COg  =  a  Vol.  Og.     Let  x 

be  the  part  of  O2  used  in  combustion  of  carbohydrate,  and  Vol.  Og  —  a;  the 

part  utilized  in  combustion  of  fat.     Then  Vol.   COo  —  x  is  the  CO2 

resulting  from  combustion  of  fat.     The  R.  Q.  of  fat  being  0.7  it  follows 

,      Vol.    CO2  — oj        ^^  Vol.    O^—x      ^^       ^ 

that-p- ~ =0.7   or,  a    ^^  1    r^  =  0.7,      From    which 

Vol      O2  —  X  Vol.  O2  —  X 


(a  — 0.7)  Vol.  O2 
03 


which  is  the  quantity  of  O2  utilized  in  combustion 


of  carbohydrate.    The  remainder,  Vol.  O2  —  x=  - — — — ^- '- — —  13  the 

0.3 

part  used  in  combustion  of  fat.    Calling  this  value  y  we  have :  for  carbo- 
hydrate X  =  — — — '—  and  for  fat  y  =  — -— — .    For  example  where  a.  is 
U.t>  0.3 

O  i 

0.9  a?  =  -  and  y  ==  -      The   thermal    quotient  of  oxygen  at  0^  and 
00 

2 
760  (page  556)  would  then  be  5.09  X  «  +  ^•'^  =  4.96  Cal.  per  liter,  or, 

3 

4.65  Cal.  per  liter  at  18°  C. 

A  single  example  of  the  use  of  the  respiratory  quotient  for  calculation 
of  the  heat  production  by  means  of  the  thermal  quotient  for  oxygen  will  be 
given.  Lefevre(/)  separated  the  inspired  air  from  the  expired  air  of  a 
subject  in  complete  muscular  repose  by  means  of  a  pair  of  Miiller  valves 
(page  533).  The  expired  air  was  measured  and  subsequently  analyzed. 
In  a  one-hour  period  the  amount  of  oxygen  absorbed  measured  at  18°  C, 
was  13.73  liters.  The  R.  Q.  was  0.89,  which  the  author  states  corre- 
sponds to  a  combustion  in  which  out  of  three  molecules  of  oxygen  absorbed, 
two  served  for  oxidation  of  carbohydrate  and  one  for  oxidation  of  fat. 
The  mean  thermal  quotient  then  would  be  4.77  X  2  -|-  4.41  =  4.65  Cal. 
per  liter.  The  heat  production  was  (13.73  X  4.65  =)  63.8  Cal.  per  hour 
or  about  1500  Cal.  in  24  hours.  This  minimal  metabolism  was  confirmed 
by  Lef evre  by  direct  calorimetry.  It  corresponds  well  with  later  determin- 
ations of  the  basal  metabolism  (see  page  607). 

4.  Calculation  of  Heat  Production  from  the  Respiratory  Exchange 
and  the  Urinary  Nitrogen. — The  method  outlined  above  even  when  the 
respiratory  quotient  is  known  is  defective  in  that  it  does  not  take  ac- 
count of  the  protein  metabolism  which  is  always  taking  place.  Apparently 
the  first  to  attempt  an  improvement  of  the  method  by  making  allowance 
for  the  protein  metabolism  was  Kauffmann.  His  paper  was  followed 
three  months  later  by  one  from  Laulanie  who  had  developed  similar  im- 
pi'ovements  quite  independently. 

a.  The  Method  of  Successive  Thermal  Quotients. — ^Instead  of  relying 
upon  a  mean  thermal  quotient  for  oxygen  which  answers  very  well  for 


664    ,  JOHiST  K.  MUKLUST 

long  experiments  Kauffmann  nnrlertook  to  find  an  exact  lieat  equivalent 
for  any  particular  short  period  by  what  he  called  successive  thermal  quo- 
tients. This  means  only  that  he  partitioned  the  oxygen  to  the  several 
organic  foodstuffs  and  multiplied  by  their  respective  thermal  quotients. 
For  example  in  an  experiment  on  a  dog  subjected  to  a  prolonged  fast  he 
found  that  the  animal  had  absorbed  in  1  hour  5.91)2  liters  of  Oj,  had 
given  off  4.494  1.  of  COo  and  eliminated  0.1983  gm.  JST  in  the  urine.  The 
E.  Q.  was  0.75.  The  nitrogen  corresponded  to  (0.1983  X  6.25  =)  1.239 
gm.  protein  burned,  which  in  turn  required  1.72  gm.  of  O2  to  oxidize  it  to 
the  stage  of  urea  (page  555).  Subtracting  this  from  the  total  oxygen 
(5.992  1.  =  8.57  gm.)  there  remained  6.85  gm.  for  combustion  of  fat.  The 
heat  production  w^as  found  as  follows : 

1.72  gm.  O2  X  3.19  =    5.486  Cal. 
6.85     "     "     X  3.29  =  22.536     " 
Total       28.022     " 

Applied  to  the  human  subject  in  good  nutritive  condition  and  sub- 
sisting on  a  mixed  diet  the  method  would  be  a  little  more  complicated. 
Thus  Arthus  reports  the  metabolism  of  a  man  for  24  hours: 

O2  absorbed  =  496  1.  or  709  gm. 

CO2  eliminated  =^  463  1.  or  912  gm. 

N  in  urine  17.35  gm.  =  108.44  gm.  protein 

The  protein  would  require  the  absorption  of  151  gm.  Og  and  elimination 
of  180  gm.  CO2. 

709  —  151  =  558  gm.      O2  or  390  1. 
912  —  180  ==  732     "     CO2  or  371  1. 

The  remainder  represents  the  metabolism  of  carbohydrate  and  fat. 

Let  X  be  the  volume  of  O2  for  combustion  of  fat  and  y  the  volume  of 
CO2  resulting.  Let  z  represent  the  volume  of  O2  and  CO2  for  combus- 
tion of  carbohydrate. 

Then  y  07=     0.70 
x-\-  z    ■  =  390  1. 
2/  +  «       =  371  1. 
From  which  x  =    63.33  liters  O2 
y=    44.33      ''      C62 
2=326.33      "        OgandCOg 

The  weights  of  a  liter  of  O2  at  760  mm.  Hg  and  0°  being  1.43  grams^ 
the  apportionment  of  Oo  would  be  as  follows : 

For  fat  (63.33  x  1.43  =)     90.56  gm. 
"     carbohydrate  467.12     " 

"     protein  151.0       " 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     665 

The  heat  production  then  would  be: 

90.56  X  3.29^--^-    297.9  Gal. 
467.12  X  3,56  =  1662.9     " 
157.0    X  3.19  =    481.7     " 


Total 


2442.5 


Kauffraann  confirmed  the  correctness  of  this  method  of  calculation  by 
means  of  a  calorimeter  (p.  571)  suitable  for  dogs.  His  results  may  be 
summarized  thus: 

TABLE  6 


Exp.  No. 

Heat  as  Calculated 

Heat  as  Pleasured 

I 

27.4  Cal. 

27.9 

Cal. 

II 

30.8 

(( 

30.0 

u 

III 

43.7 

« 

44.0 

€t 

IV 

39.1 

« 

38.1 

t( 

V 

37.7 

it 

37.4 

*< 

VI 

40.2 

f( 

39.0 

€t 

Mean  

36.07 

« 

36.07 

it 

The  discrepancy  between  the  two  methods  is  only  one  per  cent. 

b.  Method  of  Zuntz  atid  Schumherg  (b). — In  their  study  of  the  meta- 
bolisni  of  a  marching  soldier  Zuntz  and  Schumberg  developed  a  somewhat 
different  method  of  calculation  based,  however,  upon  essentially  the  same 
principles  as  the  method  of  Kauffmann.  All  calculations  ai*e  on  the  basis  of 
one  hour. 

The  iST  in  the  Urine  (per  hour)  (a)  X  2.56  =  C  from  protein  in  the  res- 
piration. 
The  CO2  output  in  grams  per  hour  X  3/11  =  C  output  in  gi-ams  per  hour. 
The  C  of  respiration  —  C  of  protein  in  respiration  =  C  of  carbohydrate 

and  fat  in  respiration  (b). 
N  in  urine  X  8.45  =  O2  from  protein  in  respiration. 
Total  O2  absorbed  —  O2  from  protein  f=  O2  absorbed  for  carbohydrate  and 

fat  (c). 
The  O2  for  oxidation  of  one  gTam  of  fat  =  3.751*  (average). 
The  Oo  for  oxidation  of  one  gram  of  CH  —  2.651  (average). 
Let  X  =  number  of  grams  C  f rom  fat  (1  gm.  C  from  fat  =  32.3  Cal.). 
Let  y  =  number  of  grams  C  from  CH  (1  gm.  C.  from  CH  =  9.5  Cal.). 

X  +  y  =  b.     (1  gm.  N.  from  Prot.  =  26.0  Cal.) 
3.751  x  + 2.651  y  =:c 

Solving  for  x  and  y,         a  X  26     =  Cal.  from  Prot. 

X  X  12.3  =  Cal.  from  fat. 
y  X    9.5  =  Cal.  from  CH 
Total  —  Cal.  per  hour. 
*  Compare  the  thermal  quotients  (see  page  556). 


566 


JOHN  R.  MURLIN 


5.  The  Non-Protein  Respiratory  Quotient.— It  was  but  a  step  from 
the  method  just  given  to  a  simpler  calculation  based  upon  a  table  giv- 
ing the  heat  values  of  oxygen  or  carbon  dioxid  for  the  non-nitrogenous 
combustion. 

The  respratory  exchange  due  to  protein  is  thus  given  by  Lusk  (h). 


TABLE  7 


100  gm.  meat  contain 
Eliminated     in     the 

Urine    

In  the.  Feces 


52.38  gm.C 

9.406   "    " 
1.471    "    " 


7.27     gm.  H, 

2.GG3    "     " 
0.212    "     « 


22.68  gm.O. 

14.099   "    " 
0.889    "    " 


16.65  gm.  N. 


16.28 
0.37 


1.02   gm.S. 
1.02    "     " 


Leaving  for  respira- 
tory metabolism. . . 

Deducting  intramo- 
lecular water  . . . . . 


41. .50 


4.40 
0.961 


7.69     "    " 
7.69     "    " 


41.50  gm.C. 


3.439  gm.  H. 


To  oxidize  these  amounts  of  carbon  and  hydrogen  would  require  138.18  gm. 
O2  and  there  would  be  produced  152.17  gm.  COg.  From  which  it  may 
be  deduced  that  for  every  gram  of  nitrogen  appearing  in  the  urine  from 
meat  there  would  be  absorbed  from  the  breath  (138.18  -^  16.28  =)  8.45 
grams  of  oxygen,  and  there  would  be  produced  (152.17  -r-  16.28  =)  9.35 
grams  of  carbon  dioxid.  Hence  by  multiplying  the  nitrogen  elimination 
in  the  urine  whether  of  an  hour  or  a  day  by  these  factors  and  subtracting 
from  the  total  oxygen  absorbed  and  carbon  dioxid  eliminated  the  non- 
protein  respiratory  quotient  is  obtained. 

By  a  method  entirely  analogous  to  that  of  Laulanie  (page  562)  it  is 
possible  to  learn  the  heat  values  of  oxygen  for  each  value  of  this  respiratory 
quotient.  Zuntz  and  Schumberg  (o)  prepared  a  table  setting  forth  these 
values  which  is  now  widely  employed.  As  reproduced  here  the  heat  values 
of  both  oxygen  and  CO2  per  liter  of  the  gas  at  0°  and  7G0  mm.  Hg  may 
be  read  off  for  any  value  of  the  non-protein  R.  Q.  given  to  two  places. 

It  will  be  noted  that  the  values  for  pure  fat  (R.  Q.  0.71)  and  pure 
carbohydrate  (R.  Q.  1.0)  combustion  differ  but  slightly  from  those  of 
Lefevre  given  in  Table  2  (page  556). 

The  calculation  of  the  heat  production  from  the  respiratory  exchange 
and  the  nitrogen  in  the  urine  involves  then  the  following  steps : 

(1)  Determination  of  total  Og  and  COo  of  respiration  in  grams. 

(2)  "  "      "     ]Sr  in  the  urine. 

(3)  Multiply  X  of  urine  by  8.45  =  Oo  for  protein. 

(4)  "         N  "      "       "  9.35  =  CO2 "      " 

(5)  Subtract  these  values  from  total  O2  and  CO2. 

(6)  Convert  to  volume  and  get  Non-prot.  R.  Q. 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     567 

TABLE  8 

Heat  Value  of  Oxygen  and  Carbon  Dioxid  for  Different  Non-Protein  Respiratory 

Quotients 


Caloric  value  of  1  liter  at  0 

"  and  760  mm. 

Caloric  value  of  1  liter  at  0**  and  760  mm. 

R.  Q. 

CO, 

0, 

R.  Q. 

CO, 

0, 

0.70 

6.604 

4.686 

0.86 

5.669 

4.875 

0.71 

6.606 

4.690 

0.87 

5.617 

4.887 

0.72 

6.531 

4.702 

0.88 

5.568 

4.900 

0.73 

6.458 

4.714 

0.89 

5.519 

4.912 

0.74 

6.388 

4.727 

0.90 

5.471 

4.924 

0.75 

6.319 

4.739 

0.91 

5.424 

4.936 

0.76 

6.253 

4.752 

0.92 

5.387 

4.948 

•  0.77 

6.187 

4.764 

0.93 

5.333 

4.960 

0.78 

6.123 

4.776 

0.94 

5.290 

4.973 

0.79 

6.052 

4.789 

0.95 

5.247 

4.985 

0.80 

6.001 

4.801 

0.96 

5.205 

4.997 

0.81 

5.942 

4.813 

0.97 

5.165 

5.010 

0.82 

5.884 

4.825 

0.98 

5.124 

6.022 

0.83 

5.029 

4.838 

0.99 

5.085 

5.043 

0.84 

5.774 

4.850 

1.00 

6.047 

6.047 

0.85 

5.721 

4.863 

(7)  Read  off  heat  value  of  Non-Prot.  R.  Q.  from  table. 

(8)  Multiply  by  liters  of  Non-Prot.   0^. 

(9)  Multiply  N   of  Urine  by  its  heat  value  (26.51  Cal.  for  meat  diet). 
(10)  Add  8  and  9  for  total  heat  production. 


B.    Direct  Calorimetry 

Without  the  disintegration  of  organic  substances  accompanied  by  a 
diminution  of  potential  energy  life  is  impossible.  One  of  the  fonns  which 
the  liberated  energy  inevitably  takes  is  heat,  and  in  the  resting  organism, 
i.  e.,  not  transferring  energy  in  the  form  of  mechanical  work  to  other  ob- 
jects, all  of  the  energy  finally  takes  this  form.  The  quantity  of  heat,  there- 
fore, becomes  a  measure  of  vitality. 

We  have  seen  that  this  measure  can  be  applied  in  an  indirect  way  by 
measuring  the  potential  energy  of  the  foodstuffs  or  by  assigning  a  heat 
equivalent  to  a  unit  of  oxygen  absorbed.  But  this  method  is  based  upon 
certain  assumptions  which  are  always  open  to  debate,  namely,  the  assump- 
tion that  specific  chemical  changes  are  always  accompanied  by  the  same 
transformations  of  energy  and  the  assumption  that  the  law  of  the  con- 
servation of  energy  applies  to  all  chemical  transfonnations  in  the  animal 
body.  Most  authorities  are  agreed  that  for  these  reasons  the  direct  meas- 
urement of  heat  generated  in  the  living  oi'ganism  is  at  least  more  autliori- 
tative  even  though  the  accomplishment  of  this  end  may  be  beset  with  gi-eat 
difficulties.  Krogh(c)  states  that  ^'Witli  the  recent  advances  in  calorimetric 
methods  due  to  Atwator  and  Benedict,  Rubnor  and  esi>ecially  A.  V.  Hill, 


.  668  JORN  R.  MURLIlSr 

there  is  every  reason  to  think  that  direct  determinations  of  the  total  metab- 
olism will  be  preferred  to  the  indirect  in  many  cases,  and  all  classes  of 
animals,  as  it  is  undoubtedly  preferable  theoretically."     Lefevre(r7)  says, 
"Aussi  bien  la  calorimetrie  physique  est  a  la  base  de  toute  recherche  de 
calorimetrie  biologique."    And  Rubner(/?)  points  out  that  ^'13 ie  urprling- 
liche  Auifassung  des  Tierlebens  als  eine  Verbrennung  unter  oxydativen 
Abbau  der  Stoffe  hat  der  allgemeine  energetischen  weichen  niiissen,  denn 
die  letztere  umfasst  auch  jene  primativen  Lebensformeln  bei  Bakterien  und 
Ilefe  wo  Spaltungsvorgange  ohne  Beteiligung  des  Sauerstoffs  die  Quelle 
der  Energie  fiir  die  lebende  Substanz  bilden/'     Rubner  also  draws  atten- 
tion to  the  fact  that  in  all  organisms  there  are  fermentative  reactions  not 
directly  related  to  the  needs  of  the  living  substance,  which  nevertheless  lead 
to  the  development  of  heat.    Such  heat  would  represent  pure  loss  of  energy 
unless,  as  in  the  higher  animals  which  possess  a  specific  chemical  regula- 
tion, it  were  turned  to  account  in  the  maintenance  of  the  body  temperature. 
The  different  fermentative  processes  therefore  come  within  the  field  of 
calorimetrie  investigation.     The  production  of  living  substance  in  the 
growing  organism  on  the  other  hand  is  of  the    nature    of    fermentative 
changes  which  themselves  involve  no  storage  or  liberation  of  energy,  and 
yet  they  are  dependent  upon  energ}'  changes  and  indeed  ma}*-  to  a  degree 
be  measured  by  the  intensity  of  the  oxidative  capacity  of  the  organism. 

Calorimetry  as  related  to  living  organisms  has  two  distinct  fields:  (1) 
the  physical  measurement  of  the  energy  stored  in  the  animal  tissues  and 
in  all  chemical  compounds  which  may  serve  the  animal  as  food,  likewise 
the  energy  residual  in  the  excretory  substances  rejected  by  the  cells;  (2) 
the  measurement  of  the  energy  set  free  as  heat  during  the  life  processes. 


L    The  Heat  of  Combustion 

The  unit  of  heat  which  has  been  employed  for  nearly  a  centur^^  is  the 
Calorie  of  Regnault,  i.  e.,  the  amount  of  heat  necessary  to  raise  1  kilogram 
of  water  from  0°  to  1°  C.  This  is  the  kilo-calorie  written  with  a  capital 
C.  The  small  calorie  written  "cal,"  called  also  the  gram-calorie,  i&  the 
amount  of  heat  necessary  to  raise  1  gram  of  water  from  0^  to  1^  C.  The 
calorie  more  commonly  used  to-day  is  somewhat  smaller  than  this,  namely, 
the  amount  necessary  to  raise  a  kilogram  of  water  from  15  to  16^  C  or 
from  19°  to  20*^  C.  In  terms  of  the  original  Regnault  calorie  the  value 
of  the  calorie  at  higher  temperatures  is  given  by  Longuinine  as  follows : 

18°  ^  0.9995 
20°  =0.99925 
22°  =  0.99915 
25°  =  0.99930 


INFORMAL  PROCESSES  OF  EXERGY  METABOLISM     569 

Berthelot  (a)  introduced  the  metliod  of  bvirniiig  substances  in  oxygen 
at  high  pressure,  but  because  of  the  high  cost  of  tlie  apparatus  it  did  not 
come  into  general  use  for  some  years  after  it  was  described.  The  essential 
parts  of  the  original  apparatus  were  a  double-walled  copper  vessel  filled 
with  water  in  which  was  immersed  the  vessel  capable  of  holding  the  oxy- 


Tapper 


Mo  for 


fhermometer 


..•Release 

Button 


Release  Buffo n 


.'■Stirrer' 


Ignition  Circuit" 
Con  fact  a 


Ignition  Switch  ■ 


Fuse  Wire 


lanition  and  •■ 
ffesisionce  CoH 

Tapper  Button-^ 


Motor  Switct}' 


Motor  Circuit 
Contacts 


(Rheostat  for 
Controlling  Motor speni. 
Spfed should  be 
about  300  R P.M. 


flapper  CircuH. 
Attach  one  or 
two  dry  cells, 

(16  Candle  Power 
\  Carbon  Filament 
\Lamp 


(AHachnienf  Plog  for ' 
K  Motor  and  lanition  Circuitt. 
\Hi>/olts.O.C.orA.C. 


Fig.  23.  The  bomb  calorimeter  of  Riclie  for  use  with  Berthelot  bomb.  The  Wein- 
holdt  cup  which  is  placed  inside  the  box  and  into  which  the  pump  is  lowered  is  not 
shown. 


gen  under  high  pressure  together  with  the  substance  to  be  burned.  This 
vessel  constructed  of  heavy  steel  nickeled  on  the  outside  and  lined  with 
platinum  became  known  as  the  Berthelot  bomb,  and  whatever  the  modifica- 
tion from  the  original  pattern  it  is  still  known  by  the  inventor's  name. 
The  outer  containei*  filled  with  water  is  the  calorimeter  proper.  A  success- 
ful modern  construction  is  that  of  Riclie  shown  in  Fig.  23.    It  consists  of  a 


570  JOHN^  R  MUKLIN 

wooden  box  lined  with  a  heavy  layer  of  compressed  cork  boai'd.  Inside  this 
is  a  Weinholdt  vacmini  cup  which  serves  as  the  receptacle  for  water.  The 
bomb  is  lowered  into  the  water  by  a  carriage  attached  to  the  top  of  the 
box  which  slides  upon  two  metal  supports  at  the  sides.  The  top  also  car- 
ries a  motor  for  operating  a  stirrer  in  the  water  and  a  Beckman  ther- 
mometer. The  substance  to  be  bunied  is  placed  in  a  nickel  vessel  supported 
upon  platinum  wires  inside  the  bomb.  The  l3omb  is  then  charged  with 
oxygen  and  immei*sed  in  the  water.  When  the' temperature  of  the  water 
has  become  constant  (at  about  20°  C.)  the  combustion  is  started  by  throw- 
ing a  switch  which  connects  the  house  circuit  with  a  platinum  or  nichrome 
wire  inside.  A  standard  amount  of  current  is  secured  by  means  of  a  fuse 
wire,  which  burns  off  with  just  enough  current  to  ^^fire"  the  combustible 
.material.  The  reading  at  ignition  is  taken  as  the  initial  reading.  This  sub- 
tracted from  the  final  reading  gives  the  total  rise.  The  increase  in  tem- 
perature multiplied  by  the  weight  of  water  contained  in  the  vacuum  cup 
(plus  the  hydrothennal  equivalent  of  the  apparatus)  gives  the  total  heat 
liberated.  Certain  corrections  have  to  be  applied  for  the  heat  caused  by 
the  current  in  firing,  and  for  any  nitric  acid  formed  from  oxidation  of 
nitrogen.  For  example  in  burning  a  sample  of  standard  cane  sugar  the 
weight  of  substance  taken  was  1.1466  grams.  Weight  of  water  in  the 
cup  was  2530  gm. 

Hydrotherraal  equivalent  470  gm. 

Water  equivalent  of  apparatus  3000  gm. 

Kise  in  temp,  was  1.530°C.  Ignition  heat — 60      cal. 

1.530°  X  3000  gm.  =  4590  cal.  Nitric  acid    —    4.6  cal. 


4590  —  64.6  =  4525  cal.  64.6 

4525  H-  1.1466  gm.  =  3947  cal.  per  gm. 

The  table  on  page  571  compiled  from  various  sources  gives  the  heat  value 
of  the  most  important  organic  substances  concerned  in  metabolism  of  the 
hig-her  animals.  .  • 


•&• 


IL    Animal  Calorimetry 

1.  Forms  of  Calorimeters. — The  various  types  of  apparatus  devised 
for  measuring  the  heat  eliminated  by  an  animal  body  are  classified  by 
Lefevre(^)  into  four  gioups :  (1)  those  which  make  use  of  latent  heats;  for 
example,  the  ice  calorimeter  of  Lavoisier  and  the  distillation  calorimeter 
of  D'Arsonval ;  (2)  those  which  depend  upon  the  wanning  of  a  fixed  quan- 
tity of  water  such  as  the  calorimeters  of  Dulong  and  Laulanie  for  animals 
and  the  bath  calorimete!*  of  Lefevre  for  man;  (3)  those  which  employ 
circulating  mediums  (air  or  water)  to  carry  away  the  heat  just  as  rapidly 
as  it  is  produced  (compensation  method)  ;  such  as  the  respiration  calorim- 


IS^OEMAL  PEOCESSES  OF  ENERGY  METABOLISM     571 


TABLE  9 
Heat  Value  of  One  Gram  of  Each  Substaxce  in  Large  Calories 


Substance 

Stohmann 

Berthelot 

Rubner 

Benedict 

Glycerin   

4.316 
3.743 
3.755 
3.722 
3.955 
i         3.737 
\         3.722 

*4.i83' 

4  32T 

Glucose    

3.702 

3.739 
3.729 

Levulose    

Galactose    

Cane  sugar    

3.062 
3.777 

4,001 

Milk  sugar 

Maltose   

3  737 

3  776 

Dextrin    



4.110 
4.228 

0.265 -0..360 
0.420-0..549 
0.511 

Starch    

Palmitic  acid   

9.745 
9.745 
9.334 

9.318 

Stearic  acid 

9  499 

Oleic  acid 

,    . 

9  423 

Animal  fat  

9.500 
9.231 

Butter    

Vegetable  oil 

9.520 
5.687 

White  of  egg 

5.735 
5.841 
5.721 
5.663 
5.850 
5.942 

Yolk  of  egg 

Beef  (ext.  free  of  fat)   

Veal   

5.728 

5.778 

Casein    

5.626 

Peptone  from  fibrin 

Glycogen   

4.227 

Alanin   

4.401 

Asparagin  

3.065 

Aspartic  acid   

2.882 

Creatin    

4.240 

Creatinin    

4.988 

Cystin    

4.137  • 

Glutamic  acid 

3.662 

Glycocoll    

3.110 

Tyrosin    •••• 

6.915 

Alcohol    

7.104 

Lactic  acid  

3.615 

2.537 
2.741 

I 

eters  of  Atwater  and  Rosa,  Pompilian,  and  Lefevre ;  and  (4)  those  which 
do  not  absorb  the  heat  from  the  subject  but  which  record  only  the  effects 
of  heat  in  one  way  or  another.  Examples  are  the  anerao-calorimeter  or  the 
thermo-electric  calorimeter  of  D'Arsonval,  the*  siphon  calorimeter  of 
Richet,  and  the  second  calorimeter  of  Rubner. 

It  is  not  necessary  to  describe  more  than  two  oi*  three  calorimeters. 
The  first  method  described  above  has  never  been  used  in  studying  the 
metabolism  of  man  and  is  now  wholly  obsolete.  The  second  as  a  means 
of  following  the  heat  production  of  animals  has  fallen  more  or  less  into 
disfavor  on  account  of  the  cooling  correction  which  is  necessary.  Lau- 
lanie(&)  has  overcome  this  to  some  extent  by  using  a  pair  of  calorimeters 
of  the  Dulong  type,  running  one  of  them,  constructed  in  exactly  the  same 
manner  as  the  other,  as  a  control  of  the  effects  of  environment.  With  this 
apparatus  Laulanie  confirmed  the  theimal  quotients  of  oxygen  (page  557) 
in  an  apparently  satisfactory  manner. 


672 


JOHN  K.  MURLIN 


As  a  means  of  studying  the  heat  production  of  man  the  second  method 
has  heen  employed  in  the  form  of  a  hath  in  which  the  subject  could  be  di- 
rectly immersed.  The  first  to  use  this  method  at  all  successfully  was 
Liebermeister  (a),  but  his  technique  was  subjected  to  very  severe  criticism 
a  few  years  later  and  the  method  fell  into  disfavor  until  rescued  by  Le- 
fevre(a)  in  1804.  The  chief  objections  to  Liebermeister's  method  were: 
(1)  that  he  used  too  large  a  volume  of  water,  (2)  that  ho  read  its  tempera- 
ture on  only  a  single  thermometer  and  (3)  did  not  guard  against  stratifica- 


Fig.  24.  The  air  calorimeter  of  Lefevre.  000,  wall  of  the  chamber;  T,  ther- 
mometer for  measuring  the  temperature  of  the  atmosphere  after  it  has  passed  over 
the  subject;  e,  e,  battle  plates  for  distributing  the  air  as  it  enters;  F,  G,  11,  baffle  plates 
to  prevent  channeling  of  the  air  as  it  leaves  the  chamber;  A,  the  aspirator;  C,  covering 
for  the  head  which  prevents  radiation  of  heat  to  the  exterior. 


tion  of  the  water.  Lefevre  overcame  these  objections  and  proved  that  the 
heat  production  of  a  man  could  be  measured  w4th  a  high  degree  of  accuracy 
by  this  very  simple  method.  Even  the  heat  of  vaporization  of  water  which 
ordinarily  is  lost  through  the  hmgs  can  be  compensated  by  having  the  bath 
at  35 °C.  in  which  case  the  subject  respires  an  atmosphere  already  satu- 
rated with  moisture. 

One  of  the  simplest  types  of  compensation  calorimeters  is  that  of  Le- 
fevre (e)  designed  for  measurement  of  the  heat  production  of  a  man  by 
carrying  away  the  heat  of  his  body  just  as  rapidly  as  produced  with  a  cur- 
rent of  air.  The  calorimeter  consists  of  a  zinc  chamber  3  meters  long,  nar- 
row at  the  two  ends,  but  broader  in  the  middle  where  the  subject  sits  On  a 
stool  (Fig.  24).  Air  is  draw^i  through  the  chamber  by  means  of  an  aspira- 
tor shown  at  A.  The  volume  of  air  is  recorded  by  means  of  an  anemometer. 


NOKMAL  PKOCESSES  OF  ENERGY  METABOLISM  573- 

The  increase  in  temperature  is  observed  by  continuous  readings  of  ther- 
mometers placed  in  the  inlet  and  other  thennometers  placed  in  the  cur- 
rent after  it  has  passed  over  the  man's  body.  Tlie  heat  elimination  is  found 
by  multiplying  the  volume  of  air  by  factors  converting  it  to  weight,  by  its 
specific  heat  and  by  the  average  rise  in  temperature. 

The  two  methods  of  Lefevre  just  described  are  well  suited  for  a  study 
of  the  influence  of  environing  temperature  ujxjn  heat  production.  One  has 
only  to  vary  the  tem])crature  of  the  bath  or  current  of  air  before  it  strikes 
the  body  to  vary  the  cooling  effect.  Lefevre  combined  the  water-bath  meth- 
od with  a  method  for  obtaining  the  respiratory  exchange. 

2.  The  Atwater-Rosa-Benedict  Respiration  Calorimeter  (Atwater  and 
Benedict)  ((i). — The  fimdamental  principles  of  this  apparatus  which  was 
designed  to  measure  accurately  the  heat  elimination  of  a  man,  are  as  fol- 
lows :  The  subject  is  confined  in  a  heat-proof  chamber  through  which  a  cur- 
rent of ^ cold  water  is  kept  constantly  passing.  The  amount  of  water,  the 
flow  of  which  is  kept  constant,  is  carefully  weighed.  The  temperatures  of 
the  water  entering  and  leaving  the  chamber  are  read  at  frequent  intervals 
on  sensitive  themiometers  to  0.01  of  a  degree.  The  walls  of  the  chamber 
are  held  at  such  a  temperature  as  to  prevent  the  loss  of  any  heat  through 
them,  and  withdrawal  of  heat  b}'  the  water  current  is  so  regulated  by  vary- 
ing the  temperature  of  the  ingoing  water  that  the  heat  brought  away  from 
the  calorimeter  is  exactly  equal  in  amount  to  the  heat  eliminated  by  radia- 
tion and  conduction  from  the  subject  This  is  accomplished  by  having  ac- 
curate knowdedge  of  the  temperature  of  the  air  inside  the  apparatus  and 
the  temperature  of  the  walls  of  the  calorimeter.  About  25  per  cent  of  the 
heat  produced  by  the  human  subject  is  eliminated  at  ordinary  temperatures 
through  vaporization  of  water  fi'om  the  lungs  and  the  skin.  This  latent 
heat  in  the  water  of  vaporization  is  determined  by  measuring  the  amoiuit 
of  water  vaporized  and  passing  in  the  ventilating  current  to  the  first  sul- 
phuric acid  absorber.  The  gain  in  weight  of  this  absorber  is  taken  as  the 
water  of  vaporization. 

The  respiration  chamber  of  this  calorimeter  has  been  constructed  in 
several  different  sizes.  The  original  construction  at  Middletown,  Conn., 
had  a  chamber  with  a  cubic  capacity  of  5.03  cubic  meters,  or  with  the  sub- 
ject inside  a  residual  air  volume  of  4500  liters.  This  apparatus  was  dis- 
mantled at  the  time  the  Nutrition  Laboratory  of  the  Carnegie  Institution 
was  established  at  Boston  and  in  its  place  have  been  constructed  a  number 
of  different  calorimeters  (Benedict  and  Carpenter(a))  designed  for  dif- 
ferent purposes.  The  first  of  these  known  as  the  chair  calorimeter  (Fig. 
25)  has  a  cubic  capacity  of  approximately  1400  liters.  A  .second  con- 
struction known  as  the  bed  calorimeter  (Fig.  36)  has  a  cubic  capacity  of 
1347  liters.  That  part  of  the  original  Atwater-Kosa  calorimeter  which 
was  the  property  of  the  U.  S.  Government  was  shipped  to  Washington  and 
has  been  reconstructed  into  a  successful  calorimeter  by  Langw^orthy  and 


574 


JOHN  E.  MURLIN 


]Milner.  More  recently  calorimeters  have  been  constructed  at  the  Cornell 
^[edical  College  (Williams,  H.  B.)  and  at  Bellevue  Hospital  (Riche  and 
Soderstroni)  in  New  York.  The  operation  of  these  calorimeters  has  been 
under  the  scientific  direction  of  Graham  Lusk.  The  small  calorimeter  at 
the  Medical  School  constructed  by  Williams  has  a  cubic  capacity  of  ap- 
proximately 480  liters. 


DEAD     AIR 


This     calorimeter     was 
designed  for  the  study 
of    metabolism    in    in- 
fants   and    children    as 
well  as  of  animals  (Fig. 
29).     The    large    calo- 
rimeter at  the  hospital 
known  as  the  Sage  cal- 
orimeter is  designed  for 
the  study  of  patients  in 
a   reclining,    sitting   or 
supine  position  and  has 
a     cubic     capacity     of 
1123  liters.    Still  larger 
calorimeters     on     the 
same     principles     have 
been    constructed    by 
Benedict  at  the  Nutri- 
tion Laboratory  in  Bos- 
ton,  having  a   capacity 
large  enough  to  accom- 
modate   a    man    doing 
active   muscular    work, 
and  by  Armsby  at  the 
Pennsylvania  State  Col- 
lege     (Armsby      and 
Fries)     designed     for 
measuring     the     heat 
production  of  the  larger 
farm  animals. 

The  wall  construc- 
tion is  essentially  the  same  in  all  of  these  calorimeters.  The  inner 
wall  consists  of  copper  tinned  on  both  sides,  thus  permitting  of 
soldering,  while  a  second  metal  wall  consists  of  zinc.  In  the  cross  sec- 
tion represented  in  Fig.  25,  A  represents  the  copper  and  B  the  zinc  wall. 
Surrounding  the  latter  and  providing  air  insulation  is  a  series  of  panels 
constructed  of  asbestos  lumber  lined  with  hair  felt  or  with  compressed  cork. 
The  whole  construction,  therefore,  is  more  or  less  of  the  refrigerator  type 


Fig,  25.  Cross  section  of  chair  calorimeter  of 
Benedict  and  Carpenter.  A,  copper  wall;  B,  zinc  wall; 
C,  hair  felt;  F,  asbestos  lumber.  At  the  upper  right 
hand  corner  of  the  figure  is  shown  the  ingoing  and 
outgoing  pipes,  below  this  at  C  the  food  aperture  and 
the  ingoing  and  outgoing  water  pipes  with  their  re- 
spective thermometers.  The  chair  is  suspended  from  a 
balance  carried  on  the  frame  of  the  apparatus  above 
the  chamber. 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     575 

permitting  very  little  opportunity  for  radiation  or  conduction  of  heat  front 
the  inside  out  or  from  the  outside  in.  For  additional  security  against 
the  radiation  of  heat  from  the  calorimeters  the  original  device  of  Rosa  is 
repeated  in  all  of  these  calorimeters.  This  is  based  upon  the  ability  to 
hold  the  temperature  of  the  zinc  wall  at  the  same  level  as  that  of  the  cop- 
per wall.  To  this  end  it  is  necessary  to  know  first  that  there  is  a  tempera- 
ture difference  between  the  zinc  and  copper  and  second  to  have  some  method 


Fig.  2G.  The  Sage  calorimeter  at  Bellevue  Hospital,  New  York  City.  The  ab- 
sorber table  is  shown  at  the  extreme  left,  the  observer's  table  in  the  middle  and  the 
respiration  chamber  at  the  right.  Air  is  circulated  by  a  blower,  shown  on  the  lower 
shelf  of  the  absorber  table,  through  overhead  pipes  which  may  be  seen  entering  the 
calorimeter  at  the  upper  left  hand  corner.  Oxygen  is  admitted  from  a  cylinder  shown 
on  the  extreme  right. 


for  controlling  the  temperature  of  the  former.  The  temperature  differences 
of  the  two  walls  are  recorded  by  means  of  electrical  thermo-j unctions,  sepa- 
rate series  of  which  are  arranged  in  the  sides,  in  the  top  and  in  the  bot- 
tom of  the  apparatus  (the  ends  of  several  thermal  junctions  can  be  seen 
in  Fig.  29).  A  current  flowing  through  these  thermal  junctions  is  read 
on  a  Wheatstone  bridge  at  the  observer's  table  and  fluctuations  of  tempera- 
turo  between  the  two  walls  alters  the  amount  of  this  current.  To  insure 
a  cooling  effect  on  the  zinc  wall  a  coil  of  copper  tubes  carries  a  thin  cur- 
rent of  water  and  to  counteract  this  cooling  effect  a  wire  nmning  in  the 
same  space  and  between  the  cooling  pipes  is  heated  by  sending  through  it 
the  desired  amount  of  current.     Adjustable  rheostats  are  within  reach  of 


576 


JOIIISr  R.  MURLIjSr 


the  observer  who  reads  the  electrical  variations  on  the  Wheatstone  bridge, 
so  that  the  amount  of  current  iflowing  through  the  several  ^^parts"  is  under 
accurate  control.  Any  tendency  for  heat  to  pass  outward  would  be  indi- 
cated by  a  deflection  of  the  galvanometer  showing  that  the  zinc  wall  was 
cooler  than  the  copper.  Such  an  indication,  however,  would  be  immediately 
checked  by  turning  additional  current  into  the  heating  wire,  thus  restoring 
the  temperature  of  the  zinc  wall  to  that  of  the  copper  wall  and  thereby 
preventing  escape  of  heat. 

The  interior  of  the  chamber  is  so  arranged  as  to  give  the  utmost  com- 
fort to  the  subject.     It  is  obvious  that  if  the  heat  were  not  can-ied  away 


Fig.  27.  The  wiring-  diagram  of  the  observer's  table  with  the  Sage  calorimeter. 
In  the  center  is  the  Kolilrausch  bridge,  to  the  right  a  tapping  key  with  an  arrange- 
ment for  throwing  in  300  olmis  resistance  when  needed.  This  key  is  used  in  reading 
the  thermopiles  connected  witli  the  switch  on  the  right.  To  the  left  of  the  bridge 
is  a  switch  for  connecting  either  thermopiles  or  resistance  thermometers  with  the 
galvanometer.  On  the  extreme  left  is  the  switch  for  the  air,  wall,  rectal,  ingoing  and 
outgoing  water  thermometers,  each  of  which  contains  100  ohms. 

from  so  confined  a  space  the  temperature  would  very  shortly  become  un- 
bearable. The  heat  absorbing  apparatus  is  installed  on  the  ceiling  of  the 
chamber.  In  the  later  constructions  this  absorber  consists  merely  of  a 
continuous  grid  of  cop|)er  pipes  covering  the  entire  ceiling.  In  the  Cornell 
and  Sage  calonmcters  the  temj)erature  of  the  water  as  it  enters  is  brought 
to  the  desired  level  by  means  of  a  Gouy  temperature  regulator.  This  device 
insures  great  constancy  in  the  temperature  of  the  water.  With  the  speed 
of  the  water  current  properly  regulated  and  its  temperature  brought  to 
a  constant  level  as  it  enters  the  apparatus  fluctuations  in  the  heat  pro- 
duction will  1)0  manifested  by  fluctuations  in  the  temperature  of  the  water 
as  it  leaves  the  chamber.  Extreme  variation  in  the  former,  however,  re- 
quires readjustment  of  both  speed  and  temperature  of  entering  water. 

After  circulating  through  the  heat  absorber  the  water  is  caught  in  a 


IS^OKMAL  PROCESSES  OF  ENERGY  METABOLISM     577 


meter  (can)  and  weighed  in  kilograms.  An  electrical  devico  nnder  the 
control  of  an  observer  enables  him  to  stop  instantly  the  flow  of  water  into 
this  meter  upon  tlu^  termination  of  a  period  by  the  second  hand  of  a  clock. 


Fig.   28.     Diagram   of   the   Atwater,   Rosa,    Benedict   respiration   calorimeter   as 
prepared  by  DuBois  for  the  Sage  Calorimeter. 


Ventilating  System: 

O2  Oxygen   introduced  as  consumed  by 
subject. 

3,  H2SO4  to  catch  moisture  given  off  by 
soda  lime. 

2,  Soda   lime  to  remove  COj. 

1,  H2SO4  to  remove  moisture  given  off 
by  patient. 

Bl,   Blower  to  keep   air   in   circulation. 
Indirect  Calorimetry: 

Increase    in    weight    of    ILSO,     (1)    =: 
water  elimination  of  subject. 

Increase  in  weight  of  soda  lime  (2)  + 
increase  in  weight  of  H2SO4  (3)  = 
CO2  elimination.  Decrease  in  weight 
of  oxygen  tank  =  oxygen  consump- 
tion of  subject. 
Heat-Absorbing  System : 

A,  Thermometer  to  record  temperature 
of   ingoing    water. 

B,  Thermometer   to  n-cord  temperature 
of  outnroin;;  wator. 


V,  Vacuum  jacket. 

C,  Tank  f<jr  weighing  water  which  has 
passed  through  calorimeter  each 
hour. 

W,  Thermometer  for  measuring  tem- 
perature of  wall. 

A„  Thermometer  for  measuring  tem- 
perature of  the  air. 

R,    Rectal    thermometer    for  measuring 
temperature  of  subject. 
Direct  Calorimetry: 

Average  difference  of  A  and  B  X  liters 
of  water  -f-  (gm.  water  eliminated  X 
0.580 »  it  (change  in  temperature  of 
wall  X  hydrothermal  equivalent  of 
box)  it  (change  of  temperature  of 
body  X  hydrothermal  equivalent  of 
body  >    =  total  calories  pro<luced. 

Th.  thermocouple;  Cu,  inner  copper 
wall:  CU2,  outer  copper  wall;  E,  F, 
dead  air-spaces. 


The  average  rise  in  temperature  of  the  niimerous  readiirgs  which  have 
been  taken  during-  the  period  nmltiplied  by  the  weight  of  the  water  gives 
the  amount  of  heat  eliminated  bv  radiation  and  conduction  and  carried 


578  JOHN  R  ]MURLi:Nr 

away  by  the  water  current.    To  this  must  be  added  the  latent  heat  in  the 
water  of  vaporization  and  any  heat  stored  in  the  body  itself. 

For  the  measurement  of  this  latter  quantity  an  electrical  resistance 
theiTiiometer  is  inserted  into  the  rectum  to  a  depth  of  10  or  12  cm.  Fluc- 
tuations in  the  body  temperature  can  thereby  be  followed  accurately  by 
readings  on  the  Wheatstone  bridge.  If  the  body  temperature  rises  during 
the  course  of  a  period  of  observation  the  amount  of  heat  stored  is  found  by 
multiplying  the  rise  in  temj^eraturc  by  the  weight  of  the  body  and  by 
the  specific  heat  of  the  animal  body  (0.83).  Should  the  body  temperature 
fall,  heat  will  be  given  up  to  the  calorimeter  and  may  be  deducted  by  a 
similar  calctilation. 

The  temperature  of  the  ingoing  air  must  likewise  be  adjusted  so  as 
to  be  at  all  times  equal  to  the  temperature  of  the  outgoing  air;  otherwise, 
heat  would  be  added  to  or  taken  away  from  the  chamber  by  the  air  cur- 
rent. Thermal  junctions  are  so  placed  as  to  have  one  terminal  in  the 
outgoing  air  and  the  other  in  the  ingoing  air  immediately  adjacent  to 
the  calorimeter  so  that  any  difference  in  temperature  of  the  two  air  cur- 
rents is  instantly  detected  by  connecting  the  circuit  with  the  galvanometer. 
A  cooling  effect  in  the  ingoing  air  is  brought  about  by  means  of  a  continu- 
ous current  of  water  running  at  a  very  slow  rate  against  which  a  warming 
effect  produced  by  an  electric  lamp  is  kept  in  action. 

Finally  heat  may  be  stored  in  the  calorimeter  itself.  To  detect  such 
a  change  resistance  thermometers  are  attached  to  the  inner  walls  of  the 
calorimeter  and  if  the  temperature  of  these  walls  rises  or  falls  between 
the  beginning  and  the  end  of  an  experiment  a  correction  is  made.  With 
the  chair  calorimeter  it  has  been  found  that  19.5  Calories  of  heat  are  ab- 
sorbed when  the  inner  wall  rises  one  degree  of  temperature.  Conversely, 
19.5  Calories  are  lost  by  the  wall  when  the  temperature  falls  one  degree. 
This  quantity  is  known  as  the  hydrothermal  equivalent  of  the  calorimeter. 
For  the  bed  calorimeter  of  Benedict  the  hydrotheraial  equivalent  is  21 
Calories;  for  the  Sage  calorimeter  at  Bellevue  19  Calories.  When  all  of 
these  con-ections  are  made  the  result  gives  the  amount  of  heat  actually 
produced  by  the  body  in  the  period  of  observation. 

a.  Control  Tests. — A  calorimeter  must  be  very  carefully  controlled  as 
regards  its  heat  measuring  capacity.  What  is  known  as  a  ''heat  check" 
is  run  in  the  following  manner :  A  current  of  electricity  of  known  voltage 
is  run  through  a  resistance  coil  placed  inside  the  respiration  chamber.  To 
secure  uniformity  in  the  electrical  current  and  therefore  in  the  amount  of 
heat  dissipated,  Williams  used  an  accumulator  battery  as  a  source  of 
current.  This  battery  was  of  sufficiently  large  capacity  (about  45  ampere- 
hours)  to  deliver  the  required  amount  of  energy  over  periods  of  four  or 
five  hours  without  much  diminution  in  voltage.  The  current  passes  from 
the  battery  through  a  ballast  resistance,  then  through  the  heat  coil  and 
back  through  a  standard  resistance.    A  precision  milli-voltmeter  measures 


NOEMAL  PROCESSES  OF  ENERGY  METABOLISM     579 

the  fall  of  potential  across  the  terminals  of  the  standard  resistance  and 
seizes  to  detennine  the  current.  From  the  heating  coil  in  the  chamber  a  pair 
of  wires  runs  out  to  a  voltmeter.  A  key  is  provided  in  this  circuit  so 
that  the  voltmeter  may  he  connected  momentarily  to  determine  the  fall  of 
potential  across  the  tenninals  of  the  heating  coil.  The  reading  of  the  milli- 
voltmeter  is  maintained  constant  by  manipulation  of  the  ballast  resistance 


Tig.  29.  The  small  calorimeter  at  Cornell  University  Medical  College  shown  in 
process  of  construction.  The  observer's  table  is  at  the  extreme  left.  The  Gouv  regu- 
lator is  shown  as  a  cubical  box  on  top  the  calorimeter.  The  arrangement  of  heating 
and  cooling  elements  on  the  outside  of  the  zinc  wall  is  shown  at  the  open  end  of  the 
calorimeter.  The  water  meter  E,  suspended  on  a  balance  is  shown  at  the  extreme 
right.  The  tank  supplying  the  heat  absorber  with  water  under  constant  pressure  is 
shown  at  the  extreme  top  of  the  picture.  Water  passes  from  this  tank  through  a 
pipe  to  the  Gouy  regulator,  thence  to  a  reheater  at  the  upper  left  hand  corner  of 
the  calorimeter,  thence  through  the  heat  absorber  which  is  a  grid  of  pipes  on  the 
ceiling  of  the  inner  clianiber,  thence  back  to  the  meter.  From  the  waste  tank.  A, 
water  is  pumped  up  again  into  the  pressure  tank. 


and  the  voltmeter  is  read  several  times  during  each  period  of  the  experi- 
ment. The  heat  dissipated  is  given  by  multiplying  together  the  numbers 
expressing  the  fall  of  potential  across  the  terminals  of  the  heating  coil 
(in  international  volts),  the  current  in  amperes  and  the  time  in  seconds 
and  dividing  by  the  number  expressing  the  mechanical  equivalent  of  heat 
at  the  temperature  of  the  flowing  water.  For  example  in  a  heat  controlled 
experiment  performed  with  the  small  resj)iration  calorimeter  on  May  Gth, 
1911^  Williams  obtained  the  following  results:     The  strength  of  current, 


580 


JOHJST  K.  MUKLIN 


I  was  2.1  amperes.  The  fall  of  potential  across  the  terminals  of  the  heat- 
ing coil  was  5.70  volts  and  the  time  for  each  period  was  3500  seconds. 
The  heat  is  given  by  the  product  E.  I.  t  X  0.2393  =  10^470.  This  is 
expressed  in  small  calories  and  is  equal  to  10.47  large  calories.  The  fol- 
lowing is  a  tabulation  of  this  experiment. 


TABLE  10 

Hour 

Calories  Calculated 

Calories  Found 

Error  in  Cal. 

1           

10.47 
10.47 
10.47 

10.64 
10..55 
10.64 

0.17 
0.08 
0.17 

o 

.3   

The  advantage  of  this  sort  of  a  check  experiment  is  that  the  measure- 
ments can  be  made  very  accurately,  rapidly  and  in  short  periods.  It.  is 
customary  in  making  such  checks  to  place  the  resistance  coil  in  the  calo- 
rimeter and  make  the  connections.  The  current  is  then  passed  through  the 
coil  and  simultaneously  the  water  is  started  flowing  through  the  heat  ab- 
sorbing system  and  the  whole  calorimeter  is  adjusted  in  temperature 
equilibrium.  As  soon  as  possible  when  the  temperature  of  the  air 
and  walls  is  constant  and  the  themial  junction  system  in  equilib- 
rium, the  exact  time  is  noted,  and  the  water  current  is  deflected  into  the 
water  meter.  At  the  end  of  the  first  hour,  the  usual  length  of  a  period, 
the  water  current  is  deflected  from  the  meter,  the  water  weighed  and  the 
average  temperature  difference  of  the  water  is  obtained  by  averaging  the 
results  of  all  the  temperature  readings  during  the  hour.  Usually  during 
an  experiment  of  this  nature  records  of  the  water  temperature  are  made 
every  four  minutes.  Occasionally,  when  the  fluctuations  are  somewhat 
greater  than  usual,  records  are  made  every  two  minutes.  Tests  witli  the 
chair  calorimeter  of  the  Nutrition  Laboratory  made  in  January,  1909, 
show  between  the  heat  developed  inside  the  apparatus  in  the  electric  coil 
and  the  heat  as  measured  by  the  water  current  with  corrections  a  discrep- 
ancy of  about  0.5  per  cent  (Benedict  and  Carpenter  (a)).  A  series  of 
electric  checks  made  upon  the  Sago  calorimeter  by  the  same  method  shows 
a  total  error  for  the  entire  series  of  less  than  0.4  per  cent  (Riche  and  Sod- 
erstrom). 

Another  method  of  checking  the  heat  measuring  capacity  of  the  calo- 
rimeter is  known  as  the  "alcohol  check."  In  this  method  alcohol  is  burned 
inside  the  apparatus  by  means  of  a  small  alcohol  lamp,  the  rate  of  flow 
of  the  alcohol  being  made  as  nearly  constant  as  possible  and  the  amount 
consumed  in  a  period  of  obsei'vation  being  carefully  recorded  upon  a  finely 
graduated  burette  or  by  weighing.  In  planning  such  a  test  to  ascertain  the 
magnitude  of  the  errors  which  are  likely  to  occur  in  using  the  apparatus 
with  subjects  of  kno\NTi  size  it  is  of  importance  to  provide  that  the  amount 
of  alcohol  consumed  per  hour  shall  be  enough  to  dissipate  approximately 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     581 

the  same  amount  of  heat  as  the  subject  would  be  expected  to  eliminate  in  a 
given  time.  With  an  experimental  apparatus  the  en-or  will  be,  assuming 
a  uniform  technique,  about  constant  in  absolute  amount  so  that  the  total 
error  will  diminish  as  the  total  quantity  measured  increases. 

When  tlie  rate  of  flow  of  the  alcohol  ta  the  lamp  has  been  adjusted  so 
that  it  is  fed  into  the  burette  just  as  rapidly  as  consumed  therefrom  by 
the  lamp,  the  apparatus  is  sealed  and  after  a  preliminary  period  during 
which  the  calorimeter  is  brought  inta  equilibrium,  the  burette  is  read, 
the  supply  bottle  from  which  the  alcohol  is  fed  into  the  burette  is  changed 
for  another  which  has  been  weighed,  and  the  experiment  starts  in  the  usual 
way. 

To  insure  complete  combustion  of  the  alcohol  it  is  necessary  to  employ 
a  lamp  so  constructed  that  the  region  of  the  edge  of  the  wick  will  always 
be  sufficiently  hot  to  insure  immediate  ignition.  Williams  finds  that  by 
using  a  short  piece  of  hard  glass  tubing  for  the  top  of  the  burner  and  a 
wick  of  a  glass  wool  the  difficulties  attending  the  combustion  of  alcohol 
are  most  readily  overcome. 

The  specific  gravity  of  the  alcohol  must  be  determined  with  a  high  de- 
gree of  precision  after  which  the  theoretical  amounts  of  heat,  carbon  dioxid 
and  water  which  the  known  combustion  will  generate  may  be  calculated. 
Likewise,  the  amount  of  oxygen  necessaiy  to  support  this  combustion.  In 
the  case  of  the  water  one  must  make  a  con-ection  for  the  amount  of  water 
of  dilution  present  in  the  alcohol.  The  heat  of  combustion  of  alcohol  has 
been  determined  a  gi-eat  many  times.  As  the  result  of  25  observations  with 
the  bomb  calorimeter  Atwater  and  Rosa  found  the  heat  of  combustion 
of  pure  ethyl  alcohol  to  be  7.067  large  calories  per  gTam.  This  figiire 
is  generally  employed  in  this  country.  In  all  of  the  different  calorimeters 
of  Atwater,  Rosa  and  Benedict  here  described  the  coi*respondence  between 
the  amounts  of  heat  generated  by  the  alcohol  and  the  heat  actually  measured 
has  been  very  close.  For  example,  in  a  long  series  of  experiments  of  three 
or  four  hours'  duration  the  average  error  with  the  Sage  calorimeter  for  the 
heat  of  combustion  was  0.0  per  cent,  for  the  oxygen  absorption  1.6  per 
cent,  and  for  the  carbon  dioxid  elimination  0.6  per  cent. 

3.  The  Emission  Calorimeters.^ — The  fourth  gToup  of  calorimeters  ac- 
cording to  the  classification  of  Lefevre  are  those  which  do  not  absorb 
the  heat  but  allow  it  to  escape  into  the  external  medium.  Because  of  this 
feature  the  name  calonmhters  deperdtteurs^  or  emission  calorimeters,  \vas 
proposed  by  D'Arsonval(«),  who  devised  several  diiferent  types.  Some  of 
these  calorimeters  have  single  walls  and  the  effect  of  the  heat  generated 
within  is  recorded  in  some  way.  In  the  so-called  anemo-calorimeter  of 
D'Arsonval  the  subject  stands  inside  a  tent -like  cubicle  which  has  a  nar- 
row chimney  or  ventilator  at  the  top.  In  the  chimney  is  a  delicate  wind- 
gauge.  The  heat  from  the  man's  body  induces  a  strong  convection  current 
which  is  free  to  enter  the  cubicle  below  and  which  sets  the  wind-gauge  in 


582 


JOHN  R.  MUELIJS^ 


rapid  motion.     By  calibration  of  the  apparatus  with  known  sources  of 
heat  it  is  possible  to  determine  the  heating  effect  of  the  live  subject. 

Another  gi-oup  of  these  calorimeters  have  double-walls,  between  which 
is  a  cushion  of  air.  The  effect  of  heat  generated  within  the  chamber  is  re- 
corded by  expansion  of  this  air  cushion.  Among  those  employing  this  prin- 
ciple of  registering  the  effect  of  heat  are  the  siphon  calorimeter  of  Richet 
(b)  (Fig.  30)  and  the  second  calorimeter  designed  by  Rubner  (/)  (Fig. 
31).  Both  these  calorimeters  have  rendered  extremely  important  sen'ico 
to  physiological  science  for  it  was  by  means  of  the  former  that  Richet  made 
his  contributions  on  the  relation  of  heat  production  to  body  size  and  it  was 
by  means  of  the  latter  that  Rubner  first  proved  with  a  high  degree  of 


Fig.  30.    Richet  siphon  calorimeter.    For  description  see  the  text. 


precision  that  the  law  of  the  conservation  of  energy  applies  to  the  animal 
body  (see  page  584).  The  siphon  calorimeter  is  very  simple  in  principle. 
The  space  between  the  walls  of  the  base  and  cover  between  which  the  rab- 
bit in  the  figure  is  placed  communicate  by  a  common  tube  with  a  pressure 
bottle  containing  about  three  liters  of  water.  A  siphon  from  this  bottle 
terminates  in  a  funnel-like  vessel  which  catches  the  overflow  and  delivers 
it  into  a  burette.  By  expansion  of  the  air  water  is  forced  into  the  measur- 
ing limb  of  the  siphon  or  over  into  the  burette.  By  calibration  of  the  ap- 
paratus with  known  sources  of  heat  the  heat  of  the  animal  body  can  be 
determined.  It  should  be  noted  that  an  apparatus  of  this  sort  takes  no 
account  of  the  heat  of  vaporization. 

Buhner's  apparatus  is  a  respiration  calorimeter.  It  is  ventilated  in 
the  same  manner  as  the  original  Pettenkofer  apparatus,  and  determines 
directly  only  the  water  and  carbon-dioxid.     The  heat-measuring  device 


NOKMAL  PROCESSES  OF  ENERGY  METABOLISM     583 

consists  of  a  constant  temperature  bath  of  water  in  which  the  respiration 
chamber  is  immersed.  A  cushion  of  air  immediately  surrounds  the  cham- 
ber whose  walls  are  of  metal.  The  heat  of  the  animaFs  body  (dog)  passes 
readily  through  the  metal  and  causes  the  air  to  expand.  The  expansion  is 
recorded  by  means  of  a  spirometer  which  registers  its  movements  graphi- 
cally on  a  white  surface  (in  Fig.  31  two  spirometers  may  be  seen  on  a  shelf 


Fig.  31.    The  second  calorimeter   of  Rubner.     Description   in  the  text. 

back  of  the  calorimeter).  As  a  control  mechanism  another  spirometer 
registers  in  the  same  manner  the  summated  expansion  of  four  vertical 
air-cushions  in  the  four  corners  of  the  water  bath  isolated  from  the  first 
air-cushion.  Fluctuations  due  to  variations  of  temperature  from  ex- 
traneous causes  or  to  variations  of  barometric  pressure  are  thereby  con- 
trolled. 


G.    Basic   Principles  of   Energy   Metabolism 

Only  the  most  important  generalizations  concerning  the  energy  metabo- 
lism in  normal  waim-blooded  animals  will  be  attempted  here.  While  some 
of  these  are  not  yet  universally  accepted,  sufficient  evidence  is  at  hand  in 
the  case  of  all  of  those  which  will  be  discussed  to  dignify  them  with  the 


584: 


joh:^^  r.  mueltn 


desig-nation  of  '^basic  principles."  Some  iiideod  are  so  fundamental  and 
so  universal  in  their  application  as  to  deserve  the  designation,  "laws  of 
metabolism."  But  it  will  avoid  controversy  to  employ  the  more  conserva- 
tive term. 

L    The  Principle  of  the  Conservation  of  Energy 
in  the  Animal  Organism 

Lavoisier,  the  father  of  metabolism,  foresaw  that  the  heat  of  the 
animal  body  could  be  measured  by  two  means :  the  computation  based  upon 
the  chemistry  of  combustion,  and  direct  measurement  (Gavarret),  and  it  is 
almost  certain  that  had  he  been  permitted  to  complete  his  researches  in  this 
field  the  demonstration  of  complete  agi-eement  by  the  tw^o  methods  would 
have  lain  to  his  credit.  Without  following  the  historical  development  of  the 
subject  or  recording-  the  failures  which  intervened  we  may  pass  at  once  to 
the  work  pf  Rubner(<^).  With  the  calorimeter  just  described  Rubner 
studied  the  heat  production  of  dogs  by  the  two  methods.  He  determined 
the  C  and  X  of  the  excreta  and  computed  the  amount  of  protein  and  fat 
metabolized  in  fasting*  and  after  feeding  with  meat  and  lard.  Multiplying 
the  protein  and  fat  by  the  physiological  heat  values  of  these  foodstuffs  re- 
cently determined  by  him  (page  551)  he  obtained  the  heat  production  by 
and  indirect  method.  At  the  same  time  his  calorimeter  recorded  the  actual 
amount  of  heat  eliminated.    His  results  are  given  in  Table  11. 

TABLE  11 
Heat  Production  of  Dogs  by  Direct  axd  Indirect  Calorimetrt   (Rubner) 


No. 

Animal 

Food  per  Day 

No.  Days 

Calories 
Heat  Prod. 
Calculated 

Calories 
Heat  Prod. 
INIeasured 

Difference 
in  per  Cent 

1 
2 
3 

4 
5 

6 

7 
8 

Dog  I 
Dog  II 
Dog  I 
Dog  I 
Dog  I 

Dog  I 
Dog  I 
Dog  II 

Fasting 

Fasting 

390  gm.  meat 
40  gm.  lard 
80  gm.  meat 
30  gm.  lard 
same 

350  gm.  meat 

580  gm.  meat 

5 
2 

1 

5 

12 

8 
6 

7 

1,206.3 
1,091.2 
329.9 
1,510.1 
3,985.4 

2,402.4 
2,249.8 
4,780.8 

1,305.2 
1,056.6 
333.9 
1,495.3 
3,958.4 

2,488.0 
2,760.9 
4,709.3 

0.69 

—  3.15 
1.20 

—  0.97 

—  0.68 

—  0.17 
1.20 

—  0.24 

46 

17,735.9 

17,683.6 

—  0.30 

In  a  total  of  forty-six  days  of  experimentation,  with  his  animals  Rubner 
thus  found  a  difference  of  only  0.3  per  cent  between  the  heat  production 
as  calculated  and  the  heat  production  as  directly  measured.  This  proves 
that  the  energy  set  free  by  oxidation  (in  the  absence  of  external  work), 
whatever  transfonnations  it  may  undergo  in  the  body,  finally  leaves  the 
body  as  heat.  In  other  words,  all  the  available  energy  which  entered  the 
body  in  potential  fomi  has  been  recovered  as  heat,  and  the  applicability 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     585 

of  the  law  of  tlie  conservation  of  energy  to  the  animal  body  was  thus 
demonstrated. 

Atwater  and  his  colleagues,  Rosa,  Woods,  Benedict,  Smith  and  Bryant 
studied  this  balance  of  energy  in  a  series  of  rest  and  work  experiments  by 
means  of  the  Atwater-Rosa  calorimeter  (Atwater  and  Benedict(a,  &)).  On 
four  different  human  subjects  the  agreement  between  the  direct  and  indi- 
rect methods  were  almost  as  close  as  those  reported  by  Rubner.  The  re- 
sults may  be  summarized  briefly  as  follows: 

TABLE  12  , 

Heat  Production  of  Human  Subjects  by  Direct  and  Indirect  C-ALORixiETRr 

(Atwater  et  al.) 


Heat  as 

Calculated 

Cal. 

Heat  as 

Measured 

Cal. 

Difference 
per  Cent 

Average  of  67   days  rest  ex- 
periments     

2258 

4567 
3597 

2270 

4554 
3577 

0.6 

Average  of  76  days  work  ex- 
periments     

—  0.3 

Average  of  all  experiments  . . 

—  0.6 

The  results  are  perfectly  clear-cut.  The  heat-production  as  calculated 
from  the  heat  value  of  the  food  and  from  the  heat  value  of  the  excreta 
(for  method  of  calculation  see  page  552)  agrees  exactly  with  the  amount 
of  heat  eliminated.  The  food  in  these  experiments  consisted  of  the  three 
classes  of  foodstuffs  and  on  certain  days  included  alcohol  in  small  amounts. 
The  assumption  was  made  (see  page  554)  that  carbohydrate  absorbed 
enters  into  combustion  before  the  fat.  The  close  agreement  between  direct 
and  indirect  measurement  seems  to  justify  the  assumption. 

All  of  the  experiments  thus  far  cited  in  suppoii;  of  the  principle  of  the 
conservation  of  energy  continued  for  24  hours.  We  now  know,  however, 
that  the  principle  holds  for  short  periods  as  well.  Thus  Ilowland(a-)  work- 
ing with  the  Cornell  calorimeter  found  that  with  young  children  the  heat 
production,  expressed  in  calories  per  hour,  as  measured  by  the  calorimeter 
differed  from  the  heat  production  as  calculated  from  the  respiratory  ex- 
change and  the  nitrogen  output,  on  six  different  days,  by  only  2,1  per  cent. 

With  the  same  calorimeter  Murlin  and  Lusk  found  in  a  series  of  twenty- 
two  experiments  in  hourly  periods  on  a  dog,  which  was  being  fed  large 
amounts  of  fat  alternating  with  fasting  periods,  2244  calories^  by  indirect 
calorimetry  as  against  2230  calories  by  direct  calorimetry,  a  difference  of 
0.6  per  cent.  A  large  part  of  tbe  energy  was  derived  from  the  emulsified 
fat  given  for  the  most  part  without  other  food.  These  peculiar  circum- 
stances did  not  interfere  in  any  way  with  the  fundamental  dynamic  prin- 
ciple. 

•Throughout  this  chapter  the  large  calorie  is  not  capitalized  unless  abbreviated 
as  in  Table  12.  In  human  metabolism  the  large  calorie  is  always  understood  unless 
otherwise  designated. 


686  JOHN  R.  MUELIiSr 

Gephart  and  DnBois(a.)  in  the  first  twenty  experiments  with  the  Sage 
calorimeter  upon  normal  subjects,  some  of  them  in  the  post-absorptive  state 
and  others  soon  after  taking  foods  of  various  kinds,  reported  a  total  heat 
production  of  4577.37  calories  by  calculation  as  against  45G9.4  by  direct 
measurement,  a  discrepancy  of  only  0.17  per  cent. 

Instances  might  be  multiplied  further  but  it  is  unnecessary.  The 
potential  energy  of  the  food  in  so  far  as  it  is  oxidized  is  returned  by  the 
body  without  loss,  in  kinetic  fomi;  and  even  when  measurable  work  is 
done  the  energy  can  all  be  accounted  for. 


II.  The  Energy  of  Muscular  Work  is  Definitely  Related 
to  the  Potential  Energy  of  the  Food 

1.  Origin  in  Non-Nitrogenous  Food. — When  Liebig  had  completed  his 
classification  of  the  foodstuffs,  and  had  found  that  all  animal  tissues  con- 
tained proteins,  i.  e.,  are  nitrogenous,  he  suggested  that  the  excretion  of 
nitrogen  by  the  animal  might  be  used  as  a  measure  of  protein  destruction 
in  the  animal's  body.  Carl  Voit,  who  had  been  a  pupil  of  Liebig,  was 
among  the  first  to  put  this  suggestion  to  practical  use.  Among  many 
other  important  facts,  regarding  the  metabolism  of  proteins,  Voit  discov- 
ered tliat,  contrary  to  the  teaching  of  Liebig,  the  protein  of  the  body  is 
not  the  source  of  the  muscular  energy;  for,  during  muscular  work,  no 
more  nitrogen  is  eliminated  than  in  muscular  rest.  Since  it  had  been 
known  from  the  time  of  Lavoisier  that  muscular  exercise  increased  the  heat 
production,  it  followed,  from  the  obser\'ations  of  Voit,  that  the  non-nitro-, 
genous  foodstuffs  must  be  the  source  of  the  extra  heat  production  as  weil\ 
as  of  the  energy  of  muscular  contraction.  This  fact  is  now  thoroughly  ' 
established  by  almost  numlierless  experiments  (Lusk(7i)  ).  An  illustration 
may  be  taken  from  the  work  of  At  water  cited  above.  A  subject  doing  work 
on  the  bicycle  ergometer  produced  in  twenty-four  hours  5,100  calories  of 
heat,  of  which  434  calories  came  from  the  protein  CN  X  6.25  X  4.1).  In 
muscular  rest  this  same  individual  produced  2,270  Calories,  of  which  400 
came  from  protein.  The  day's  work  had  increased  the  total  heat  pro- 
duction 2,830  Calories,  but  the  heat  from  protein  had  been  increased  only 
thirty-four  calories.  All  of  the  rest,  2,800  Calories  (nearly),  came  from 
non-nitrogenous  food. 

2.  Mechanical  EfRciency  of  Muscular  Work. — Soon  after  the  law  of 
the  conservation  of  energy  was  enunciated  by  Mayer,  the  mechanical  effi- 
ciency of  muscular  work  done  by  a  horse  was  computed  by  Joule.  He 
showed  that  a  horse  could  perform  work  equivalent  to  twenty-four  million 
foot  pounds  in  one  day,  during  which  time  the  food  consisted  of  12  pounds 
of  hay  and  12  pounds  of  corn.  From  original  measurements  of  the  heat 
value  of  this  food  Joule  inferred  that  one  grain  of  food  consisting  of  equal 


NORMAL  PEOCESSES  OF  E:^ERGY  ]METAB0LISM     587 

parts  of  undried  hay  and  corn  could  raise  one  pound  of  water  0.682^  F., 
wliicli  from  previous  experiments  lie  knew  was  equivalent  to  557  foot- 
pounds. From  these  results  it  ap{>eared  that  one-qiuirter  of  tlie  whole 
amount  of  energy  generated  by  combustion  of  the  food  could  be  conveited 
into  useful  mechanical  work,  the  remaining  three-quarters  being  required 
to  keep  lip  the  animal  heat,  etc.  (Scorcsby  and  Joule). 

Since  these  first  measurements  by  Joule  many  estimates  have  been  made 
of  the  mechanical  efficiency  of  various  kinds  of  muscular  work  both  in  ani- 
mals and  men.  It  turns  out  that  tho  efficiency  depends  upon  the  type  of 
work  performed,  i.  e.,  the  particular  muscles  used,  the  training,  the  speed 
with  which  the  work  is  done,  and  the  kind  of  food  which  sustains  the 
metabolism. 

It  is  necessary  at  this  point  to  distinguish  between  gross  efficiency  and 
net  efficiency.  The  fonner  term  is  found  by  dividing  the  mechanical 
work  in  terms  of  heat  by  the  total  metabolism  of  the  time ;  while  net  effi- 
ciency, the  more  exact  term  from  tho  standpoint  of  bio-physics,  is  found 
by  dividing  the  heat  equivalent  of  the  mechanical  work  by  the  extra  metab- 
olism due  to  the  work  accomplished.  This  is  found  of  course  by  subtract- 
ing the  basal  or  resting  metabolism  from  the  total  work  metabolism.  Un- 
less otherwise  specified  the  figures  used  in  this  chapter  refer  to  net  effi- 
ciency. 

From  data  obtained  by  Lavoisier  upon  his  assistant,  Seguin,  whose 
oxygen  absorption  was  measured  during  rest  and  while  working  a  treddle, 
Benedict  and  Cathcart  have  calculated  that  at  most  an  efficiency  (net) 
of  7.7  per  cent  can  be  ma^e  out.  This  work  of  Lavoisier  represents  the 
earliest  collection  of  data  from  which  the  efficiency  of  human  muscles  can 
be  computed.  Helmholtz  presented  tho  next  in  order  historically  when 
he  assembled  data  from  the  work  of  Edward  Smith,  of  Dulong  and  of 
Despretz,  which  according  to  his  reckoning  showed  a  gross  efficiency  of 
approximately  20  per  cent.  Amar  cites  experiments  by  Him  done  in 
1857  which,  assuming  that  the  total  heat  elimination  was  correctly  meas- 
ured, demonstrate  an  efficiency  of  about  the  same  amount.  Other  im- 
portant workers  of  the  French  school  in  this  field  are  Laulanie(^)  and 
Chauveau(a).  The  former  studied  especially  the  influence  of  speed  upon 
efficiency.  He  found  in  ex}>eriments  upon  himself  that  so  long  as  the  rate 
was  constant,  turning  a  wheel  with  a  brake  attachment  5,  10  or  15  minutes 
gave  the  same  efficiency,  but  when  the  load  and  speed  were  varied  the 
efficiency  varied  from  9  to  23  per  cent.  The  load  varied  from  1  to  15  kilo- 
grams and  the  speed  from  1.49  to  0.13  meter  per  second.  The  highest 
efficiency  was  shown  with  a  moderate  load  (4  kilograms)  and  a  moderate 
speed  (0.61  meter  per  second).     This  accords  with  everyday  experience. 

Chauveau's  observations  made  upon  his  assistant,  Tissot,  were  directed 
especially  to  the  question  of  the  kind  of  foodstuffs  which  supports  mus- 
cular work.     They  will  be  referred  to  later. 


688  JOHIST  E.  MUELIN 

The  Gennan  laboratories  which  have  contributed  most  to  the  lite^'ature 
of  iTiecliauical  efficiency  in  muscular  work  are  those  of  N.  Zuntz  and  of 
Kronecker.  Both  used  the  method  of  Zuntz  in  determining  the  respiratory 
exchange.  Magnus-Levy (<7),  Durig  (c),  and  Loewy  (a),  all  of  the  Zuntz 
school  of  workers,  have  given  important  summaries  of  this  work  up  to  1911. 
Durig's  own  experiments  under  Kronecker's  direction,  as  well  as  those  of 
Zuntz,  and  Loewy,  Muller(a),  Caspari(a),  Zuntz  and  Schumburg(a),  and 
L.  Zuntz,  show  plainly  the  effect  of  training  upon  muscular  efficiency,  as 
well  as  the  influence  of  velocity.  Much  of  the  work  was  done  with  the  tread- 
mill, some  with  an  arm  ergometer  and  other  experiments  in  which  the  res- 
piratoiy  exchange  was  measured  by  means  of  the  Zimtz  portable  apparatus 
was  done  in  marching  on  roads  or  climbing  mountain  trails.  The  treadmill 
showed  net  efficiencies  as  high  as  37  per  cent,  with  the  average  at  31  per 
.cent.  The  arm  ergometer  gave  the  lowest  efficiency,  namely,  19  per  cent 
and  the  mountain  climbing  and  marching  experiments  intermediate  results. 
In  certain  experiments  of  the  latter  class  carried  out  in  summer  upon  a 
mountain  trail  which  had  an  inclination  of  16.4  per  cent  Durig's  o\\ti  ef- 
ficiency w^as  31.1  per  cent  and  that  of  his.three  companions  was  30.3,  31.7 
and  30.1  per  cent  respectively.  In  bicycle  riding  L.  Zuntz,  who  was  the 
first  to  make  studies  of  the  respiratory  exchange  in  this  type  of  work,  found 
values  which  later  were  calculated  to  show  a  net  efficiency  of  28  per  cent 
(Berg,  DuBois-Reymond  and  Zuntz,  L.).  Benedict  and  Carpenter,  using 
the  same  type  of  work  but  changing  the  bicycle  to  a  stationary  ergometer, 
found  an  average  of  only  21.5  per  cent,  a  figure  which  has  been  substan- 
tially confirmed  by  a  more  recent -and  extensive  study  by  Benedict  and 
Cathcart. 

The  effect  of  training  is  shown  in  the  following  table  from  Benedict  and 
Cathcart  exhibiting  the  maximum  gross  and  net  efficiencies  for  their  six 
subjects.  The  highest  efficiency  in  both  senses  is  shown  by  the  one  pro- 
fessional bicycle  rider  (M.A.M.)  of  the  group. 

TABLE  13 

Maximum  Gross  and  Net  Efficiencies  with  the  Bicycle  Ergometer  (Benedict  and 

Cathcart) 


Subje,jt 

Gross,  per  Cent 

Net,  per  Cent 

e.  p.  c. 

19.9 

23.1 

J.  J.  c. 

17.8 

20.4 

H.  L.  H. 

18.C 

21.6 

J.  E.  F. 

19.8 

22.7 

K.  H.  A. 

18.2 

20.8 

M.  A.  M. 

21.2 

25.2 

Benedict  and  Cathcart  have  also  given  attention  to  the  relation  of  speed 
to  muscular  efficiency.  They  find  that  while  in  general  the  efficiency  in- 
creases with  the  load   (amperage  of  current  actuating  the  brake)   with 


NOIJMAL  PEOCESSES  OE  ENERGY  METABOLISM     589 


the  heaviest  loads  there  were  definite  indications  of  decreased  efficiency. 
Figure  32  exhibits  the  relationship  of  total  metabolism  to  effective  work 
at  varyinc:  speeds  but  with  a  constant  load.  In  computing  the  net  effi- 
ciency the  hasal  metabolism  obtained  with  the  subject  lying  quietly  on 


a  couch  was  used  and  since  this 
is  practically  constant^  the  net 
efficiency  would  be  effected  by 
speed  in  the  same  way  as  the 
gross  efficiency  (total  heat  out- 
put). The  figure  shows  that 
in  order  to  produce  1.5G5  cal- 
ories of  effective  muscular 
work  at  TO  revolutions  per 
minute  it  is  necessary  for  the 
subject  to  produce  a  total  of 
7.61  calories  (gross  efficiency 
20.6  per  cent)  ;  while  to  pro- 
duce 2.425  calories  of  work  at 
130  revolutions  required  15.04 
calories  of  heat,  (gross  effi- 
ciency 16.1  per  cent).  "From 
the  upper  curve  it  is  seen  that 
the  output  of  heat  is  constant 
per  10  revolutions;  on  the 
other  hand,  the  increase  in 
effective  muscular  work  per- 
formed is  not  constant  for  each 
ten  revolutions,  but  there  is  a 
distinct  falling  off.  If,  there- 
fore, we  divide  the  increase  in 
the  external  muscular  work 
between  any  two  points  on  the 
curve  by  the  increase  in  the 
total  heat  output  correspond- 
ing to  the  same  two  points,  we 
get  an  efficiency  based  upon 
increasing  speed,  the  load 
being  the  same.  For  instance, 
in  changing  from  70  to  80  revolutions  per  minute,  the)*o  is  an  increase  in 
the  effective  muscular  work  equivalent  to  0.205  calorie.  Under  tliese  con- 
ditions there  is  an  increase  in  the  total  heat  output  of  1.24  calories.  Divid- 
ing the  increase  in  heat  output  due  to  the  muscular  work  (0.204  calorie) 
by  the  increase  in  the  total  heat  output  (1.24  calories)  we  find  an  efficiency 
for  the  increased  amount  of  work  pei*fonned  of  16.53  per  cent."    Compu- 


15.5 


15.0 


11.5 


14.0 


13.5 


13.0 


12.5 


12.0 


11.5 


11.0 


10.5 


10.0 


9.5 


9.0 


8.5 


8.0 


7.5 


7.0 


6.5 


!    ! 

1 

/ 

/ 

J- 

/ 

/ 

ij 

C 

y 

y 

/ 

K 

1 

,  y 

V 

v/ 

¥' 

^^ 

V 

4 

f 

/ 

\A 

'V 

L 

'0 

'i 

/ 

/ 

2.50 


2.40 


2.30 


2.20 


2.10 


2.00 


1.90 


1.80 


1.70 


1.60 


60  70   80   90   100  110  120  130 


1.50 

1.40 
140 

Fig-.  32.  Curves  showing:  the  total  heat 
output  per  minute  and  corresponding  external 
muscular  work  per  minute,  expressed  in  cal- 
ories, for  subject  riding  with  constant  load — 
l.o  amperes — at  varying  speeds.  (Benedict  and 
Cathcart.) 


500 


JOHX  R.  MURLIN 


tations  for  the  corresponding  increase  of  ten  revolutions  gives  from  90  to 
100  revolutions  11.94  per  cent,  and  from  120  to  130  revolutions  7.82  per 
cent,  with  intermediate  values  in  percentage  for  the  intervening  incre- 
ments. !N'et  efficiency  showed  a  similar  falling  off  with  the  higher  rates  of 
speed.  For  example,  when  the  effective  muscular  work  was  1.95  calories 
per  minute,  at  a  rate  of  90  revolutions  the  net  efficiency  was  22.G  per  cent, 
while  at  124  revolutions  per  minute  it  was  only  15.7  per  cent. 

3.  Relative  Value  of  Different  Foodstuffs  as  a  Source  of  Energy  in 
Muscular  Work. — From  his  experiments  upon  Tissot  as  subject  in  climb- 
ing and  descending  stairs,  Chauveau  came  to  the  conclusion  from  a  con- 
sideration of  the  respiratory  quotients,  that  carbohydrate  alone  furnishes 
the  energy  of  muscular  work  and  that  fat  can  only  bo  utilized  by  first 
undergoing  transformation  to  carbohydrate.  Zuntz  and  Ileinemann,  how- 
ever, point  out  that  if  Chauveau's  hypothesis  of  transformations  were 
true,  30  per  cent  more  energv'  for  each  unit  of  work  performed  should 
be  liberated  when  fat  bums  than  when  carbohydrate  is  the  starting  point. 
Zuntz  further  criticizes  Chauveau's  experiments  as  being  too  extreme 
in  severity  (the  subject  was  exhausted  at  the  end  of  70  minutes)  xmd 
not  of  sufficient  duration.  Experiments  by  himself  and  associates  in 
which  precautions  in  both  respects  were  carefully  observed  gave  respiratory 
quotients  during  work  which  were  exactly  the  same  as  in  muscular  rest. 
He  cites  especially  the  following  results  of  Ileinemann  made  with  the 
Gartner  ergostat  and  the  Zuntz  respiration  apparatus. 

TABLE  14 
Energy  Production  of  Muscular  Work  on  Different  Diets  (Heinemann) 


Rest 

Work 

Amount  of 
Work, 
Kgm. 

Per  Kgm.  of  Work 

Food 

Cper 

Min., 

c.c. 

R.  Q. 

O^per 

Min., 

c.c. 

R.  Q. 

0,  c.c. 

Cal. 

Fat   

Carbohydrate. 
Protein    

319 

277 
306 

0.72 
0.90 
O.SO 

1029 
1029 
1127 

0.72 
0.90 
0.80 

3.54 
346 
345 

2.01 
2.17 
2.38 

9.39 
10.41 
11.35 

It  appears  from  this  comparison  that  there  really  is  little  diiTerence  between 
fat  and  carbohydrate,  and  that  protein  likewise  as  the  chief  constituent  of 
a  diet  occupies  a  place  only  a  little  less  favorable  as  a  source  of  muscular 
energy.  The  respiratory  quotients  were  the  same  for  each  foodstuff  dur- 
ing muscular  work  as  during  rest. 

This  last  statement  seems  to  be  true,  however,  only  with  the  moderate 
intensity  of  work  which  Zuntz  obser\'ed.  Benedict  and  Cathcart  found 
the  average  respiratory  quotients  with  their  professional  bicycle  rider 
were  as  follows: 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     591 


16  days  moderate  work 
16  days  heavy  work    . .  , 


Before  Work 


0.84 
0.85 


Durinir  Work 


0.84 
0.90 


After  Work 


0.77 
0.78 


Brezina  and  Kolmer  likewise  noted  that  the  height  of  the  initial  respiratory 
quotients  during  periods  of  muscular  work  varied  with  the  intensity  of 
the  work  perforaied.  When  ^1.6  calories  per  minute  was  the  rate  of 
metabolism  the  R.  Q.  was  0.83;  but  when  the  rate  rose  to  10  calories 
per  minute  the  quotient  was  0.99.  Lusk,  who  quotes  this  experiment,  ex- 
plains the  higher  quotients  as  due  in  part  to  the  formation  of  acid  with 
consequent  liberation  of  CO2  from  the  plasma  more  rapidly  than  it  was 
formed.  Other  factors,  he  states,  are  the  increased  ventilation  of  the 
lungs  and  carbohydrate  utilization ;  for  acid  formation  accelerates  the  con- 
version of  glycogen  to  glucose.  In  very  extreme  w^ork,  especially  in  short 
spurts,  it  is  quite  possible  also  that  oxygen  absoi^ption  does  not  quite  keep 
pace  with  COg  elimination  from  the  lungs.  Hence  tlie  purplish  color*  of 
ihe  face  in  muscular  exhaustion  as  contrasted  with  the  lighter  but  healthier 
color  of  moderate  exercise.  After  exercise  when  the  oxygen  absorption 
is  gaining  on  the  CO2  elimination  the  tendency  would  be  for  the  R.  Q.  to 
be  depressed.  That  there  is  a  real  and  not  an  imaginaiy  mobilization 
of  carbohydrate  during  work  Benedict  and  Cathcart  infer  from  the  fact 
that  following  carbohydrate-rich  diets  the  quotient,  rises  somewhat  more 
in  work  than  it  does  following  carbohydrate-poor  diets. 

As  regards  the  mechanical  efficiency  upon  different  diets  Zuntz  was 
convinced  that  there  was  nothing  to  choose  between  carbohydrate  and  fat. 
He  cites  experiments  performed  by  his  students,  especially  Frentzel  and 
Reach  and  also  of  Atwater  and  his  colleagues,  "vvhich  show  that  the  absorp- 
tion of  oxygen  is  essentially  the  same  whether  carbohydrate  or  fat  is  burned 
(see  Table  14).  Benedict  and  Cathcart  support  this  view  with  their 
findings  that  the  energy  quotient  (total  calories  produced  per  calorie  of 
effective  w^ork  performed)  was  the  same  on  days  following  a  carbohydrate- 
rich  diet  as  on  days  following  a  diet  poor  in  this  foodstuff  whether  the 
amount  of  work  was  large  or  small.  Anderson  and  Lusk  performed  ex- 
periments upon  a  9  kilo  dog  while  nmning  upon  a  treadmill  inside  the 
calorimeter  both  before  and  after  feeding  with  large  amounts  of  glucose 
and  noted  a  distinct  difference  in  efficiency  after  the  carbohydrate  ingestion. 
When  the  dog  had  been  without  food  for  18  hours  and  the  average  re- 
spiratory quotient  was  0.78  it  required  0.580  kilograrameter  of  work  to 
move  1  kilo  of  the  body  weight  1  meter  on  the  horizontal.  In  the  first 
hours  after  carbohydrate  when  the  average  quotient  was  0.95  the  same 
work  was  done  at  an  expenditure  of  0.550  kilogrammeter,  a  saving,  of 
5  per  cent.  Krogh  and  Lindhard  point  out  that  if  the  metabolism  per  * 
unit  of  work  is  assumed  to  be  a  straight  line  function  of  the  quotient  the 


592 


JOHN  R  MURLIN 


waste  of  energy  from  fat  in  these  experiments  works  out  as  eight 
per  cent. 

The  last-named  authors  have  carried  the  comparison  between  fat  and 
carbohydrate  as  a  source  of  muscuUir  work  much  farther.  They  devised 
experiments  upon  human  subjects  with  the  bicycle  ergometer  of  Krogh 
placed  inside  a  Jaquet-Grafe  (page  520)  respiration  chamber,  which  would 
be  done,  after  the  manner  of  Benedict  and  Cathcart's  experiments,  before 
the  first  meal  of  the  day,  but  following  two  or  more  days  upon  controlled 
diets  containing  in  turn  a  decided  preponderance  of  the  two  non-nitro- 
genous foodstuffs.  The  two  most  successful  subjects  were  college  athletes 
familiar  with  bicycling,  and,  in  one  series,  freshly  trained.  Both  these 
students  and  three  out  of  five  older  subjects  experienced  gi-eat  difficulty  in 
doing  the  prescribed  work  and  suffered  much  fatigue  thereafter  following 
heavy  fat  feeding,  but  did  the  work  with  ease  and  without  fatigue  follow- 
ing carbohydrate.    This  experience  accords  with  that  of  other  observers. 

The  results  of  Krogh  and  Lindhard  are  summarized  below. 

TABLE  15 

Comparison  of  I  at  and  Carbohydrate  as  Source  of  Muscular  Energy 
(Krogh  and  Lindhard) 


Calories  per  Unit  Work 

Difference 

Subject 

No.  of  Exp. 

From  Fat 

From 
Carbohy. 

Cal. 

Per 

Cent 

Efficiency 

J.L 

5.69 

4.59 

1.10 

19.4 

10 

G  L 

5.84 
5.04 

5.09 

4.28 

0.75 
0.76 

12.8 
15.1 

15 
15 

18  3 

A.K 

21.6 

R.E 

4.72 

3.72 

1.00 

21.2 

13 

23.7 

M.N.Tb.XIT    . 

4.70 

4.02 

0.68 

14.5 

33 

23.0 

M.  N.  Tb.  XIII . 

4.73 

4.10 

0.63 

13.3 

18 

22.7 

O.H.Tb.IX   ... 

4.79 

4.32 

0.47 

9.8 

33 

22.0 

O.H.Tb.XVI    . 

4.52 

4.10 

0.42 

9.3 

49 

23.2 

0.  H.  Tb.  XVII . 

4.52 

4.15 

0.42 

9.2 

24 

23.0 

The  simple  average  of  the  percentage  differences,  the  autliors  state,  would 
be  very  misleading  partly  because  of  the  different  number  of  experiments 
for  the  different  subjects  and  partly  because  the  several  series  are  by  no 
means  equally  concordant.  By  assig-ning  definite  "weights"  to  each  series 
in  proportion  to  the  number  of  determinations  and  in  inverse  ratio  to  the 
standard  deviations  within  each  series  the  average  percentage  waste  of 
energy  from  fat  as  compared  with  carbohydrate  is  11.25.  It  follows 
clearly  that  work  is  more  economically  perfonned  on  carbohydrate  than 
on  fat 

From  the  table  it  may  be  seen  that  the  net  expenditure  of  energy  neces- 
sary to  perform  one  calorie  of  mechanical  work  on  the  ergometer  vai-ies 


:^rOKMAL  PKOCESSES  OF  EI^EEGY  METABOLISM     593 

between  about  5.5  and  4.0  Cal.  At  a  constant  quotient  the  authoi*s  find 
that  it  varies  somewhat  with  the  subject,  and  for  the  same  subject  it  de- 
creases with  training  (see  page  588). 

The  question  may  fairly  be  raised,  Where  does  protein  stand  in  the  scale 
of  efficiency'  as  a  source  of  muscular  work  ?  This  question  has  been  studied 
in  relation  to  the  specific  dynamic  action  of  protein  by  Rubner(o)  and  more 
recently  by  Anderson  and  Lusk.  Both  sets  of  observations  sliow  that  there 
is  practically  complete  summation  of  the  extra  energy  production  due  to 
the  specific  dynamic  action  of  meat  and  the  energy  production  caused 
by  the  muscular  work.  There  is  nothing  specifically  uneconomical  in 
doing  work  on  a  high  protein  diet  except  in  the  sense  that  the  extra  heat^of 
dynamic  action  is  added  to  the  extra  heat  of  muscular  work  and  this  throws 
extra  burdens  on  the  organs  charged  with  the  dissipation  of  heat.  With 
cane  sugar,  as  proved  in  Buhner's  experiments  or  glucose  as  proved  in 
Lusk's,  the  specific  dynamic  effect  of  the  food  disappears,  i.  e.,  merges  into, 
the  extra  metabolism  of  muscular  work.  These  facts  make  it  clear 
that  the  mechanism  of  energ;^'  release  in  muscular  work  is  more  nearly 
akin  to  the  mechanism  by  which  carbohydrate  raises  the  metabolism 
(metabolism  of  plethora,  see  page  606)  than  it  is  to  the  mechanism  of  pro- 
tein stimulation.  The  work  of  Fletcher  and  Hopkins  and  of  A.  V.  Hill 
on  the  details  of  muscular  contraction  make  it  appear  that  certain  reac- 
tions take  place  between  definite  substances  which  must  be  closely  allied  to 
carbohydrates.  It  becomes  more  intelligible  therefore  why  carbohydrate 
should  support  muscular  work  more  economically  than  fat  ®  and  why  its 
dynamic  action,  unlike  that  of  protein,  should  not  be  superimposed  upon 
the  metabolism  of  muscular  work. 


III.    The  Energy  Metabolism  is  Determined  in  Part  by 
the  Environing  Temperature 

1.  How  Heat  is  Lost  from  the  Body. — In  general,  there  are  four  main 
avenues  of  escape  for  the  heat  which  is  produced  in  the  body  of  a  warm- 
blooded animal:  (1)  Wanning  the  food  and  air  which -enter  the  body; 
(2)  Vaporization  of  water  and  setting  free  of  CO2  in  the  lungs;  (3) 
Evaporation  of  water  from  the  surface  of  the  body;  (4)  Radiation  and 
conduction  from  the  surface  of  the  body. 

Tigerstedt(a)  gives  the  following  calculations  made  by  Rubner  for  a 
man  producing  2,700  calories  daily : 

•Kro*?l»  and  Lindhard  note  that  the  standard  metabolism  (called  basal  metabolism 
more  commonly)  is  somewhat  higlier  when  the  respiratory  quotient  is  low  than  when 
it  lies  in  the  median  range.  There  is  just  a  hint  in  this  fact  that  tlie  so-called  waste  of 
energy  when  muscular  woric  is  supported  by  fat  may  be  bound  up  with  the  specific 
dynamic  action  of  that  foodstuff  as  it  is  in  the  case  of  protein. 


^94  JOHN  R.  MURLm 

Calories 

(1)  Warming  food  and  drink  to  body  temperature 42 

(2)  Warming  air  from  17.5''  to  30**  C 35 

(3)  Evaporation  of  water  from  lungs  and  skin 658 

(4)  Heat  equivalent  of  external  work  done  51 

(5)  Loss  of  radiation   from  entire  surface  of  body    1,181 

(6)  Loss  by  conduction  to  air  from  entire  surface 833 

Total 2,700 

Atwater,  in  his  calorimctric  studies,  made  tlie  following  estimations: 
L  Resting  man,  mean  of  fourteen  experiments  comprising  forty-two  days; 

Calories 

1.  Heat  loss  by  radiation  and  conduction 1,683 

2.  Heat  loss  by  urine  and  feces    , 31 

3.  Heat  loss  by  evaporation  from  lungs  and  skin    "    548 

Total 2,262 

II.  Man  at  work,  mean  of  twenty  experiments  comprising  sixty-six  days: 

Calories 

1.  Heat  loss  by  radiation  and  conduction    3,340 

2.  Heat  loss  by  urine  and  feces    46 

3.  Heat  loss  by  evaporation  from  lungs 'and  skin     859 

4.  Heat  equivalent  of  muscular  work 451 

Total    : 4,676 

It  is  evident,  from  these  estimates,  that  fully  eighty  per  cent  of  all  the 
heat  produced  in  the  hody  is  lost  through  the  skin. 

2.  The  Law  of  Surface  Area. — Closely  related  to  this  matter  of  the 
loss  of  heat  through  the  skin  is  the  relationship  of  heat  loss  to  heat  pro- 
duction known  as  the  law  of  surface  area,  first  enunciated  over  80  years 
ago  by  certain  French  writers.  To  quote  one  of  the  earliest  communica- 
tions :  **As  the  heat  loss  is  proportional  to  the  extent  of  free  surfaces  and 
these  latter  are  to  each  other  as  the  squares  of  their  homologous  sides,  it 
follows  of  necessity  that  the  quantity  of  oxygen  absorbed,  or  what  amounts 
to  the  same  thing,  the  heat  produced  on  the  one  hand  and  lost  on  the  other, 
is  proportional  to  the  square  of  the  corresponding  dimensions  of  tlie  ani- 
mals one  is  comparing  (Robiquet  and  Thillaye)."  The  first  experimental 
evidence  of  relationship  between  skin  sui*face  and  the  food  requirement  of 
animals  seems  to  have  been  furnished  by  Miintz  who  in  1879  ijivostigated 
the  maintenance  ration  of  horses.  Emphasizing  the  part  played  by  the  sur- 
face he  says :  "A  notable  part  of  the  food  certainly  is  consumed  to  main- 
tain the  vital  heat  which  has  a  tendency  constantly  to  be  lost  by  radiation 
or  conduction  to  the  surrounding  medium.  Another  cause  of  cooling  is 
cutaneous  eva}X)rati(m  which  is  a  function  of  the  surface  if  it  is  not  directly 
proportional  thereto.  The  evaporation  produced  by  the  organs  of  respira- 
tion may  equally  be  regarded  as  having  a  relation  to  the  surface  of  the  Ixnly 
rather  than  to  the  weight.    We  are  then  by  these  considerations  in  position 


NORMAL  PROCESSES  OF  EXERGY  METABOLISM     595 

to  admit  the  preponderating  influence  of  surface  upon  the  apportionment  of 
the  maintenance  ration." 

This  law  of  surface  a  few  years  later  was  placed  upon  a  firmer  basis 
by  researches  of  Kubner(a.)  upon  dogs  and  of  Ilichet(c)  upon  rabbits. 

A  small  animal  has  a  greater  surface,  in  proportion  to  its  weight,  than 
has  a  large  animal.  This  will  be  clear  from  the  following  illustration. 
Suppose  we  have  two  spheres  of  two  and  four  centimeters  diameter.  The 
surface  of  the  smaller  would  be  12.56  square  centimeters  and  of  the  larger 
50.24  square  centimeters.  The  volume  of.  the  first  would  be  4.18  c.c.  and 
of  the  latter  33.49  c.c.  The  surface  of  the  smaller,  in  proportion  to  its 
volume,  therefore,  would  be  as  3:1,  while  of  the  larger  it  would  be  only 
as  1.5:1.  Since,  now,  more  than  four-fifths  of  the  animal's  heat  escapes 
through  the  skin,  by  one  physical  means  or  another,  it  is  clear  that  heat 
must  be  produced  in  proportion  to  the  surface  rather  than  in  proportion 
to  the  mass,  if  the  body  temperature  is  to  be  maintained.  Hence,  if  two 
animals,  with  similar  coats  of  fur,  had  skin  surfaces  that  bore  to.  each 
other  the  relation  of  these  spheres,  the  smaller  animal  would  produce  twice 
as  much  heat  per  unit  of  weight  as  the  larger.  Rubner  found  that  the . 
average  heat  production  per  square  meter  of  body  surface  for  man,  dog, 
rabbit,  guinea  pig,  and  mouse  was  1,088  calories  with  variations  of  +  104 
calories  to  —  103  calories,  i.  e.,  of  about  ten  per  cent  either  way. 

a.  Measurement  of  the  Surface  Area. — Several  methods  have  been 
proposed  for  determining  the  surface  area  of  the  human  subject.  The  first 
was  that  of  Meeh  who  marked  out  some  parts  of  the  body,  which  were 
favorable  for  the  purpose,  in  geometrical  figures,  covered  them  with  trans- 
parent paper  and  made  tracings  of  the  figures.  The  areas  of  these  figures 
were  then  calculated  or  determined  by  weighing  the  paper.  Other  parts 
of  the  body  were  measured  directly  by  wrapping  with  millimeter  paper. 
Bouchard  suggested  a  plan  which  was  later  improved  upon  by  DuBois  and 
DuBois(a),  namely,  of  clothing  the  body  in  tights  made  of  some  thin  in- 
elastic material  which  could  be  weighed.  D'Arsonval(c)  clothed  a  man  in 
silk  tights  and  after  charging  the  clothing  with  electricity,  determined  the 
surface  relative  to  a  metal  plate  of  known  surface  by  releasing  the  charge 
as  from  a  Leyden  jar.  Lissauer  measured  the  surface  of  dead  infants  by 
covering  the  skin  with  adhesive  material,  applying  silk  paper,  and  then 
measuring  the  area  of  the  paper  by  means  of  a  planiraeter. 

The  measurement  was  accomplished  by  DuBois  in  the  following  man- 
ner. A  light,  flexible,  inelastic  covering  was  obtained  by  clothing  the  body 
with  a  close-fitting  knitted  union  suit,  and  pasting  this  over  with  ad- 
hesive paper.  But  instead  of  attempting  to  w^eigh  this  "model"  of  the 
body  surface,  it  was  cut  up  into  pieces  which  would  lie  out  flat  and  the 
area  of  each  piece  determined  by  photographing  it  on  sensitive  paper. 
The  total  area  was  then  found  by  weighing  the  photographic  silhouettes 
and  comparing  with  the  weight  of  a  unit  area  of  the  same  sensitive  paper. 


596 


JOHN  K.  MUKLIN 


The  areas  of  the  several  members  of  the  body  as  measured  were  then  com- 
pared with  the  areas  as  given  by  multiplying  their  lengths  by  sums  of 
measurements  representing  circumferences.  For  example,  the  area  of 
the  arm  was  given  by  multiplying  the  length  from  the  outer  end  of  the  clav- 
icle to  the  lower  border  of  the  radius  (F)  by  the  sum  of  the  three  circum- 
ferences at:  upper  border  of  axilla  (G)  ;  largest  girth  of  forearm  (H)  ; 
smallest  girtli  of  wrist  (I).  This  calculated  area  compared  with  the  actual 
area  for  several  individuals  gave  a  factor  which,  used  with  the  product 
first  given,  made  up  a  so-called  linear  formula  for  the  arm;  thus:  F 
(G  +  H  -f-  I)  0.558.  The  several  sub-formulse  added  together  could  then 
be  employed  for  measuring  the  surface  of  the  entire  body. 

This  method  resembles  the  one  proposed  by^Roussy  in  which  the  surface 


Fig.  .33.  A  method  of  calculating  the  surface  area  by  treating  the  body  as  a  series 
of  cylinders.  The  average  is  taken  of  29  diflFerent  circumferences  (mean  perimeter) 
and  this  is  multiplied  by  the  sum  of  the  several  lengths.     (Roussy.) 


was  given  by  multiplying  the  mean  perimeter  (Pm)  by  the  mean  peripheral 
total  height  (Hm)  ;  thus  S  =Pm  X  Hm.  The  first  factor  was  found  by 
taking  the  mean  of  20  different  circumferences  (Fig.  33)  while  Ilm  is  the 
sum  of  3  partial  heights,  (a)  head,  neck  and  shoulders;  (b)  trunk  and 
lower  extremities ;  (e)  upper  extremities. 

From  his  measurements  Meeh  devised  a  formula  based  upon  the  well 
known  relationship  of  surfaces  to  masses  of  similar  solids ;  namely,  that  the 
former  varies  as  the  %  power  of  the  latter.  By  employing  a  constant, 
12.3,  Meeh  found  that  the  formula  S  =  J/(w)  -  gave  results  within  7 
per  cent  of  those  detennined  by  actual  measurement.  DuBois  found  an 
agreement  between  measured  and  calculated  values  for  5  cases  within 
2  per  cent.  Later  his  measurements  were  simplified  and  a  formula  con- 
taining total  height,  weight  and  certain  constant  factors  was  devised.  This 
is  known  as  the  weight-height  formula.     A  =  W  ^-^25  ><  H  ^•'^^s  >^  q^ 


NOEMAL  PROCESSES  OF  ENERGY  METABOLISM     597 

where  A  is  the  area  in  sq.  cm.,  H  the  Itcight  in  centimeters,  W  the  weight 
in  kgm.,  and  C  a  constant  71.84.  A  chart  based  upon  this  formula  for 
direct  reading  of  the  surface  area  when  height  and  weight  in  metric  units 
are  known  is  given  in  Fig.  J33-a. 

b.  Criticisms  of  the  Law  of  Surface  Area^ — Various  criticisms  have 
been  leveled  at  the  law  of  surface  area,  some  of  them,  based  upon  fact, and 
some  upon  interpretation.  Of  the  criticisms  based  upon  fact  that  recently 
published  by  Harris  and  Benedict  is  perhaps  the  most  important.  They 
have  subjected  the  body  surface  law  to  a  critical  biometric  study  and  have 
reached  the  conclusion  that  the  correlations  between  body  surface  and  basal 
heat  production  in  normal  adults  are  of  about  the  same  magnitude  as 
those  between  body  weight  and  heat  production.  "These  results  do  not, 
therefore,  justify  the  conclusion  that  metabolism  is  proportional  to  body 
surface  and  not  proportional  to  body  weight."  In  the  opinion  of  these 
authors  the  closer  agreement  between  heat  production  of  different  indi- 


100         flO 


50         60         70         80 
WEIGHT-KILOGRAMS 

Fig.  33-a.  Chart-  for  determining  surface  area  of  man  in  square  meters  from 
weight  in  kilograms  (Wt.)  and  height  in  centimeters  (Ht.)  according  to  the  formula: 
Area  (Sq.  M.)   =  Wf"-*"  X  Ht-"-'==^  X  71.84  (DuBois). 


viduals  and  their  surfaces  than  between  heat  production  and  body  weight 
is  not  due  to  any  causal  relation  between  heat  loss  and  heat  production 
as  a  mechanism  for  preservation  of  heat  loss  and  body  temperature,  but 
in  part  at  least  proceeds  from  the  fact  that  body  surface  being  proportional 
to  the  %  power  of  weight  is  less  variable  than  the  weight  itself,  and  the 
ratio  of  heat  produced  to  body  surface  consequently  is  likewise  less  variable. 
As  a  matter  of  fact  the  mathematical  relationship  does  not  stop  here; 
for  in  many  instances  the  constant  employed  in  the  formula,  for  example, 


598 


JOHN  R  MUELIN 


of  IMeeh  or  of  Lissauer  by  which  the  %  power  of  the  weight  is  multiplied 
equalizes  the  proportions  between  surfaces  and  weights.  This  fact  gives 
a  slightly  different  posture  to  the  argument.  A  few  illustrations  will 
make  this  clear.  Suppose,  for  example,  wo  have  two  infants  weighing  7 
and  8  kilograms  respectively.  Expressing  their  weights  in  kilogi-ams  and 
their  surfaces  in  sq.  M.  by  the  lleeh  and  Lissauer  formulas,  v/e  have  the 
proportions  shown  in  the  following  table. 

TABLE  16 
Relation  of  Body  Weights  a^d  Surfaces  to  Each  Otheb 


Meeh-Rubner 

Lissauer 

Weight, 

Ratio 

ll.OVT^* 

Ratio 

10.3V  (w)» 

Ratio 

kgm. 

Surface, 

Surface, 

sq.  M. 

sq.  M. 

7 

0.4353 

0.3769 

8 

0.88 

0.4760 

0.91 

0.4120 

0.91 

20 

0.8708 

0.7589 

21 

0.95 

0.9058 

0.97 

0.7840 

0.97 

40 

1.3920 

1.205 

41 

0.98 

1.41.50 

0.98 

1.225 

0.08 

4 

0.299 

0.259 

40 

0.10 

1.3920 

0.210 

1.205 

0.21 

3.5 

0.274 

0.237 

70 

0.05 

2.021 

0.135 

1.750 

0.136 

The  ratio  of  weights  is  .88  :  1  and  of  surfaces  .91  :  1.  ]^ow  it  is  ob- 
vious that  if  the  metabolism  of  these  two  children  is  proportional  to  their 
weights  it  must  of  necessity  also  be  nearly  proportional  to  surface.  With 
two  youths  weighing  40  and  41  kilos  the  surfaces  bear  to  each  other  ex- 
actly the  same  ratio  as  the  weights,  whether  the  !^^eeh  or  Lissauer  formula 
be  employed.  Eoth,  therefore,  will  be  equally  good  measures  of  metabolism 
for  the  two  individuals. 

Contrast  witli  this  the  relationship  between  individuals  weighing  4  and 
40  kilograms,  or  still  better,  an  infant  at  birth  weighing  314  kilograms  and 
a  man  weighing  70  kilograms.  In  the  latter  the  weights  are  to  each  other 
as  .05  to  1,  and  the  surfaces  as  .135  to  1.  In  other  words,  the  weight  of  the 
larger  individual  is  twenty  times  that  of  the  smaller,  w^hile  the  surface  is 
a  little  over  seven  times  that  of  the  smaller.  In  this  case  weight 
and  surface  cannot  possibly  be  of  equal  value  as  measures  of  the  metab- 
olism. One  is  nearly  three  times  as  good — or  as  bad — as  the  other.  As  a 
matter  of  fact  it  is  now  well  known  that  surface  is  about  two  and  one-half 
times  as  good  a  measure  as  weight  between  tw^o  such  individuals. 

Benedict  and  his  colleagues  have  fallen  into  the  error  of  supposing  that 
physiologists  have  believed  the  basal  metabolism  to  be  absolutely  propor- 
tional to  surface  regardless  of  circumstances.  This  is  quite  incorrect. 
Rubner  for  the  German  literature  and  Richet  for  the  French  are  respon- 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM     599 

sible  for  the  first  demoustiat.ions  of  the  applicability  of  the  law.  Rubner 
worked  with  dogs  of  adult  stature  but  widely  ditferent  size,  estimating  their 
metabolism  by  the  indirect  method.  Richet  worked  first  with  rabbits 
langing  from  2000  to  '>500  grams  in  weight  but  he  determined  only  the 
heat  of  radiation  and  c<;uduction,  neglecting,  as  nearly  all  subsequent 
French  observers  have  done,  the  heat  given  off  by  evaporation.  Naturally 
his  quantities  would  be  mere  nearly  proportional  to  surface  than  the  total. 
However,  in  the  estimation  of  surfaces  he  says,  "If  one  supposes  that 
animals  of  different  size  are  like  spheres  of  different  volumes,  then  the 
respective  volumes  are  related  among  themselves  as  the  cubes  of  their 
radii ;  while  the  respective  surfaces  are  related  among  themselves  as  the 
squares  of  their  radii.  These  considerations  apply  to  living  animals,  and, 
since  their  form  is  so  irregular  compared  with  that  of  a  perfect  sphere, 
one  can  only  apply  the  geometrical  facts  to  them  approximately."  Fur- 
ther in  summing  up  the  factors  which  determine  heat  production  Richet 
notes  that  one  of  these  is  "the  nature  of  the  integument."  In  two  im- 
portant respects,  therefore,  Richet  made  saving  clauses  regarding  the 
application  of  the  law  of  surface,  one  conceniing  the  measurement  of 
surface  and  the  other  concerning  the  natui*o  of  the  skin,  meaning,  of 
course,  its  conducting  properties.  Rubner  in  the  beginning  considered 
that  he  had  demonstrated  the  law  only  for  adult  animals  and  later  in 
applying  it  to  children  made  this  very  emphatic  resen-ation :  "The  law 
of  surface  area  holds  under  all  physiological  conditions  of  life,  but  for  its 
proof  it  is  a  reasonable  presumption  that  only  organisms  of  similar 
physiological  capacities,  as  regards  nutrition,  climatic  influences,  tem- 
perament, and  fimctional  power,  should  he  compared."  Other  students  of 
metabolism  have  made  similar  reservations.  Thus  Schlossmann  says,  "The 
presumption  is  on  the  one  hand  that  the  environment  is  relatively  normal, 
on  the  other  that  the  child  has  a  relatively  normal  surface,  that  is,  a 
functioning  and  good  conducting  skin  with  the  nonnal  amount  of  sub- 
cutaneous fat."  Otherwise,  he  thinks,  the  law  could  not  be  expected 
to  apply. 

The  arguments  against  the  law,  so  far  as  they  rest  upon  facts,  seem, 
as  we  have  just  seen,  to  have  been  misconceived.  It  never  was  supposed 
by  its  chief  proponents  that  the  law  would  apply  to  all  physiological  and 
pathological  conditions  but  only  to  similar  physiological  (normal)  condi- 
tions. Also,  a  very  superficial  understanding  of  the  necessary  mathematical 
relations  shows  that  the  law  has  natural  limitations  which  must  be  recog- 
nized if  one  is  to  avoid  compromising  it  with  impossible  conditions. 

There  is  no  doubt  vhat  Rubner,  following  Bergmann,  has  conceived 
of  the  law  as  causally  related  to  Newton's  law  of  cooling.  This  dependence 
as  commonly  accepted  may  be  phrased  in  this  way.  Solid  bodies  when 
warmed  lose  heat  in  piojK)rtion  to  the  difference  between  the  temperature 
of  the  body  and  the  temj)erature  of  the  surrounding  medium.     Since  this 


GOO  JOHX  K.  MURLI]N^ 

heat  must  all  pass  through  the  surface  it  follows,  other  things  equal,  that 
they  will  lose  heat  for  any  particular  gradient  of  temperature  in  propor- 
tion to  surface.  As  applied  to  the  animal  body  it  is  observed  that  the  body 
temperature  is  nearly  constant.  Hence,  if  heat  is  lost  in  proportion  to 
surface,  it  must  also  be  produced  in  proportion  to  surface.  This  im- 
plies a  causal  relationship  between  surface  loss  and  interior  produc- 
tion of  heat.  An  elaborate  biometric  analysis  proves  nothing  more  re- 
garding this  causal  relationship  than  is  proved  by  the  simple  mathe- 
matical analysis  shown  in  Table  16.  Whatever  the  physiological  measure- 
ment of  surface,  if  it  can  be  expressed  even  approximately  by  a  fonnula 
such  as  !Meeh's  it  will  follow  that  the  ratio  of  body  weights  for  certain 
ranges  will  be  the  same  as  the  ratio  of  body  surfaces  provided  the  weights 
are  not  far  apart,  and  for  subjects  of  a  continuous  series  in  which  weights 
differ  by  small  increments  it  will  follow  that  surface  will  be  only  a  little, 
if  any,  better  as  a  measure  of  metabolism  than  v/eight. 

The  question  of  causal  relationship  stands  just  where  it  always  has 
stood.  If  the  possession  of  a  large  surface  in  proportion  to  weight,  as  in 
a  mouse,  is  accompanied  by  a  vastly  higher  heat  production  per  unit  of 
weight  as  compared  with  a  horse,  but  the  heat  production  is  found  to 
be  proportional  to  the  surfaces  in  two  such  animals  with  approximately 
the  same  body  temperature,  it  seems  to  follow  that  surface  loss  of  heat 
is  at  least  a  more  probable  cause  of  heat  production  than  body  mass.  The 
same  is  true  as  between  a  baby  and  a  man. 

On  the  basis  of  interpretation  the  objections  to  the  law  of  surface  run 
in  this  way.  Since  the  heat  production  of  animals  seems  to  be  propor- 
tional to  surface  area,  it  would  seem  to  follow  that  heat  is  produced  in 
order  to  replace  that  which  is  lost,  or  to  maintain  body  temperature.  This 
view,  some  say,  denotes  an  all  too  naive  conception  of  nature.  Blood  does 
not  coagulate  in  order  to  prevent  hemorrhage,  but  because  certain  chemical 
agents  are  present  with  certain  properties.  The  fact  that  it  does  stop 
hemorrhage  is  quite  incidental.  It  may  have  selective  value,  so  that  a 
species  whose  blood  did  not  clot  would  have  the  worst  of  it  in  the  struggle 
for  existence,  but  it  will  never  do  to  say  that  this  chemical-physiological 
function  originated  for  the  purpose  of  preventing  hemorrhage;  for  that 
would  imply  a  mind  at  work  in  anticipation  of  the  result.  So  also  with 
heat  production.  These  critics,  of  whom  Kassowitz(c)  has  been  chief,  pre- 
fer to  account  for  heat  production  in  a  perfectly  causal  manner.  "Small 
animals  maintain  a  higher  rate  of  oxidation,  it  is  true,  than  large  ones,  but 
this  is  not  because  they  lose  heat  more  rapidly  in  consequence  of  greater 
(relative)  surface,  but  because  their  alternating  movements  (later  phases 
caused  reflexly  by  earlier  phases)  follow  one  another  more  rapidly  on  ac- 
count.of  shorter  nerve  paths.^'  Kassowitz(J)  indeed  finds  that  the  higher 
rate  of  oxidation  in  small,  wann-blooded  animals  has  even,  for  them  *'dys- 
teleological  consequences ;  for  because  of  the  more  extensive  muscular  con- 


NORMAL  PROCESSES  OF  EKERGY  METABOLISM     601 

tractions  more  food  and  reserve  substances  are  placed  in  requisition  and  by 
this  means  the  deposit  of  reserve  fat  in  the  whole  body,  and  especially 
in  the  subcutaneous  tissues,  is  made  more  difficult,  so  that  the  protection 
against  cooling— which  a  thick  layer  of  fat  prevents— fails  in  part  amongst 
the  very  animals  which  need  it  most."  Even  Kassowitz  is  obliged  to 
admit,  however,  that  ''in  warm-blooded  animals  which  are  in  a  position 
to  maintain  their  own  body  temperature  under  the  most  diverse  conditions, 
one  can  claim  the  appearance  of  some  justification  that  their  living  parts 
produce  heat  in  order  to  protect  the  body  against  loss  by  radiation,  etc." 

Whether  this  is  a  real  justification  or  only  the  appearance  of  one  will 
not  trouble  the  practical  physiologist  so  long  as  the  generalization  that  hu- 
man beings  of  different  size  produce  heat  in  proportion  to  surface  rather 
than  weight,  and  therefore,  require  food  energy  in  proportion,  helps  him 
to  understand  his  feeding  problems;  and  there  is  no  doubt  that  the  law 
of  surface  area  has  been  immensely  useful  in  this  connection.  It  explains 
the  much  higher  basal  metabolism  per  unit  of  weight  of  the  small  individual 
in  comparison  with  the  large,  better  than  the  so-called  causal  explanation- 
cited  by  Kassowitz.  It  explains  also  much  better  the  need  for  conservation 
of  heat  in  the  infant,  and  the  role  which  subcutaneous  fat  plays  in  this  con- 
nection. 

3.  Heat  Production  as  Affected  by  External  Temperature. — a.  In 
Cold-blooded  Animals— Van't  Hoff's  Law, — Increased  activity  in  living 
tissues  is  almost  invariably  accompanied  by  an  increased  evolution  of  heat. 
Since  this  heat  is  derived  from  the  chemical  changes  which  proceed  in  the 
living  cells,  and  since  all  chemical  processes  are  quickened  by  a  rise  of  tem- 
perature, we  should  expect  to  find  that  the  heat  produced  in  the  metabolic 
processes  of  the  organism  would  tend  of  itself  to  quicken  these  processes. 
This  is  found  in  fact  to  be  the  case.  In  most  chemical  reactions  a  rise 
of  10°  C.  would  increase  the  velocity  of  the  reaction  from  two  and  a  half 
to  three  times  (Van't  Hoff's  Law),  and  the  same  law  is,  within  the  limits 
of  the  stability  of  living  tissues,  found  to  apply  to  the  process  of  oxidation. 
For  example,  in  the  early  growth  of  a  lupine  seedling  it  has  been  found 
that  the  output  of  COg  bears  to  the  temperature  the  following  relationship : 

0®  C 6  milligrams  per  hour 

lO**  C 18  "  "        " 

20"  C 44  "  "        «* 

30°  C 86  *•  "        « 

The  same  relationship  has  been  found  to  obtain  for  the  production  of  COg 
in  the  snail,  the  leech,  and  the  earthworm.  Perhaps  the  absoi*ption  of 
oxygen  is  a  still  better  measure  of  the  heat  production.  Within  the  range 
of  5  to  21°  C.  it  has  been  observed  that  the  factor(Qio),  which  in  biological 
literature  expresses  the  number  of  times  the  process  is  accelerated  for  a 
rise  of  10°,  has,  for  the  absorption  of  oxygen  by  the  crayfish,  a  value  of 


602  JOHK  R  MUELIIsr 

2.5  to  3.5.  In  the  case  of  the  leech,  the  same  factor,  between  10  and  24°, 
is  from  2.4  to  3.0  (Putter,  A.). 

In  living  things  the  range  within  which  any  such  law  applies  is  neces- 
sarily very  narrow  as  compared  with  its  range  in  inorganic  reactions ;  and- 
the  factor  (Qio)  varies,  according  to  the  best  deteraiinations  which  have 
yet  been  made,  very  widely.  Xevertheless,  it  may  be  said  that  the  law 
that  the  rate  of  ciiemical  change  (metabolism)  varies  with  the  temperature 
of  the  living  substance  is  a  universal  law  for  all  animals  and  plants.  As 
applied  to  the  production  of  heat  in  living  things,  this  law  would  result 
in  a  vicious  circle  (the  temperature  increasing  the  oxidation  and  the  oxida- 
tion increasing  the  temperature)  which  would  rapidly  destroy  the  living 
substance  itself,  if  special  mechanisms  did  not  exist  for  the  removal  of 
the  heat.  Where  these  mechanisms  break  down,  as  in  fevers,  the  heat 
must  be  removed  by  artificial  means. 

DuBois(&)  has  recently  shown  that  the  metabolism  of  men  in  fevers  in- 
creases from  30  to  60  per  cent  for  a  rise  of  three  degrees  (from  37  to  40° 
C.)  and  the  value  of  Q^q  therefore  is  about  2.3.  In  other  words  the 
metabolism  in  fevers  obeys  Van't  Hoif's  law. 

b.  In  Warm-hlooded  Animals. — In  warm-blooded  animals  with  the 
development  of  the  capacity  to  regulate  the  body  temperature  indepen- 
dently of  the  surrounding  medium,  Van't  Hoif^s  law  is  apparently  re- 
versed, so  that  the  lower  the  external  temperature  becomes  the  greater 
is  the  heat  production.  This  is  necessarily  the  case  if  the  body  tempera- 
ture is  to  be  maintained.  Confirming  the  original  observation  of  Lavoisier 
that  more  heat  is  produced  in  the  human  subject  when  the  external  tem- 
perature is  low,  C.  Voit(e)  exposed  a  man  in  light  clothing  in  his  respira- 
tion apparatus  to  different  temperatures  and  found  that,  as  the  temperature 
fell,  the  metabolism  increased  independently  of  any  muscular  motions. 
Kubner(/z.)  can'ied  this  line  of  investigation  much  farther,  using  dogs  and 
guinea  pigs,  and  formulated  his  laws  of  the  chemical  and  physical  regula- 
tion of  the  body  temperature.  In  brief,  these  laws  are  :  (1)  That,  from 
a  temperature  of  about  30°  C.  do'v\Tiward5  the  body  temperature  is  regu- 
lated chiefly  by  varying  the  heat  production  (chemical  regulation).  Heat 
loss  is  regulated,  to  some  extent,  by  decreasing  the  amount  of  blood  brought 
to  the  surface.  (2)  From  30°  C.  upward  the  body  temperature  is  regu- 
lated chiefly  by  varying  the  amount  of  water  evaporated  from  the  surface 
(sweating)  and  again  by  decreasing  the  amount  of  blood  brought  to  the 
surface  (physical  regulation). 

The  conclusions  of  Voit  and  Rubner  with  regard  to  the  efi:ect  of  cold 
as  such  have  frequently  been  called  in  question,  the  contention  being  that 
even  if  visible  shivering  and  increased  tonus  of  the  muscles  are  avoided 
no  more  heat  is  produced  at  low  temperature.  Lusk(&)  found  that  a  man 
immersed  for  a  few  minutes  in  a  cold  bath  at  8°  C.  would,  immediately 
thereafter,  shiver  enough  to  increase  his  metabolism  180  per  cent  above  the 


NORMAL  PROCESSES  OF  EI^^ERGY  METABOLISM     603 

normal.  Loewy(c)  and  Johansson  conducted  carefully  controlled  respira- 
tion experiments  by  two  different  methods  with  a  view  to  the  determination 
of  the  pure  effect  of  cold.  The  former  employed  sixteen  different  subjects, 
cooling  the  body  nut  only  by  exposure  to  a  temperature  of  12  to  IG'  C, 
but  also  by  evaporation  of  water,  alcohol  and  ether  from  the«skin.  The 
latter  performed  experiments  upon  himself  as  subject  after  acquiring  the 
power  to  suppress  all  shivering  or  even  increased  tonus,  when  the  naked 
body  was  exposed  to  a  room  temperature  of  13  to  20^  C.  Both  observers 
found  that  there  was  no  increase  in  the  elimination  of  carbon  dioxid  when 
the  muscular  factor  was  really  ruled  out.  Uncontrolled  shivering  in 
Loewy's  experiments  produced  an  increase  of  100  per  cent  in  the  metabo- 
lism. 

Lefevre(<^)  has  demonstrated  that  the  loss  of  heat  from  the  skin  does 
not  follow  Xewton's  law  of  cooling  exactly  because  of  certain  physiological 
adjustments  of  which  the  skin  and  subjacent  structures  are  capable. 
Nevertheless  a  bettor  estimate  of  the  influence  of  the  environing  tempera- 
ture can  be  obtained  by  measuring  the  cooling  power  of  the  environment 
on  a  surface  at  body  temperature  than  is  given  by  a  record  of  the  outside 
temperature  alone.  The  recognition  of  this  truth  led  Leonard  Plill(^)  to 
invent  an  instrument  known  as  the  "Kata-thermometer."  This  consists  of 
a  large-bulbed  spirit  thermometer  wdiich  is  warmed  up  until  the  meniscus 
rises  above  100°  F.  The  rate  of  cooling  is  then  determined  with  a  stop-watch 
as  the  meniscus  falls  from  100°  F,  to  95°  F.  The  constants  of  the  instru- 
ment are  determined,  from  which  the  cooling  can  be  expressed  in  mille- 

'         .  1 

calories  (        ,   grm.  calories)   per  sq.  cm.  of  surface  per  second.     The 

instrument  when  used  dry  gives  the  rate  of  cooling  by  convection  and  radia- 
tion and  when  used  wet  (covered  with  a  damp  muslin  glove)  gives  the 
rate  of  cooling  by  convection,  radiation  and  evaporation.  From  the  read- 
ings of  the  dry  instrument  can  be  deduced  the  velocity  of  movement  of  the 
dry  air.  The  evaporative  cooling  power  of  the  wet  instrument  depends 
on  absolute  humidity  and  wind. 

Comparisons  made  by  Hill  between  the  rate  of  cooling  of  the  Kata- 
thermometer  with  that  of  the  naked  pig  as  determined  by  Lefevre  and 
of  the  naked  surface  of  the  human  foreaim  as  detennined  by  Waller,  and 
with  the  dryness  or  sweating  of  the  skin. of  soldiers  producing  a  known 
amount  of  heat,  suggests  that  the  Kata-themiometer  in  air  cools  alx)ut 
three  to  five  times  as  quickly  as  the  naked  skin  when  the  temperature  of  the 
skin  approximates  closely  to  the  body  temperature. 

Ordinary  light  clothes  reduce  the  cooling  power  of  the  atmosphere 
of  a  man  as  well  as  of  the  instniment  to  one-half  its  value  when  unclothed. 

The  cooling  power  by  radiation  and  convection  exerted  on  the  surface 
of  the  dry  Kata-thcrmometer  at  36.5°  C.  in  mille-calories  per  sq.  cm.  per 
second  according  to  Hill  is  as  follows. 


604 


JOHN  R  MUELIlSr 


TABLE  17 

COOUNO   POWEB  OF  AlB  CURRENTS   AT   DIFFERENT  VELOCITIES     (Hill) 


Temp. 

9  M.  per  Sec, 

4  M.  per  Sec., 

1  M.  per  Sec, 

%  M.  per  Sec, 

Still  Air 

*»  Cent. 

20  mi.  per  Hr. 

8.8  mi.  per  Hr. 

2.2  mi.  per  Hr. 

1.1  mi.  per  Hr. 

0 

49.3  mille-cal. 

36.1  mille-cal. 

23.1  mille-cal. 

19.0  mille-cal. 

9.8 

6 

42.5 

31.2 

19.8 

16.4 

8.5 

10 

35.0 

26.2 

16.7 

13.8 

7.1 

15 

29.0 

21.3 

13.5 

11.2 

5.8 

20 

22.3 

16.3 

10.4 

8.6 

4.4 

25 

15.5 

11.4 

7.2 

6.0 

3.1 

Flack  and  Hill  made  observations  on  the  respiratory  metabolism  of  several 
students  by  the  Doublas-bag  method  (p.  537)  and  found  that  the  heat  pro- 
duction as  calculated  l>y  the  Zuntz-Schumberg  method  (p.  565)  increased 
in  different  subjects  from  27  to  82  per  cent  when  they  were  sitting  quietly 
on  the  roof  of  the  laboratory,  over  tho  metabolism  shown  in  the  laboratory  - 
in  the  same  clothing.  For  example,  in  one  instance  the  heat  production 
was  1.57  calories  per  minute  in  the  laboratory  and  3.12  Cal.  in  a  strong 
cold  wind  on  a  snowy  day.  In  anbther  instance  exposure  to  the  inclement 
cold  winds  of  an  April  (1918)  day  increased  the  resting  metabolism  of  a 
young  woman  from  37  to  65  calories  per  sq.  M.  of  body  surface  per 
hour. 

Lefevre  had  a  subject  who  while  lying  on  a  bed  naked,  in  an  air  cur- 
rent at  5°  C.  and  of  1-2  meter  per  second  velocity,  for  3%  hours,  exhibited 
a  heat  loss  of  3  Cal.  per  minute  as  contrasted  with  1.55  calories  at  20°  C. 
Sitting  quietly  in  ordinary  light  clothes  a  man  gave  the  following  records 
of  heat  loss  in  air  currents  of  3.5  and  1  M.  per  second. 


TABLE  18 


Weight,  65  Kg. 

Surface  19,000  Sq.  Cm. 

Temperature 

Wind  Velocity 

Wind  Velocity 

3.5  M.  per  Sec. 

1  M.  per  Sec. 

Cal.  per  Diem. 

Cal.  per  Diem. 

—  l** 

6,654 

5,400 

5<» 

4,704 

4,000 

lO** 

3,690 

3,060 

15* 

3,144 

2,317 

20» 

2,754 

1,896 

26** 

2,270 

IV.    The  Ingestion  of  Food  Increases  the  Metabolism 

The  observation  of  Lavoisier  that  the  heat  production  was  increased 
by  taking  food  was  confirmed  by  Pettenkofer  and  Yoit{b),  who  found  that 
the  total  metabolism  of  a  dog  was  increased  from  34.9  to  65  calories 
per  kilogram  as  the  result  of  eating  about  two  and  one-half  pounds  of 


NOEMAL  PROCESSES  OF  ENERGY  METABOLISM  605 

meat.  Feeding:  fat  they  observed  no  increase  in  the  heat  production  un- 
less the  amount  fed  was  far  in  excess  of  the  body  requirements.  Feeding 
carbohydrate  in  the  form  of  starch,  they  found  that  379  grams  in  the 
food  increased  the  metabolism  17  per  cent  over  tliat  of  the  starving  animal, 
^foro  exact  information  concerning  the  influence  of  carbohydrate  came 
with  the  invention  of  methods  by  Zuntz  and  by  Benedict  by  which  the 
oxygen  absorption  could  ])e  determined,  since,  \vithout  this  knowledge, 
it  was  impossible  to  distinguish  the  part  taken  by  fat  in  the  total  heat 
production  from  that  taken  by  carbohydrates.  Magnus-Levy,  using  the 
Zuntz  method  with  human  subjects,  came  to  the  conclusion,  substantially 
in  accord  with  those  of  Pettenkofer  and  Voit,  namely,  that  moderate  quan- 
tities of  fat  do  not  increase  the  heat  production  (absorption  of  oxygen), 
but  that  both  carbohydrate  and  protein  increase  it  considerably.  Rubn'er, 
using  only  the  excretion  of  CO2  as  the  measure  of  heat  production,  formu- 
lated laws  regarding  the  influence  of  difl^erent  foods  given  to  dogs^  as  fol- 
lows :  Since  the  different  foodstuffs  affect  the  heat  production  to  a  different 
degree,  we  may  speak  of  their  ^'specific  dynamic  action."  The  proper  basis 
of  comparison  is  the  amount  of  heat  produced  by  the  fasting  animal.  Tak- 
ing this  quantity  as  the  minimal  requirement  of  the  animal  for  energy 
(in  potential  fonn),  and  feeding  this  quantity  in  the  form  of  different 
foodstuffs,  the  effect  is  for  protein  an  increase  of  heat  production  of  30 
per  cent,  for  fat  11  per  cent,  for  carbohydrate  5.8  per  cent.  In  order  to 
keep  the  animal  in  an  energy  equilibrium,  therefore,  it  is  necessary  to  feed 
him  in  protein  140  per  cent  of  the  requirement,  in  fat  114  per  cent,  and  in 
carbohydrate  lOG  per  cent. 

Lusk  and  his  co-workers,  using  the  small  respiration  calorimeter  (de- 
scribed on  page  579),  have  demonstrated  that  the  increased  heat  pro- 
duction in  dogs  after  ingestion  of  proteins  is  due  to  the  amino-acids  into 
which  the  protein  is  broken  up  by  digestion.  It  is,  however,  not  the  mere 
absorption  of  the  amino-acids  themselves,  nor  their  direct  oxidation  which 
accelerates  the  metabolism,  but  the  stimulating  effect  of  the  intermediate 
oxyacids  which  are  formed  from  them.  Quantitatively  the  results  of  these 
more  modern  researches  confirm  the  conclusions  of  Rubner  as  to  the  speci- 
fic effect  of  protein.  These,  however,  relate  to  the  dog.  In  man  the  dyna- 
mic effect  is  ordinarily  not  so  great.  Ilio  dynamic  effect  of  protein  in 
milk  upon  the  metabolism  of  the  infant  will  be  discussed  later  (page  644). 
It  need  only  be  added  here  that  protein  which  becomes  a  part  of  the  body 
does  not  affect  the  heat  production. 

The  dynamic  effect  of  fat,  it  turns  out,  is  not  so  high  as  Rubner  found 
it,  if  reckoned  for  the  entire  day,  but  for  individual  periods  up  to  six  hours 
after  feeding,  may  increase  the  metabolism  as  much  as  30  per  cent  (Murlin 
and  Lusk),  as  contrasted  with  protein  (meat)  which  may  raise  it  100  per 
cent.  Bloor  found  that  the  fat  in  the  blood  also  increases  up  to  six  hours 
after  feeding. 


606 


JOHN  K.  MUEim 


Following  Eubner's  fundamental  observation  on  the  influence  of  car- 
bohydrate on  the  respiratory  metabolism  of  a  fasting  dog,  Magnus-Levy, 
Johansson,  Durig,  and  DuBois,  made  confirmatory  observations  on  the  hu- 
man subject  (Lusk  (h)).  One  hundred  grams  of  glucose  causes  an  average 
increase  of  nine  per  cent  in  the  heat  production  of  a  man  of  75  kilos;  and 
200  grams  one  of  12.5  per  cent  during  3  to  6  hours  after  the  ingestion.  Thef 
same  dose  with  a  smaller  man  produces  a  proportionally  greater  accelera- 
tion of  the  metabolism.  Lusk  and  his  pupils  have  found  that  the  period  of 
highest  metabolism  after  heavy  sugar  feeding  to  dogs  coincides  with  an 


85  R.Q. 


79 

iO  Calories 
35 
30 
29 


2X)6ms. 
N. 
IJ9 


.1 


I 


1- 


-^\ 


2?23OI23450-7  89l0ue  13  14 
HOURS  AFTLR  1200  CRAMS  MEAT 


V 


^s 


X 


16  17  16  iS  20  21 


Fi^.  34.  After  Williams,  Riche  and  Lusk,  showing  the  R.Q.,  the  total  metabolism 
determined  by  indirect  (heavy  black  line)  and  direct  (broken  line)  calorimetry  as 
well  as  the  nitrogen  elimination  (dotted  line)  during  hourly  periods  after  the  inges- 
tion of  1200  grams  of  meat,  by  a  dog. 


osmotic  dilution  of  the  Hood  caused  by  the  rapid  absorption  of  the  sugar, 
and  a  sudden  fall  in  the  metabolism  coincides  with  a  removal  of  sugar  from 
the  circulation  by  the  liver  and  a  rapid  elimination  of  w^ater  through  the 
kidney.  Lusk  believes,  therefore,  that  the  heightened  metabolism  follow- 
ing rapid  absorption  of  fat  or  carbohydrate  may  be  called  a  "metabolism  of 
plethora/'  or,  in  words  of  one  syllable,  oil  on  the  fire.  Since  a  summation 
effect  is  produced  when  carbohydrate  and  an  amino-acid  or  both  are  added 
at  a  time  when  fat  is  producing  a  maximal  effect  and  from  other  considera- 
tions  which  need  not  be  entered  into  here,  Lusk  infers  that  separate  mechan- 
isms for  oxidation  of  several  foodstuffs  exist  within  the  body 
cells. 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM    607 


V.     Basal  Metabolism 

By  way  of  summary  of  the  preceding  sections  one  may  say  that  the 
three  factors  which  have  most  to  do  with  determining  the  level  of  the 
energy  metabolism  in  the  normal  subject  are  muscular  activity,  external 
temperature  and  food.  A  subject  removed  from  the  influence  of  these 
three  factors  would  be  (a)  completely  resting;  (b)  at  a  comfortable  tem- 
perature; (c)  and  w^ould  be  observed  several  hours  after  the  ingestion  of 
food.  The  metabolism  under  these  conditions  would  correspond  to  the 
minimal  functional  activity  of  the  body  and  for  this  reason  has  been 
called  basal  metabolism  after  Magnus-Levy (^)  (Grundumsatz).  The 
term  "maintenance  metabolism*'  (Erhaltungsumsatz)  has  also  been  given 
by  Loewy(a),  and  the  term  "standard  metabolism^'  is  preferred  by 
Krogh(c)  who  points  out  that  even  under  complete  suppression  of  mus- 
cular activity  the  metabolism  of  the  heart  may  amount  to  as  much  as  4 
to  15  per  cent  of  the  total  metabolism  of  the  body,  and  the  metabolism  of 
respiration  to  a  like  amount.  The  true  basal  metabolism  according  to 
Krogh  w^ould  be  found  by  deduction  of  those  quotas  assignable  to  the 
heart  muscle  and  the  muscles  of  respiration. 

Whichever  teim  is  applied  it  should  bo  understood  that  this  minimal 
metabolism  is  the  line  of  reference  for  the  measurement  of  the  various 
functional  increases  such  as  that  due  to  food  or  to  muscular  work.  The 
term  basal  metabolism  will  be  employed  in  this  chapter  as  being  considered 
more  appropriate  than  either  of  the  other  terms  suggested.  It  is  useless 
in  the  writer's  opinion  to  use  as  the  reference  line  a  minimal  metabolism 
lower  than  that  which  is  attainable  in  the  normal  subject.  It  is,  however, 
a  fair  question  whether  the  metabolism  of  sleep  should  be  taken  as  the 
basal  metabolism  in  man,  or,  whether  the  condition  defined  by  Benedict 
and  his  co-workers  as  the  post-absorptive  condition  combined  with  com- 
plete muscular  rest  gives  the  better  line  of  reference.  F.  G.  Benedict  has 
shown  that  in  a  fast  of  31  days  the  metabolism  during  deep  sleep  may  be 
as  much  13.2  per  cent  lower  than  the  metabolism  of  the  same  subject  wdiile 
awake  but  lying  perfectly  still.  In  this  series  the  increased  metabolism 
could  not  be  attributed  to  muscular  activity  for  a  comparison  of  the  graphic 
records  showed  that  the  degree  of  muscular  repose  was  even  more  ncurly 
perfect  in  the  morning  experiments  wdiilo  waking  than  in  the  night  experi- 
ments during  which  the  subject  slept  in  the  bed  calorimeter.  There  was 
also  no  question  of  influence  of  food  in  the  alimentary  tract;  for  during 
the  entire  period  of  31  days  the  subject  ale  absolutely  no  food  and  drank 
only  about  900  c.c.  of  distilled  water  daily.  It  is  fairly  certain,  therefore, 
that  the  only  cause  of  diflFerence  was  that  state  of  the  nervous  system 
which  we  recognize  as  sleep.  Presumably  the  lower  metabolism  in  this 
state  is  due  to  the  more  complete  suppression  of  muscular  activity  owing 


608  JOHINT  R.  MURLIN  . 

to  the  absence  of  reflexes,  with  possibly  a  factor  due  to  the  suppression  of 
neural  activity  in  the  brain,  spinal  cord  and  peripheral  nerves.  In  time 
it  may  become  necessary  to  revise  the  standard  conditions  for  basal  metabo- 
lism and  to  include,  in  addition  to  complete  muscular  rest  and  complete 
alimentary  quiescence,  neural  rest  For  the  present  sufficient  data  do  not 
exist  to  warrant  the  change  in  standard;  hence,  the  basal  metabolism  as 
ordinarily  defined  will  be  used  in  this  chapter  to  determine  the  influence  of 
age,  sex,  physical  characteristics,  etc.,  in  the  noniial  individual. 

Even  under  the  most  uniform  conditions  thus  far  applied  the  basal 
metabolism  has  been  found  to  vary  from  day  to  day  and  from  hour  to 
hour  in  the  same  individual,  and  even  more  in  different  individuals.  For 
example,  Johansson  found  on  himself  an  average  CO2  production  per 
hour  of  22.2  grams  with  an  average  deviation  from  the  mean  of  3.6  per 
cent.  Nevertheless,  he  found  this  metabolism  to  remain  constant  within 
the  variation  given  over  a  period  of  seven  months.  Magnus-Levy (&)  ob- 
served a  similar  degree  of  constancy  over  a  period  of  two  years.  In  a  series 
of  51  observations  made  during  complete  muscular  rest  upon  an  athlete 
Benedict  and  Cathcart  found  a  standard  deviation  from  the  mean  of  4.9 
per  cent  When  different  individuals  are  considered  the  variation  is 
much  greater.  The  simple  average  percentage  deviation  from  the  mean 
in  35  different  subjects  observed  by  Benedict  was  13.9  per  cent. 

1.  The  Influence  of  Physical  Characteristics. — From  an  exhaustive 
biometric  study  of  basal  metabolism  in  the  noraial  human  adult  including 
137  inen  and  103  women,  Harris  and  Benedict  find  that  the  most  intimate 
eoiTelations  are  obtained  when  correction  for  body  size  is  made  by  express- 
ing heat  production  in  calories  per  square  meter  of  body  surface.'' 

As  regards  the  effect  of  body  weight  upon  the  energy  metabolism  Har- 
ris and  Benedict  find  that  an  increase  of  1  kgm.  of  weight  in  the  adult  man 
increases  the  consumption  of  oxygen  on  the  average  2.27  c.c.  per  minute 
and  the  carbon  dioxid  1.87  c.c.  per  minute;  for  women  the  values  are  1.17 
c.c.  oxygen,  and  1.02  c.c.  carbon  dioxid.  A  kilogram  of  body  weight  added 
to. the  adult  increases  the  total  heat  production  for  twenty-four  hours  on 
the  average  15.8  Cal.  for  men  and  8.27  Cal.  for  women. .  There  is  also 
a  distinct  and  independent  correlation  between  stature  and  energy  metal> 
olism,  but  this  is  not  so  close  as  with  body  weight.  For  each  1  cm.  in- 
crease in  stature  the  heat  production  increases  about  16.6  Cal.  per  day  in 
man  and  6.9  Cal.  per  day  in  women.  The  same  authors  find  that  there 
is  no  verj'  high  degree  of  correlation  between  heat  production  and  heart 
activity  as  measured  by  pulse  rate,  unless  correction  is  made  for  body 
weight  or  body  surface. 

'This  admission  tlie  authors  are  obliged  to  make  although  they  do  not  belirvc 
that  the  closer  agreement  between  heat  production  by  different  individuals  and  their 
surfaces  than  between  heat  production  and  body  weight  is  due  to  any  causal  relation- 
ship (see  page  51)7). 


NORMAL  PJROCESSES  OF  ENERGY  METABOLISM     600 


Referred  to  body  weight  the  metabolism  even  in  men  of  nearly  the 
same  size  and  weight  may  differ  considerably.  The  results  obtained  by 
Jaqiiet  and  by  Caspari  vary  from  0.8  Cal.  per  kgm.  and  hour  to  1.6  Cal.  per 
kgm.  and  hour.  The  latter  figui'e  was  obtained  by  Caspari  upon  a  trained 
athlete.  Benedict  and  Smith  have  also  shown  that  athletes  have  in  general 
a  higher  basal  metabolism  than  untrained  individuals  of  the  same  physical 
measurements.  Fat  persons  generally  have,  as  would  be  expected,  a  lower 
metabolism  per  unit  of  weight  than  lean  ones;  for  the  fat  tissues  are  rela- 
tively inactive.  Other  differences  on  the  basis  of  weight  may  be  accounted 
for,  to  some  extent  at  least,  by  differences  in  muscular  tonus,  and  differ- 
ences in  '^endocrine  efficiency." 

As  a  convenient  reference  point  the  average  obtained  by  Tigerstedt 
from  a  long  series  of  determinations  of  the  basal  metabolism  in  man 
(namely,  1.04  calories  per  kgin.  and  hour)  should  be  borne  in  mind.  The 
average  individual  variation  from  this  average  is  roughly  plus  or  minus 
10  per  cent. 

The  physical  characteristic  which  has  proved  to  be  most  useful  as  a 
criterion  or  measure  of  metabolism  is  the  surface  area  of  the  body.  Rub- 
ner's  original  study  on  full-grown  dogs  is  given  in  Table  19.     Here  it 

TABLE  19 
Influence  of  Body  Size  on  Metabolism  (Rubner) 


Weight, 

Body  Surface  in 

Cal.  per  Kgm.  and 

Cal.  per  Sq.  M.  (Meeh) 

Kgm. 

Sq.  Cm. 

24  Hrs. 

and  24  Hrs. 

31.20 

10750 

35.68 

1036 

24.00 

8805 

40.91 

1112 

19.80 

7500 

45.87 

1207 

18.20 

7662 

46.20 

1097 

9.61 

5286 

65.16 

1183 

6.50 

3724 

66.07 

1153 

3.19 

2423 

88.07 

1212 

was  demonstrated  how  much  more  nearly  proportional  to  surface  the 
metabolism  is  than  to  body  w^eight.  While  it  is  true  that  absolutely  basal 
conditions  were  not  present  the  animals  were  not  observed  to  move  about 
to  any  considerable  extent.  The  original  observations  of  Richet  upon  rab- 
bits likewise  are  worthy  of  repetition  here.  The  heat  given  off  by  radia- 
tion from  the  animaFs  body  caused  the  air  enclosed  within  the  walls  of  the 
calorimeter  to  expand  and  to  displace  water  in  the  siphon  (page  582). 
Heat  is  expressed  in  Table  20  as  the  number  of  c.c.  of  water  displaced. 
The  number  expressing  the  surface  of  the  animal  was  found  by  Richet  by 
regarding  the  body  as  a  geometric  sphere.     Since  its  weight  (volume)- 

4  Jt  R^ 
is  equal  to  — - —   and  the  surface  by  4  Jt  R^,  the  volume  would  be  to  the 

surface  as  4.2R^:  12.6R2.     Finding  R  from  the  known  weight  (volume) 
the  relative  surface  was  obtained  by  multiplying  the  square  of  this  number 


610 


JOHlSr  R.  MURLIlsr 


TABLE  20 
Relation  of  Heat  Radiation  to  Sxtiface  of  the  Animal  Body  (Richet) 


Weight, 

Surface 

Gm. 

(A  Relative  Number) 

2100 

786 

2300 

841 

2500 

889 

2700 

932 

2!)00 

976 

3100 

1021 

Heat  Radiated 

pressed  as  c.c.  of 

Displaced 


Ex- 

*Vater 


Heat   Radiation   per 
Unit  of  Sur/ace 


119 
110 
115 
119 
125 
130 


129 
130 
129 
127 
128 
127 


by  12.6.  It  is  evident,  Richet  concludes,  that  the  production  of  heat  is  a 
function  of  the  surface  and  not  of  the  weight  of  the  animal.  IMore  nearly 
basal  conditions  were  observed  in  experiments  accomplished  later  by  Slowt- 
zoff  (a)  on  dogs  and  by  Kettner  on  guinea  pigs.  The  former  calculated  the 
surface  by  Hecker's  formula  (S=^  12.'^3  X  W^^)  and  found  that  the 
oxygen  absorption  per  unit  of  surface  in  animals  of  different  size  (5.04 
to  38.9  kgm.)  "remains  fairly  constant"  (±10  per  cent  mean  deviation 
from  the  average,  as  against  ±:  12.5  per  cent  on  the  basis  of  weight). 
Kettner  found  that  the  COg  production  per  100  gm.  body  weig:ht  and 
hour  varied  from  0.108  gm.  in  the  largest  (full-grown)  animals  to  0.254 
gm.  in  the  smallest  (and  youngest),  a  difference  of  135  per  cent,  while 
on  the  basis  of  surface  the  extreme  variation  was  only  30  per  cent. 

In  the  human  subject  the  comparison  of  basal  metabolism  per  unit 
of  weight  witb  the  basal  per  unit  of  surface  is  even  more  striking.  The 
following  table  from  Gephait  and  DuBois(&)  shows  how  much  more  the 
metabolism  of  different  classes  of  human  individuals  differs  from  the  av- 
erage for  adult  men  on  the  basis  of  weight  than  on  the  basis  of  surface. 


TABLE  21 

Comparison  of  Basal  Metabolism  per  Kgm.  and  per  Square  Meter  of  Surface 

(Gephart  and  DuBois) 


b. 

Per   Cent  Variation 

a. 

Cal  per 

Kgm.  and 

Hr. 

Cal.  per 

from  Average  for 

Investigator 

Subjects 

Sq.  M. 

(Meeh)    and 

Hr. 

Men 

a                 b 

Benedict    and    Colla- 

borators     

79  men 
Dwarf  wt.  23  kgm. 

1.08 
1.21 

34.7 
32.3 

Lusk  and  MeCrudden 

12            —7 

Murlin  and  Hoobler. 

6  infants 

2.69 

36.3 

150                 5 

Benedict  and  Talbot. 

Average    10    nor- 
mal   infants    un- 

der 1  month 

1.95 

25.6 

81          —26 

Benedict  and  Talbot. 

Average    11    nor- 
mal    infants    be- 

tween 1  &  10  mos. 

2.21 

35.5 

105                 2 

FORMAL  PROCESSES  OF  ENERGY  METABOLISM  611 

This  table  was  prepared  before  it  was  appreciated  bow  much  tbe 
metabolism  varies  with  age  and  before  tbe  new  method  of  measuring  sur- 
face area  devised  by  DuBois  and  DuBois  was  completed,  but  it  shows  bow 
even  on  the  old  basis  the  metabolism  was  proportional  to  body  surface 
rather  than  to  weight.  DuBois  and  DuBois  in  reviewing  the  literature  of 
surface  measurement  found  that  a  consistent  plus  error  occurs  in  the  use 
of  the  Meeh  formula  which  may  rise  in  very  fat  individuals  to  as  much 
as  36  per  cent.  By  their  own  method  (see  page  596)  checked  with  actual 
linear  measurements  they  found  a  total  error  in  the  case  of  five  indi- 
viduals of  widely  different  shapes  of  only  1.7  per  cent.  On  the  basis  of 
the  new  method  for  surface  area  Gephart  and  DuBois(?))  later  gave  the  av- 
erage basal  metabolism  of  nine  normal  men  whose  surface  had  been  accur- 
ately measured  as  39.7.  Cal.  per  square  meter  per  hour.  The  extremes  of 
variation  in  this  series  were  +  4  per  cent  and  —  6  per  cent.  Selecting 
fat  and  thin  subjects  from  the  work  of  Benedict,  Emmes,  Roth  and  Smith 
and  that  of  Means  the  authors  find  that  the  fat  and  thin  gi'oups  show  a  dif^ 
ference  in  metabolism  on  the  basis  of  weight  of  41  per  cent  while  on  the 
basis  of  "linear  formula"  (p.  596)  for  surface  area  the  difference  was  only 
3  per  cent.  The  law  of  surface  therefore  must  be  held  to  apply  to  fat  and 
thin  subjects  as  well  as  to  the  so-called  normal.  Nevertheless  a  variation 
of  plus  or  minus  10  per  cent  must  be  expected  even  in  perfectly  normal 
subjects;  for  there  are  variations  in  muscular  tonus,  in  the  specific  activity 
of  the  endocrine  organs  and  in  the  conducting  properties  of  the  skin  as  well 
as  in  other  factors  not  so  definitely  predictable  which  must  always  pre- 
clude the  establishment  of  a  fixed  and  rigid  standard.  Means  found  for 
example  an  average  for  sixteen  normal  subjects  of  38.8  Cal.  per  sq.  M.  by 
the  DuBois  linear  formula  and  that  all  came  wtII  within  the  10  per  cent 
(deviation  from  average)  zone.  Harris  and  Benedict  feeling  that  they 
had  totally  discredited  the  law  of  surface  as  a  measure  of  metabolism 
turned  their  attention  to  the  prediction  of  the  normal  basal  metabolism 
by  means  of  biometric  formulas  based  on  stature,  body  weight,  age,  and  sex 
and  claimed  that  by  this  means  "results  as  good  as  or  better  than  those 
obtainable  from  the  constant  of  basal  metabolism  per  square  meter  of  body 
surface  can  be  obtained  by  biometric  formulas  involving  no  assumption 
concerning  the  derivation  of  surface  area,  but  based  on  direct  physical  meas- 
urements." 

Boothby  and  Sandiford  have  tabulated  404  determinations  of  the 
''basal  metabolic  rate,"  as  they  call  it,  expressed  in  percentages  above  and 
below  normal,  using  both  the  standard  of  DuBois  and  that  of  Harris  and 
Benedict.  The  average  rates  obtained  by  the  biometric  formula  of  Harris 
and  Benedict  are  6.5  points  higher  than  those  obtained  by  the  DuBois 
method.  The  same  authors  report  that  they  have  made  more  than  10,000 
determinations  of  basal  metabolism  on  healthy  people  and  on  patients  suf- 
fering from  disease  and  that  "only  occasionally  have  we  found  patients 


612  JOHN  R  MURLIX 

who  had  metabolic  rates  beyond  the  normal  limits  established  by  DuBois 
which  could  not  be  accounted  for  by  the  presence  of  a  definite  pathologic 
condition." 

This  tiiily  phenomenal  uniformity  of  lieat  production,  quite  equal  to  the 
uniformity  of  body  teuipcrature  in  nonnal  subjects,  has  been  explained  in 
variuus  ways.  Rubner  following  Bergman  and  Regnault  and  Reiset  at- 
tempted to  bring  the  heat  production  into  causal  relationsliip  with  heat 
loss  as  we  have  seen  (p.  509).  This  attempted  explanation  has  not  been 
wholly  satisfactory  for  the  reason  that,  as  Lefevre  has  shown,  physiological 
adjustments  can  be  made  by  the  skin  which  gTcatly  modify  the  applica- 
tion of  ^N'ewton's  law  of  cooling.  Rubner  himself,  therefore,  is  obliged  to 
postulate /^similar  physiological  conditions"  (page  599)  and  to  assume  that 
the  minimal  metabolism  (basal)  cannot  undergo  rapid  changes  but  is 
adapted  to  the  usual  conditions  regarding  loss  of  heat  which  the  animal  has 
to  meet.  V.  Hoesslin(&)  has  subjected  the  hypothesis  of  Rubner  to  a  se- 
vere test  by  keeping  two  exactly  similar  young  dogs  for  a  long  time  under 
widely  different  temperatures  and  determining  their  resting  metabolism  at 
the  end.  The  rate  of  heat  loss  must  have  been  continuously  very  different 
for  the  coats  of  hair  at  the  beginning  were  the  same.  Later  it  became 
thicker  on  one  dog  and  thinner  on  the  othei-  in  very  obvious  response  to  the 
conditions  of  heat  loss  to  which  they  were  subjected.  But  the  basal 
metabolism  was  not  altered. 

V.  Hoesslin  himself  considers  that  the  metabolism  of  a  tissue  depends 
upon  the  supply  of  oxygen,  that  the  circulation  (and  consequently  the  oxy- 
gen supply)  must  for  anatomical  reasons  be  proportional  to  the  two-thirds 
power  of  the  weight  (i.  e.,  to  surface)  and  that  the  correlation  of  energy 
exchange  with  surface  finds  its  explanation  in  these  purely  mechanical 
conditions.  Dreyer,  Ray  and  Walker  have  given  some  plausibility  to  this 
view  by  the  discovery  that  in  both  mammals  and  birds  the  blood  volume, 
the  sectional  area  of  the  aorta  and  of  the  trachea  in  animals  of  different 
size  are  proportional  to  the  two-thirds  power  of  the  weight.  The  trend 
of  this  view  is  wholly  away  from  the  teleological  view  outlined  at  p.  602 
in  connection  with  the  subject  of  heat  loss,  and  probably  more  correctly 
reflects  the  attitude  of  the  modem  mechanistic  physiology. 

Dreyer  has  more  recently  attempted  the  application  of  a  more  general 
formula  to  the  normal  basal  metabolism  and  has  compared  the  results 
found  with  those  obtained  by  the  more  elaborate  prediction  formula  of  Har- 

ris  and  Benedict.     His  formula  is  K  = rTrr^To  where  W  is  the 

C  X  A"-^^^^ 

weight,  n  approximately  0.5,  C  is  calories  of  basal  metabolism,  and  A  the 

age  in  years.     Table  22  shows  that  he  gets  a  somewhat  more  concordant 

result  than  is  obtainable  with  the  prediction  formula. 

2.  Influence  of  Age  on  Basal  Metabolism. — DuBois  (a)  first  assembled 

the  data  for  the  inliuencc  of  time  of  life  from  birth  to  old  age  upon  the 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM    613 


TABLE 

22 

- 

Authors 

No.  of 
Persons 

Description 

Average  K 

% 
Av.  Devia- 
tion from  K 

% 
Av.  Devia- 
tion bv  H 

C  X  A-»-» 

and   B.  Pre- 
diction form 

Palmer,    Means  .  and 
Gamble 

Carpenter,     Emmes, 
Hendry  and  Roth 

Magnus-Levy      and 
Falk 

8 
31 

10 
5 

15 
5 
6 
8 

men 

« 

old  men 

boys 

men 

old  men 

Boy  Scouts 

0.1037 

0.1014 

0.1000 
0.1045 
0.1007 
0.0089 
0.0993 
0.0928 

3.7 

5.94 

5.06 
9.90 
3.46 
6.10 
8.20 
9.49 

4.4 

5.30 

5.27 

Gephart  and  DuBois 

DuBois  and  Aub  . . 
(t             « 

10.36 
15.60 
7.37 
19..38 
19.70 

total  heat  production.  His  chart  in  terms  of  calories  per  hour  per  square 
meter  of  body  surface  appears  below.  In  considering  the  causes  of  the  al- 
tered rate  of  heat  production,  one  must  bear  in  mind  first  the  differences 
in  body  form  which  themselves  affect  the  relationship  of  body  surface  to 
body  weight ;  secondly,  the  specific  influence  of  different  organs  which  not 


YEARS  2 


60     J^A\'nd\f^k.      _L 

u.    .. ■-    _ 

+ 

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^^  :       s  l5:i3: Jgojas- Gsiai^ 

20  -           -.    =>^X    -.X^^^^^,                               • 

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6        8       10      12      14       16       18      20      22 


Fig.  35.  Variations  of  basal  metabolism  with  age:  Calories  per  hour  per  square 
meter  of  body  surface — Meeli^s  formula.  Dash  line  shows  average  for  males,  dotted 
line  for  females.     After  DuBois. 


only  bear  different  relations  as  regards  size,  to  the  body  as  a  whole,  but 
probably  in  some  instances  also  have  quite  a  different  coefficient  of  activity. 
Thus,  in  early  life  the  liver  and  thyroid,  especially,  both  organs  of  high 
metabolic  activity,  are  perceptibly  larger  in  the  relative  sense  than  in 
the  adult  life,  and  may  be  expected  to  play  a  larger  part  in  the  total  chem- 
ical activity  of  the  body.     This  may,  to  a  large  degi*ee,  accoxmt  for  the 


-  614-  JOHN  K.  MURLIN 

heightened  metabolism  of  the  infant  one  year  old  when  reckoned  on  the 
basis  of  a  unit  of  surface  (Murlin  and  Hoobler).  That  the  rate  of  growth 
itself,  however,  may  be  partly  responsible,  is  evidenced  by  the  fact  that  boys 
at  the  age  of  prepubescence,  just  when  growth  is  accelerated,  experience  also 
a  quickening  of  heat  production.  DuBois^s  results  indicate  that  this  may 
anioimt  to  as  much  as  25  per  cent  over  the  normal  level  for  adults.  Whether 
the  awakened  activity  of  the  internal  secretory  mechanism  of  the  sex  glands 
acts  independently  ■  or  only  through  its  effect  upon  gi-owth,  can  only  be 
decided  by  experiments  upon  animals.  The  latest  experiments  of  this  kind 
by  3Iurlin  and  Bailey  support  the  view  of  Loewy  and  Richter  that  in 
the  female  at  least  there  is  an  independent  effect  quite  outside  the  effect 
upon  muscular  rest.  The  tendency  to  obesity  following  the  menopause 
in  women  is  to  be  explained,  therefore,  as  due  to  the  absence  of  a  stimulus 
wdiich  was  present  so  long  as  the  ovary  was  active.  Removal  of  the  ovary 
has  the  same  effect.  The  falling  metabolism  of  old  age  is  to  be  explained 
in  part  by  the  tendency  to  reduce  muscular  effort,  of  all  sorts  to  a  minimum, 
this,  in  turn,  being  traceable  probably  to  the  absence  of  intenial  stimuli, 
whether  reflex  or  chemical.  The  deposit  of  calcareous  material  in  certain 
organs,  which  so  frequently  accompanies  old  age,  may  also  of  itself  reduce 
their  metabolic  activity. 

Statistically  studied,  the  decrease  in  total  heat  production  per  24 
hours  for  each  year  of  age  is,  according  to  Harris  and  Benedict,  7.15  Cal. 
for  their  series  of  136  adult  men.  For  the  103  women  it  is  2.29  calories 
for  each  year  of  adult  life.  Upon  the  basis  of  a  unit  of  body  surface,  the 
con-elations  with  age  "are  of  a  more  strongly  negative  character  than 
the  correlations  between  age  and  total  heat  production,"  which  means 
that  with  each  advancing  year  of  life  there  is  a  heavier  decline  upon 
the  basis  of  a  square  meter  of  body  surface  than  upon  the  basis  of 
total  heat  production.  This  conclusion  is  in  accordance  with  X)uBois^s 
curve,  though  it  does  not  give  exactly  the  same  rate  of  change. 

3.  The  Influence  of  Sex. — Impressive  also  is  the  dift'erence  between 
the  two  sexes.  DuBois  had  already  drawn  attention  to  this  difference  in 
the  first  curve  which  he  published  showing  the  variation  with  age.  His 
curves  for  the  two  sexes  ran  about  the  same  distance  apart  (7  per  cent)  as 
do  the  newer  ones  here  reproduced.  Twenty  years  ago  ^lagnus-Levy  and 
Falk  found  the  difference  between  the  two  sexes  both  in  early  life  and  in 
advanced  age  about  five  per  cent,  but  were  of  the  opinion  that  in  adult  life 
the  two  sexes  maintain  about  the  same  metabolism,  consideration  being  had 
to  difference  in  size  and  age.  Harris  and  Benedict  have  analyzed  the  results 
of  metabolism  studies  on  the  two  sexes  very  exhaustively,  making  correction 
for  body  weight,  body  surface,  age,  and  stature,  and  find  that  on  eveiy  basis 
the  metabolism  for  the  women  is  lower  than  that  of  men.  Even  when  the 
theoretical  heat  production  of  the  woman  is  calculated  by  inserting  their  ac- 
tual physical  measurements  in  equations  based  on  the  series  of  men  (regard- 


KORMAL  PROCESSES  OF  ENERGY  METABOLISM     615 

ing  tlie  woman,  tiat  is,  as  a  man  of  the  same  size)  the  actual  heat  production 
is  generally  lowor  than  the  theoretical.  Larger  women  show  a  relatively- 
larger  deficiency  than  smaller  ones  and  the  suji'gestion  is  made  hy  the 
authors  that  the  hody  weight  is  the  primary  fnctor  in  determining  the  de- 
ficiency. ^'The  most  critical  test  shows  that  when  hody  weight,  stature,  and 
age  are  taken  into  account,  women  show  ahour  0.2  per  cent  lower  metab- 
olism than  men." 


D.    Energy  Metabolism  of  Growth 

1.  Differences  between  Growth  and  Maintenance. — The  chemical  proc- 
esses by  w^hich  the  living  substance  is  maintained  are  not  identical  with 
those  by  which  it  was  originally  produced.  For  example,  growth  and 
division  of  the  nuclei  are  essential  in  the  production  of  new  tissues,  while 
the  mere  replenishment  of  cell  materials,  such  as  is  taking  place  continu- 
ally on  a  small  scale  or  such  as  may  take  place  in  convalescence  on  a  large 
scale,  may  go  on  without  division  of  the  nuclei.  Since  it  is  known  that 
the  nucleus  is  essential  to  processes  of  intracellular  digestion  (Verworn), 
it  is  possible  that  the  nucleus  plays  some  essential  role  in  this  process  of 
replenishment;  but  the  fact  that  the  nucleus  itself  does  not  gi'ow  and  divide 
under  these  circumstances  (Loeb,  J.(&)),  together  with  the  fact  that  its 
reactions  and  constitution  are  knowm  to  be  diflPerent  from  those  of  the  cyto- 
plasm, makes  it  very  probable  that  growth  involves  chemical  processes  not 
concerned  in  the  replenishment  which  follows  ordinary  waste  or  that  which 
follows  extraordinary  whste  in  diseased  conditions.  Rubner(r(7)  has 
drawn  attention  to  the  fact  that  the  maintenance  tendency  is  of  primary 
importance  even  in  the  young  organism,  since  the  "wear  and  tear"  quota 
(Abnutzungsquote)  must  be  satisfied  before  growth  (postembryonic)  of 
the  organism  as  a  whole  can  assert  itself.  If  we  assume  that  the  every- 
day repair  concerns  mainly  the  cytoplasm,  except  w^here  cells  are  actually 
being  destroyed,  Rubner*s  view  might  be  interpreted  to  mean  that  the 
processes  in  the  nucleus  which  result  in  its  growth  and  division  can  take 
place,  even  in  the  yoiuig  organism,  only  under  certain  optimum  nutritive 
conditions  of  the  cytoplasm. 

There  is  no  reason  for  thinking  that  the  mechanism  by  which  energy 
is  liberated  in  young  cells  is  different  from  that  w^hich  perfoims  the  same 
service  in  mature  cells.  The  living  substance  of  all  cells  (with  the  ex- 
ception of  the  anaerobic  forms)  is  dependent  upon  some  power,  call  it  the 
"activation  of  oxygen,''  v/hereby  oxygen  becomes  capable  of  uniting  with 
the  elements  of  the  soluble  foodstuffs  at  a  temperature  much  below  the 
ordinary  kindling  temperature. 

Warburg's  (a)  recent  obseiTation  that  fertilized  sea  urchin  eggs  absorb 
six  to  seven  times  as  much  oxygen  in  the  same  length  of  time  as  do  im- 


61G  joh:n'  r  murlik         \ 

fertilized  eggs,  lends  weight  to  the  view  that  oxygen  is  in  some  way  essen- 
tial to  the  gi-owth  process,  but  his  further  observation  that  there  was  no 
proportion  between  the  amount  of  oxygen  absorbed  and  the  number  of 
nuclei  (blastomeres)  present,  and  that  still  more  oxygen  was  absorbed 
when  the  eggs  were  placed  in  hypertonic  solutions  and  cell  divisions  had 
ceased  (Warburg(6)),  certainly  do  not  favor  the  idea  that  oxygen  absorp- 
tion is  dependent  upon  nuclear  iictivity.  This  is  in  accordance  with  Eub- 
ner's(7/i)  view  that  the  morphological  changes  in  the  nucleus  accompanying 
cell  division  are  the  expression  of  synthetic  processes  rather  than  of  the  de- 
structive processes  of  oxidation. 

Bayliss(6)  explains  the  chemical  process  of  oxidation  in  the  cell  as  fol- 
lows :  "Some  autoxidizable  substance  in  the  cell  takes  up  molecular  oxy- 
gen, with  the  formation  of  peroxids  and  activation  of  half  the  oxygen.  The 
other  half  of  the  oxygen  seiTes  for  complete  oxidation  of  part  of  the 
autoxidizable  substance.  These  peroxids  are  acted  upon  by  peroxidase, 
with  further  increase  of  active  oxygen,  which  is  able  to  bring  about  oxida- 
tion of  substances  not  autoxidizable  and  otherwise  difficult  of  oxidation." 
The  sb-ucture  of  the  cell,  however,  also  plays  a  part.  For  example,  ac- 
cording to  'VVarburg(c),  in  a  muscle  cell  a  much  larger  part  of  the  chemical 
energy  appears  as  free  energ;^'  than  if  the  cell  is  disintegrated.  The  ar- 
rangements within  the  cell  which  we  call  cell  structure  "in  some  way  catch 
the  chemical  energy  of  the  oxidation  processes  before  it  has  fallen  to  the 
state  of  free  heat."  It  is  bv  such  arrangements  or  structure  that  the  work 
of  a  contracting,  a  secreting,  an  absorbing  cell,  etc.,  is  carried  on. 

Even  in  cells  which  do  no  external  work  or  osmotic  work,  however, 
structure  is  important  for  oxidation.  Thus,  in  the  unfertilized  eggs  of  the 
sea  urchin,  Warburg  and  Meyerhof  have  sho'wii  that  the  addition  of  iron 
salts  increasies  oxidation  very  perceptibly.  Salts  of  no  other  metal  do  this. 
Iron,  in  othei  words,  is  a  catalyst  for  oxidation.  Xow  the  significance  of 
structure  (alveolar,  if  we  please),  as  Warburg  sees  it,  is  just  this,  that  it 
affords  surfaces  for  the  condensation  of  the  catalyst  and  thereby  puts  it  to 
work. 

But  why  should  energy  be  set  free  in  cells  that  do  no  work  ?  Warburg's 
answer  to  this  is  that  the  liberation  of  energy  by  oxidation  preser^^es  the 
stnicture,  or  the  integrity,  if  one  will,  of  the  living  substance.  If  cell 
constituents  are  to  be  prevented  from  mixing  freely,  diffusion  surfaces 
must  bo  maintained,  and  the  maintenance  of  their  semi-permeable  prop- 
erties calls  for  a  certain  difference  of  electric  charges  which  can  only  be 
kept  up  by  the  liberation  of  energy  from  some  source.  Hence  it  is  that 
all  living  substance  must  respire  and  must  liberate  a  certain  amount  of  free 
heat.  The  maintenance  of  a  constant  temperature  would,  on  this  view  of 
the  matter,  be  a  fundamental  property  for  cells  whose  structure  could  be 
maintained  only  by  a  certain  rate  of  energy  release  (see  page  602). 

2.  Metabolism  of  Embryonic  Growth  (^furlin (<?)). — Development  oo- 


JSTQRMAL  PEOCESSES  OF  ENERGY  METABOLISM    617 

casions  a  more  active  production  of  carbon  dioxid  per  unit  of  mass  than 
takes  place  in  adult  tissues.  This  has  been  demonstrated  by  Farkas  for  the 
eggs  of  the  silkworm,  by  Bohr  for  the  embryo  snake,  by  Bohr  and  Hassel- 
balch,  and  by  llasselbalch  alone  for  the  developing  chick,  and  by  Bohr  for 
the  embryo  guinea  pig.  That  this  greater  evolution  of  carbon  dioxid  is  the 
expression  of  a  greater  liberation  of  energy  also  is  rendered  perfectly  cer- 
tain by  the  calorimetric  measurements  made  by  Farkas  of  the  heat  of  com- 
bustion of  unincubated  and  incubated  silkwoi-m  eggs  and  those  of  Tangl 
on  the  eggs  of  the  cadaver  fly ;  by  similar  measurements  made  by  Tangl  and 
by  Tangl  and  ^lituch  on  unincubated  and  incubated  hen's  eggs;  and  by 
the  direct  calorimetric  determinations  of  the  heat  produced  in  the  develop- 
ing hen's  egg  made  by  Bohr  and  llasselbalch. 

Bohr  and  Hasselbalch  found  on  the  fifth  day  of  incubation  of  the  hen's 
egg  a  production  of  CO2  amounting  to  2000  c.c.  per  kilogram  of  embryo 
per  hour  as  against  718  c.c.  per  kilogram  and  hour  for  the  adult  hen  (Eeg- 
nault  and  Reiset).  The  COg  production  from  the  eighth  to  the  twenty- 
first  day  (end)  of  incubation  was  only  a  little  greater  in  the  embryo 
than  in  the  adult  hen,  but  was  sufficiently  high  for  the  authors  to  feel  justi- 
fied in  concluding  that  it  was  "a  condition  for  the  organization  of  the  new 
tissue  and  not  alone  for  the  maintenance  of  tissues  already  formed."  Grafe, 
in  reviewing  this  work,  lays  special  emphasis  on  the  fact  that  the  highest 
energy  production  takes  place  at  a  time  w4ien  the  work  of  differentiation 
is  most  active.  Bohr  had  previously  supported  this  view  with  the  evidence 
derived  from  his  study  of  embryo  snakes.  Increasing  the  temperature 
from  15°  C.  to  27°  C.  increased  the  CO2  output  of  an  embryo  weighing 
3.8  g-m.  about  2.8  times,  while  the  same  increase  in  temperature  raised 
the  output  of  an  embryo  weighing  0.5  gm.  exactly  four  times.  The  greater 
increase  produced  in  the  younger  embryo,  Bohr  believes,  was  due  to  the 
greater  change  in  the  intensity  of  the  developmental  processes.  That  is,  the 
processes  of  new  fonnation  (differentiation)  are  more  active  in  the  younger 
stage  and  it  is  this  part  of  the  developmental  process  which  is  responsible 
for  the  more  active  metabolism. 

TangFs  results  on  the  hen's  egg  indicate  an  average  heat  production 
for  the  entire  incubation  period  of  100  calorics  per  kilogram  per  day  as 
against  71  calories  per  kilogram  per  day  (at  18°-20°)  for  the  adult  hen 
found  by  E.  Voit — an  increase  of  41.3  per  cent.  Tangl  concludes  that  the 
energy  required  for  development  (Entwickelungsarbeit)  is  considerably 
greater  than  that  required  for  mere  maintenance  of  the  adult  organism 
(Erhaltungsarbeit).  The  difrerence  he  designates  as  Bildungsarbcit. 
Bohr's  findings  on  the  pregnant  guinea  pig  are  not  so  convincing.  The 
average  production  of  COo  in  the  embiyo  he  found  to  be  509  c.c.  per 
kilogram  and  hour;  that  of  the  motticr  462  c.c.  per  kilogram  and  hour — - 
an  increase  of  only  10  per  cent.  Granted  that  the  conditions  of  heat  loss 
were  the  same  in  the  two,  which  is  doubtful,  the  amount  of  metabolism 


618  JOHN  R  MURLm 

which  could  be  ascribed  to  any  developmental  process  as  opposed  to  the 
maintenance  processes  would  be  very  small. 

Ilubner(m)  believes  that  the  law  of  skin  area  is  applicable  to  the  em- 
bryo. He  calculated  that  the  metabolism  of  the  new-born  mammal,  assum- 
ing its  weight  to  be  8  per  cent  of  that  of  its  mother,  would  be  nearly  double 
as  much  per  kilogram  and  hour  as  that  of  the  mother. 

Because  the  embryo  is  less  active  in  every  way  than  the  new-bom  its 
metabolism  per  imit  of  weight  should  be  considerably  less  tlian  this,  which 
indeed  the  results  of  Bohr  and  Tangl  show  to  be  the  case.  Buhner  ex- 
plains the  higher  metabolism  of  the  embryo  per  unit  of  weight,  therefore, 
as  due  not  to  any  specific  requirement  for  developmental  energy-,  but  en- 
tirely to  the  greater  loss  of  heat  by  the  relatively  greater  sui*face.  He  is 
obliged,  however,  to  eliminate  the  first  four-tenths  of  the  embryonic  life 
from  the  operation  of  this  law,  because  within  that  period  the  embryo  is 
of  no  appreciable  size  as  compared  with  the  mother.  On  the  basis  of  the 
average  composition  of  living  substance  in  mammals  and  using  seven 
tenths  of  the  metabolism  of  the  new-born  as  the  rate  for  the  embryo, 
Buhner  calculates  that  for  the  remaining  six-tenths  of  the  gestation  period 
the  "growth  quota"  of  the  embryo  in  most  mammals  is  from  38  to  40 
per  cent  of  the  energy  supplied,  as  compared  with  34  per  cent  for  extra- 
uterine life.  In  other  w(»rds,  for  each  calorie  of  heat  value  stored  in  the 
new-born  nearly  two  calories  of  energy  must  be  expended,  while  for  each 
calorie  deposited  in  the  embryo  only  one  and  one-half  calories  need  be 
expended  (on  the  basis  of  40  per  cent).  We  shall  see  that  the  higher 
metabolism  of  the  embryo  and  fetus  is  continuous  with  that  of  the  new- 
born. 

The  qualitative  differences  in  the  metabolism  of  the  embryo  from  that 
of  the  adult  depend  on  the  kind  of  food  material  supplied  by  the  mother 
in  the  egg  (oviparous  development)  or  by  the  circulation  (viviparous) 
for  the  nutrition  of  the  embryo.  A  hen's  egg  contains  no  carbohydrate; 
hence  the  respiratory  quotient  in  development  of  the  chick  can  never  be 
greater  than  0.78  (see  page  560).  The  chemical  studies  of  LiebeiTnann, 
the  calorimetric  determinations  of  the  heat  of  combustion  by  Tangl  and 
the  metabolism  studies  (using  the  direct  and  indirect  methods)  by  Bohr 
and  Hasselbalch  all  agree  in  showing  that  the  material  oxidized  in  the 
development  of  the  chick  is  fat.  Liebennann  believed  that  some  nitrogen 
was  lost,  but  both  Hasselbalch  and  Tangl  and  Mituch  have  shown  that 
this  is  incorrect.  The  nitrogenous  building  material  is  not  used  as  a  source 
of  energ}\ 

The  source  of  energy-  for  the  silkworm  embryo,  according  to  the  chem- 
ical studies  of  Tichomiroff  and  the  respiration  experiments  of  Farkas; 
for  the  blow-fly  embryo  according  to  the  respiration  experiments  of  Wein- 
land ;  and  for  the  cadaver  fly  according  to  the  calorimetric  determination 
of  Tangl  is  likewise  mainly  fat.    Xo  nitrogen  is  lost  in  gaseous  fonn  dur- 


IS^ORMAL  PROCESSES  OF  ENERGY  METABOLISM    619 

ing  the  development  of  any  of  these  insects,  but  a  portion  of  the  energy 
(according  to  Farkas  approximately  one-third)  arises  from  the  oxidation 
of  proteins  to  uric  acid.  Both  Tichomiroff  for  the  silkworm  egg  and 
Weinland  for  the  blow-fly  recorded  a  reduction  of  the  glycogen  content 
of  the  eggy  but  Weinland  believes  this  may  have  been  converted  to  chitin. 
There  is  no  evidence,  he  says,  that  glycogen  has  served  as  a  source  of 
energy. 

Our  infonnation  as  to  what  material  is  the  source  of  energy  for  the 
mammalian  embryo  is  extremely  scanty.  Cohnsteln  and  Zuntz  analyzed 
the  blood  in  the  umbilical  artery  and  vein  of  the  sheep  embryo  for  oxygen 
and  carbon  dioxid,  and  noted  a  difference  of  4.67  vols,  per  cent  Og  and 
4.72  vols,  per  cent  CO2  in  one  case  and  4.0  vols,  per  cent  O2  and  6.5 
vols,  per  cent  CO2  in  another.  These  figures  would  give  respiratory  quo- 
tients of  1.01  and  1.6  respectively  for  the  tvvo  embryos.  It  is  doubtful 
whether  these  figures  are  to  be  trusted,  since  on  the  basis  of  the  same 
analyses  the  authors  claim  a  metabolism  for  the  embiyo  of  only  one-fourth 
to  one-sixth  as  much  per  unit  of  weight  as  for  the  mother.  The  quotients, 
agree,  however,  with  those  found  by  Bohr  on  the  embryo  of  the  guinea 
pig.  Bohr  took  the  difference  between  the  total  gaseous  exchange  of  the 
pregnant  animal  (after  operation  under  anesthesia  and  immersed  in  a 
warm  bath)  before  and  p.fter  clamping  off  a  single  umbilicus.  The  res- 
piratory quotient  indicated  for  the  embryo  was  always  in  the  neighbor- 
hood of  unity.  Oddi  and  Vicarelli  report  also  a  progressive  increase  in 
the  course  of  pregnancy  in  the  mouse.  According  to  these  observations, 
therefoi-e,  the  most  diffusible  of  the  foodstuffs,  the  one  most  readily  passed 
through  the  placenta  is  probably  the  source  of  energy  for  the  mammalian 
embryo.  There  is  no  satisfactory  evidence  as  yet  that  proteins  participate 
to  any  considerable  extent  in  furnishing  such  energy. 

3.  Metabolism  of  Post-embryonic  Growth. — ^\Vhile  metabolism  is  cer- 
tainly more  active  in  the  youthful  organism  than  in  the  adult  it  is  by  no 
means  proved  that  the  growth  per  se  calls  for  any  expenditure  of  energy. 
In  recent  times  the  view  seems  in  fact  to  have  gained  rather  general  ac- 
ceptance that  the  large  metabolism  of  the  young  is  necessary  in  the 
interest  of  heat  regulation.  At  the  same  time  the  propensity  to  grow, 
which  is  the  certain  sign  of  youth  in  health,  may  be  given  a  sort  of 
energy  index.  There  is  a  considerable  body  of  evidence  that  growth  in 
a  given  genus  is  proportional  to  the  potential  energy  of  the  food  consumed, 
and  the  proportion  of  gain  in  weight  to  energy  intake  may  be  quite  similar 
in  different  genera.®  It  would  seem  that  tlie  growth  impulse  which,  in 
some  way  not  at  all  understood,  directs  and  governs  developmental  events 
through  the  processes  of  nutrition,  is  geared,  so  to  speak,  at  a  very  similar 

'  This  statement,  in  view  of  recent  developments  in  the  realm  of  the  chemically 
unknown  accessory  su])stance.s  (vitamines),  must  be  guarded  by  the  saving  proviso  that 
an  adequacy  of  these  several  substances  is  assumed. 


:•/ 


620  JOHN  R  MUKLm 

speed  in  relation  to  energy  intake  in  several  genera  and  orders  of  mam- 
mals. A  kilogi-am  of  body  substance  in  several  of  them  contains,  accord- 
ing to  Rubner(cT),  30  gm.  N  and  1722  calories  of  potential  energy.  To 
produce  this  unit  of  growth  requires  in  the  earliest  period  of  postnatal  de-* 
velopment  approximately  the  same  amount  of  food  energy ;  namely,  408S 
calories.  Tlie  human  infant,  however,  occupies  an  exceptional  position, 
in  this  regard,  which  may  bo  expressed  as  follows.  Of  100  calories  of  en- 
ergy in  the  form  of  milk  there  is  utilized  for  growth  in  the — 

Colt  33.3% 

Calf   33.1% 

Lamb 38.2% 

Pig    40.2% 

Puppy  dog •. 34.9% 

Kitten 33.0% 

Young  -rabbit   37.7% 

Average 34.3%  ^ 

Human  Infant 5.2% 

The  average  ingestion  of  milk  in  relation  to  the  maintenance  require- 
ment (this  term  in  Rubner's  usage  is  not  synonymous  with  basal  metabo- 
lism) in  the  mammal  is  202  per  cent,  while  for  the  infant  it  is  only  120 
per  cent. 

The  relatively  long  infancy  period  in  the  human  family,  it  would  seem, 
is  a  consequence  rather  than  a  cause  of  this  difference;  for  if  the  large 
amount  of  time  spent  in  sleep  explained  the  low  intake  of  food,  and  the 
slow  development  were  a  consequence  of  this,  then  keeping  the  baby  awake 
and  thereby  increasing  the  demand  for  food  ought  to  accelerate  its  growth. 
Of  course  just  the  opposite  is  true.  Owing  to  a  growth  impulse  of  low 
speed,  which  in  turn  probably  determines  capacity  for  food  (anatomical 
capacity  of  the  stomach  and  functional  capacity  of  metabolism)  on  the 
part  of  the  infant,  the  human  mother  is  called  upon  to  supply  intelligent 
care  and  protection  rather  than  bulk  of  nutrients.  Interesting  biological 
implications  are  involved  which  space  does  not  permit  us  to  develop  at  this 
time. 

It  is  doubtful  whether  the  growth  quota  of  energy,  i.  e.,  the  portion 
left  over  after  the  maintenance  factor,  the  activity  factor,  the  dynamic  fac- 
tor and  the  loss  by  non-absorption  have  been  covered,  can  ever  be  fixed 
as  a  definite  percentage  of  the  maintenance  metabolism  for  all  varieties  of 
infants.  The  growth  impulse,  as  between  individuals,  quite  as  truly  as 
between  diiferent  orders  of  animals,  is  more  a  matter  of  heredity  than 
of  food.  Moreover,  it  is  inherited  from  the  father  equally  with  the  mother, 
so  that  a  small  mother  nursing  the  child  of  a  large  father  may  not  be  able 
to  supply  milk  enough  for  the  rate  of  growth  which  the  child  has  inherited. 
x\gain  it  is  well  known  that  grow^th  in  height  often  will  proceed  at  a  time 
when  nutrition  is  not  sufficient  to  support  growth  in  weight,  and  both  vary 
with  the  season  of  the  year  (Porter,  Bleyer).     In  time  we  shall  have  in 


NOKMAL  PEOCESSES  OF  ENERGY  METABOLISM    621 

addition  to  statistical  criteria,  physiological  norms  of  growth  which  will 
simplify  the  whole  problem  of  infant  feeding.  At  present  it  is  impossible 
to  formulate  even  a  satisfactory  physiological  definition  of  the  growth  rate. 
Merely  to  emphasize  the  multiplicity  of  factors  contending  for  energy  be- 
fore growth  can  be  wholly  satisfied  and  to  visualize  what  is  known  of  their 
quantitative  relations,  the  following  tabular  arrangement  may  be  presented : 

Basal  metabolism    60  Cal.  per  kgm. 

Activity  metabolism  (12  to  40%  of  Basal)    7.2  to     24.0     "       " 

Loss  bv  feces  ( 10  to  15%  of  Basal)    6.0  to       9.0     "       " 

Dynamic  action    ( 10  to  20%  of  Basal)    6.0  to     12,0     "       " 

Growth  (10  to  20%  of  Basal)    6.0  to     12.0     "      " 

Total    85.0  to  120.0    "      " 

This  estimate  is  liberal  in  all  divisions  of  the  caloric  needs.  Careful 
reckoning  of  the  fate  of  the  food  energy  cannot  account  for  more  than 
is  here  allowed  except  in  such  extreme  restlessness  as  would  place  the  case 
clearly  in  the  pathological  field. 

This  classification  is  not  to  be  looked  upon  as  anything  fixed.  The 
basal  requirement  increases  steadily  up  to  one  year  of  age  or  later.  The 
requirement  for  activity  increases  steadily  in  the  absolute  sense  as  the 
child  spends  more  and  more  time  awake,  but  it  is  not  yet  certain  whether 
the  increase  is  also  relative  to  basal  needs  on  the  basis  of  weight  or  surface. 
Utilization  is  not  known  to  change  with  age,  the  results  with  very  young 
infants  being  often  quite  as  favorable  as  with  older  ones.  Dynamic  action 
has  not  been  sufficiently  studied  to  say  definitely  whether  it  is  greater 
or  less  as  more  and  more  food  is  ingested  at  a  meal.  There  are  indications 
that  it  is  greater.  Finally,  the  requirement  for  growth  relative  to  weight 
increases  certainly  for  the  first  three  months  and  possibly  up  to  six  months, 
after  which  it  becomes  retarded.  We  have  yet  to  learn  whether  the 
growth  increment  (in  calorics)  advances  more  or  less  rapidly  than  the 
basal  requirement.  Van  Pirquet,  who* has  recently  invented  a  system  of 
computing  food  requirements,  obviously  based  upon  energy'  units  (and 
merely  disguised  as  "nems'')  estimates  the  growth  quota  at  one-third  the 
minimal  or  maintenance  requirement.  From  the  observations  of  Soxblet 
on  the  calf  it  has  been  estimated  that  this  animal  can  iitilize  over  40  per 
cent  of  the  food  energy  for  growth  but  an  infant  of  7  months  was 
able  at  best  to  so  dispose  of  only  13  per  cent  Mere  fattening  should  not 
of  course  be  included  in  growth. 

E.    Energy  Metabolism  of  Pregnancy 

The  energy  metabolism  of  the  fetus  immediately  before  birth  has  been 
determined  separately  only  by  noting  the  difference  in  respiratory  ex- 
change of  the  mother  produced  by  clamping  off  the  umbilical  cord  (see 
page  619).     This  method,  however,  is  open  to  serious  objection  and  has 


622  JOHJT  K.  MURLIlSr 

not  given  satisfactory  results,  [in  pregnancy  the  extra  naetabolism  due 
.  to  the  product  of  conception  includes  the  energy  used  by  accessory  struc- 
^  til  res  as  well  as  by  the  fetus  itself .j  Nevertheless,  it  is  worth  while  to 
estimate  the  difference  particularly  with  a  view  to  determine  whether  any 
mntorial  change  in  energy  relations  occurs  at  the  moment  of  parturition. 
With  the  dog  ^[urlin(c)  was  able  to  show  that  the  extra  heat  production 
of  mother  and  offspring  just  before  parturition  was  very  nearly  propor- 
tional to  the  weight  of  newborn  pups  delivered,  three  days  later.  It  was 
impossible  to  record  the  metabolism  nearer  to  parturition  than  this  on  ac- 
count of  the  restlessness  of  the  dog.  Quite  fortunately  it  happened  that 
the  same  dog  gave  two  litters,  one  consisting  of  a  single,  the  other  of  five 
pups.  Comparing  the  total  metabolism  on  the  third  day  before  parturition 
in  the  two  pregnancies  with  that  of  the  dog  in  sexual  rest  after  lactation 
had  been  stopped,  it  was  found  that  the  extra  energy  metabolism  at  the 
culmination  of  pregnancy  for^the  one  pup  was  (551.3  — •  505.3  =)46  cal- 
ories or  164  calories  per  kilogi-am  of  the  single  newborn  pup;  and 
(TG3.8  — 505.3  =)258.5  calories  or  165  calories  per  kilogi*am  for  the 
five  new-bom  pups.  In  other  words,  the  extra  metabolism  was  very 
nearly  proportional  to  the  weight  of  the  newborn. 

46  Cal.  :  258.5  Cal.  :  280  gm.  :  1560  gm. 
It  should  be  emphasized  that  the  temperature  of  the  cage  was  the  same 
on  the  several  days  compared,  that  the  mother  dog  was  trained  to  lie  per- 
fectly still,  and  finally  that  the  diet  was  exactly  the  same  in  weight  and 
composition  on  all  these  days. 

\It  is  interesting  to  observe  that  the  extra  metabolism  necessary  to 
maintain  the  embryo  (and  all  accessory  structures  of  the  mother's  body) 
Cat  a  time  when  the  pregnancy  is  at  its  highest  phase* is  very  nearly  equal 
to  the  amount  which  the  newborn  of  the  same  weight  would  theoretically 
produce/C according  to  the  law  of  skin  surface),  the  first  day  after  delivery, 
if  exposed  to  ordinary  room  temperature  and  if  resting  (Murlin(c)). 

If  the  law  of  skin  surface  is  applicable  to  the  embryo  and  the  new- 
bom,  as  Rubner  believes  it  is,  we  may  conclude  that  the  metabolism  of 
the  uterus,  mammae,  etc.,  would  almost  exactly  compensate  for  the  differ- 
ence between  the  metabolism  of  the  newborn  at  room  temperature  and 
the  metabolism  of  the  embryo  at  the  temperature  of  the  mother's  body. 
In  other  words,  the  curve  of  total  metabolism  of  mother  and  offspring 
would  scarcely  suffer  any  interruption  at  birth,  if  mother  and  offspring 
after  birth  could  be  kept  sufl5ciently  quiet  for  the  demonstration.  If  this 
generalization  should  be  true  of  the  human  mother  and  her  offspring  it 
would  be  a  matter  of  considerable  interest  and  importance. 

To  secure  proper  conditions  for  this  inquiry,  the  problem  was  taken 
to  the  ^N'utrition  Laboratory  of  the  Carnegie  Institution  in  Boston,  where 
a  bod  calorimeter  had  been  perfected  large  enough  to  contain  mother  and 
cli,ild  (Carpenter  and  Murlin).   Three  subjects  were  studied.    The  metab- 


iS-QEMAL  PEOCESSES  OF  EKEEGY  METABOLISM    623 

olism  of  the  pregnant  woman  was  deteiTnined  a  number  of  times  through- 
out the  last  two  or  three  weeks,  and  similar  determinations  were  made  upon 


I    Meter 
Fig.  30.     Cross-section  of  bed  calorimeter   (Benedict  and  Carpenter),  with  which 
Studies  on  Pregnancy  were  made  by  Carpenter  and  Murlin. 


the  mother  and  child  as  well  as  upon  the  mother  alone  after  parturition.    A 
table  showing  the  comparative  results  is  given  below. 

TABLE  23 

ExEBGY  3^Ietabolism  of  Mother  and  Child  Together  Before  and  After  Parturition 

(Carpenter  and  Murlin) 


CASE 

Mean  of  All  Days  Before  and 

After  Delivery 


Case  1. 
1st,   4th,  and  Gth  days  before 

delivery    

2nd,  5th,  12th,  14th,  and  17th 
after  delivery  ......... 

Case  2. 

13th,  17th,  19th,  20th,  and  22nd 
before  delivery *  . 

2nd,  5tlj,  and  11th  after  de- 
livery     

Case  3. 

1st,  3rd,  17th,  21st,  and  24th 
before  delivery   

4th,  8th,  and  11th  after  de- 
livery     


Respiratory  Exchange 


£  S 


3G.75 
36.9 

36.68 
36.8 

36.64 
37.23 


S  p 


21.3 
20.2 

22.3 
21.7 

23.9 
23.1 


OH 


18.4 
18.5 

19.6 
20.4 

20.2 
20.3 


p4 


.85 
.80 

.83 
.78 

.86 
.81 


Energy,  Production,  Calo- 
ries per  Hr. 


60.0 
61.2 

63.6 
71.1 

72.2 
70.8 


61.3 
C1.2 

65.9 
67.5 

68.7 
68.6 


©5 


60.7 
61.2 

64.7 
69.3 

70.6 
69.7 


-f-0.87 


+  7.1 


0.9 


624  JOHN  K.  MUELm 

The  energy  production  expressed  iu  absolute  figures  In  botli  cases  1  and 
3  is  the  same  after  as  before  parturition.  In  case  2  there  \?as  an  increase 
of  about.?  per  cent  in  the  postpartum  over  the  antepartum  metabolism. 
This  can  be  accounted  for  by  the  fact  that  the  child  cried  lustily  at  times 
on  two  out  of  three  postpartum  days  and  the  crying  disturbed  the  mother. 
One  is  justified,  therefore,  in  the  conclusion  that  the  total  metabolism  of 
mother  and  child  immediately  after  birth  of  the  child  is  not  greater  in 
absolute  amount  than  it  was  immediately  before  delivery.  The  extra 
metabolism  of  pregnancy,  at  its  culmination,  due  in- part  to  the  activity 
of  the  accessory  maternal  structures  as  well  as  to  the  fetus,  as  in  the  dog, 
is  just  compensated  by  an  extra  metabolism  set  up  in  the  new-bom  as  it 
begins  an  independent  existence,  ^nce  the  mammalian  embryo  has  no 
appreciable  weight  as  compared  with  the  mother  until  near  the  middle  of 
the  gestation  period,  it  is  easily  imderstood  why  several  w^orkers  (Magnus- 
-^  I^evy)  using  the  Zuntz  method  failed  to  find  any  increase  in  the  oxygen  con- 
sumption per  unit  of  weight  in  pregnant  as  contrasted  with  non-pregnant 
women;  or  if  such  an  increase  appeared  at  all,  it  became  evident  only  com- 
paratively late  in  the  gestation  periodj  This- was  confirmed  with  respect 
to  the  total  energy  production  as  computed  from  the  output  of  nitrogen  and 
carbon  by  the  writer  in  a  series  of  experiments  on  a  pregnant  dog.  The 
only  exception  to  the  rule  is  a  single  case  reported  by  Magnus-Levy  in  which 
he  observed  both  an  absolute  and  a  relative  increase  in  oxygen  absorption  as 
early  as  the  third  month  of  gestation. 

Leo  Zuntz (6)  reported  three  cases  on  two  of  which  he  made  observations 
by  means  of  the  Zuntz-Geppeii;  method  throughout  the  gestation  period 
and  on  the  third  a  few  observations  in  the  sixth  month  only.  He  com- 
pared the  results  with  figiires  previously  obtained  from  the  same  subject 
in  sexual  rest.  The  first  two  increased  considerably  in  weight  during 
the  gestation  period,  quite  independently  of  the  product  of  conception, 
so  that  the  amount  of  ox}^gen  absorbed,  when  expressed  per  kilogram  of 
body  weight,  was  even  less  in  the  ninth  month  (Case  C)  than  it  had  been 
in  sexual  rest,  or  was  so  little  gi-eater  (Case  B)  that  Zuntz  believed  the 
difference  w^as  entirely  due  to  the  increased  labor  of  respiration.  In  the 
third  case,  however,  the  weight  was  less  in  the  sixth  month  than  it  had 
been  previous  to  conception,  the  oxygen  absorption  being  as  a  consequence 
significantly  larger  per  unit  of  weight  in  the  pregnant  condition.  On 
the  basis  of  this  experiment  and  that  of  Maguus-Levy,  Zuntz  concluded 
that  at  the  end  of  pregnancy  the  respiratory  metabolism  normally  would 
be  considerably  higher  than  in  sexual  rest  and  that  this  is  not  altogether 
due  to  increased  labor  of  respiration.  Carpenter  and  Murlin  compared 
their  determinations  on  three  normal  cases  of  pregnancy  with  basal  de- 
terminations on  seven  normal,  non-preguant  women  ranging  in  age  from 
18  to  55  years  and  in  weight  from  37  to  Q(}  kilograms.  Table  24r  presents 
a  comparison  of  the  energy  metabolism  in  the  ninth  month  of  pregnancy 


NOKMAL  PKOCESSES  OF  ENEKGY  METABOLISM    625 


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62G  JOHN"  R.  MURLIiT 

with  the  metabolism  of  the  normal,  non-pregnant  woman,  so  far  as  the 
former  has  yet  been  studied. 

It  is  suiT)rising  how  close  is  the  agreement  between  the  results  obtained 
with  the  respiration  calorimeter  and  those  obtained  by  the  Zuntz-Geppert 
method.  For  example^  Zuntz's  case  3,  agi-ees  perfectly  as  far  as  the  O2  ab- 
sorption is  concerned  with  Carpenter  and  Murlin's  cases  1  and  3.  The 
mean  oxygen  absorption  per  kilogi'am  and  minute  in  the  non-pregnant 
woman  before  conception  is  3.45  c.c,  for  the  eight  normal  women  3.48  c.c, 
but  for  the  three  cases  taken  during  the  puerperium  it  is  3.65  c.c,  an 
increase  of  5.8  per  cent.  The  mean  result  for  all  non-pregnant  women 
is  3.49  c.c.  Oo  kilogram  and  minute.  For  the  pregnant  woman  the  result 
is  3.57  c.c.  or  3.5  per  cent  more  than  the  amount  obtained  for  all  the  cases 
taken  in  complete  sexual  rest,  and  2.2  per  cent  less  than  the  average  for 
the  puerperium. 

For  the  heat  production  Carpenter  and  Murlin  found  1.03  Cal.  pei* 
kg-m.  and  hour  for  the  pregnant  cases  as  against  1.02  Cal.  per  kilogram  and 
hour  for  all  the  non-pregiiant  subjects.  For  the  woman  in  complete  sexual 
rest,  however,  the  mean  result  for  the  eight  cases  is  0.99  Cal.  per  kilo- 
gram and  hour,  i.  e.,  about  4  per  cent  less  than  for  the  pregnant  woman. 
P-lie  agreement  between  the  oxygen  difference  and  the  total  energy  differ- 
ence is  very  satisfactory.  The  conclusion  which  may  be  drawn  with  entire 
confidence  is,  that  the  basal  energy  metabolism  expressed  per  hilogram  and 
hour  J  of  the  pregnant  ivoman  in  the  last  month  of  her  pregnancy,  is  but  little 
larger  (4  per  cent)  than  for  the  woman  in  complete  sexual  restT^ 

While  we  have  but  little  data  as  to  the  depth  of  respiration  or  as  to 
the  increased  labor  of  respiration  in  pregnancy,  one  may  be  inclined  to 
think  that  so  slight  a  difference  might  be  attributable  entirely  to  such  a 
cause,  instead  of  only  partly  so,  as  L.  Zuntz  believed.  In  fact,  according 
to  Zuntz's  own  estimate  of  the  increased  labor  of  respiration  in  his  Case 
B  the  difference  in"  oxygen  absorption  between  the  pregnant  and  the  non- 
pregnant condition  is  exactly  accounted  for  in  this  way.  This  conclusion 
would  mean,  very  clearly,  that  the  metabolism  of  the  fetus,  together  with 
all  accessory  structures,  is  the  same  as  so  much  maternal  tissue.  If  the 
metabolism  of  the  fetus  itself  were  slightly  higher  in  the  human,  as  it 
seems,  from  Bohr  s  experiments,  to  be  in  the  guinea  pig,  this  factor  would 
be  counterbalanced  by  the  fact  that  the  liquor  amnii  (and  possibly  the 
membranes)  takes  no  part  in  the  metabolism. 

On  the  other  hand,  the  heat  production  in  the  pnerperinm  is  dis- 
tinctly higher  than  that  for  complete  sexual  rest  or  for  the  pregnant  con- 
dition— ^the  average  for  Carpenter  and  Murlin's  three  cases  being  1.10  cal- 
ories per  kilogram  and  hour,  or  11  per  cent  higher  than  the  average  for 
the  former  and  7  per  cent  higher  than  the  average  for  the  latter. 

What  is  the  explanation  of  this  higher  energy  production  of  the  puer- 
perient  mother  ?    That  it  was  not  fever  is  apparent  from  the  very  accurate 


IS^OEMxVL  PEOCESSES  OF  EISnEEGY  METABOLISM    627 

temperature  measureuieuts  made  by  rectal  thermometer.  It  is  conceivable 
that  the  processes  of  involution,  ^vhich  \\XiYe  not  yet  entirely  complete 
at  the  time  of  the  above  obsei-v^ations  were  made,  set  free  decomposition 
products  which  stimulate  the  general  heat  production  in  a  manner  anal- 
ogous to  the  stimulation  of  the  mammary  glands  by  fetal  products.  If 
so,  the  processes  by  which  heat  is  lost  from  the  body  (evaporation  of  water, 
radiation  and  conduction)  must  1)0  equally  stimulated,  for  there  is  no 
i'.ccumulation  of  heat.  A  state  of  hyperactivity  of  the  sweat-glands,  es- 
pecially during  the  early  days  of  the  puerperium,  is  a  phenomenon  well 
known  to  obstetricians  and  it  is  possible  that  this  activity  is  a  primary 
cause  of  the  increased  heat  production — a  cooling  of  the  body  surface 
generally  resulting  in  a  reflex  stimulation  of  the  heat-producing  tissues. 
The  writer  believes,  however,  that  the  most  important  factors  are  the 
activity  of  the  mammary  glands  and  the  specific  dynamic  action  of  the 
foodstuffs  bui-ning — especially  the  increased  protein  combustion  due  to 
involution  of  the  ntenis.  The  lower  respiratory  quotient  found  in  the 
puerperium  is  to  be  ascribed  to  the  restricted  diet  very  commonly  imposed 
immediately  after  delivery,  and  is  a  sign  that  the  patient  has  used  np  her 
store  of  glycogen  during  labor  and  is  thrown  back  on  her  reser\^e  of  fat,  and 
On  the  protein  resorbed  from  the  uterus  for  her  supply  of  energy.  The 
dynamic  action  of  the  latter  would  considerably  increase  the  heat  pro- 
duction. 


F.    Energy  Metabolism  of  the  Newborn 

Infant 

1.  The  Kespiratory  Quotient  of  the  Newborn. — In  the  observations 
of  Mensi,  Scherer,  and  Babak,  the  respiratory  quotient  of  the  newborn 
child  was  found  to  be  extremely  low,  so  much  so  that  it  was  inferred  that 
oxygen  must  be  utilized  in  the  infant's  body  for  some  other  purpose  than 
that  of  combustion.  More  recent  observations  have  discredited  this  inter- 
pretation, for  it  has  been  rendered  very  probable  that  the  technique  of 
the  early  observers  was  seriously  at  fault.  Hasselbalch  points  out  that 
Scherer's  oxygen  must  have  contained  a  much  larger  percentage  of  nitro- 
gen than  he  assumed,  from  an  old  analysis,  to  be  present;  also  that  there 
was  an  admitted  error  of  6  per  cent  on  the  carbon  dioxid. 

Hasselbalch  (a)  himself  obtained  quotients  which  were  much  higher. 
Since  his  technique  seems  to  have  been  carefully  controlled,  it  is  probable 
that  his  results  are  much  more  reliable.  In  fact,  Hasselbalch  lays  stress 
on  the  fact  that  the  E.  Q.  of  the  newborn  infant  before  it  begins  to  take 
food  is  often  much  higher  than  that  of  an  adult  in  a  similar  state  of  inani- 
tion, and  he  thinks  it  is  fair  to  infer  that  in  such  cases,  which. in  his  tables 
include  both  the  well-nourished  infants  born  at  terra  and  infants  prema- 


C28  JOHN  E.  MUKLrN" 

tiirely  bom,  there  is  a  plentiful  amount  of  glycogen  available  at  birth  and 
it  is  the  requisition  upon  thi^  reserve  carbohydrate  which  produces  the 
high  quotients. 

Ilasselbalch  infers  much  from  tlic  single  experiment  of  Bohr  on  the 
pregnant  guinea  pig  (quoted  at  page  611))  showing  that  the  respiratory 
quotient  of  the  embryo  is  1.0.  It  is  quite  possible  that  this  is  true,  but 
the  single  experiment  of  Bohr  can  hardly  be  accepted  as  proving  the  case 
beyond  doubt  Recent  analyses  of  the  blood  of  the  mother  and  of  the  um- 
bilical vein  taken  simultaneously  at  parturition  show  clearly  that  other 
materials  than  glucose  can  pass  the  placenta  very  readily,  and  wliile  one 
may  be  prepared  to  believe  that  the  main  reliance  of  the  embryo  for  energ;^' 
is  the  most  diffusible  of  the  foodstuffs,  it  must  not  be  inferred  that  no 
other  substance  is  available  for  combustion  in  the  fetus.  Were  carbo- 
hydrate the  only  fuel  available  during  antenatal  life,  it  might  be  argued 
that  the  enzymes  are  not  yet  ready  for  liberation  of  energy  from  fat  (which 
certainly  is  present),  even  if  a  large  store  of  glycogen  could  not  be  demon- 
strated; and  we  might  expect  to  find  the  quotients  rather  higher  immedi- 
ately after  birth  than  a  little  later.  Hasselbalch  himself  admits  that  the 
facts  are  not  quite  so  easily  explained.  Referring  to  Table  25  it  is  seen 
that  the  highest  quotients  do  not  always  come  at  the  earliest  hour.  When 
the  same  subject  was  used  in  two  successive  experiments,  however,  this 
was  found  to  be  true. 

So  convinced  was  Ilasselbalch  that  the  quotient  was  higher  the  bet- 
ter the  state  of  nutrition  of  the  newborn  that  he  thought  he  could  tell 
when  the  quotient  was  low^er  than  0.9  by  signs  of  hunger  in  the  infant. 

The  occurrence  of  high  quotients  within  the  first  seven  or  eight  hours 
after  birth  was  observed  independently  also  by  Bailey  and  Murlin.  They 
drew  attention  to  the  particular  interest  which  the  quotient  at  this  time 
presents,  as  indicating  the  kind  of  material^ available  for  combustion  as 
the  child  breaks  connection  with  the  maternal  circulation.  They  were 
on  their  gaiard,  however,  against  inferring,  \vithout  further  infonnation 
regarding  the  absorption  of  oxygen  at  this  age,  that  the  high  quotient 
necessarily  proves  a  predominantly  carbohydrate  combustion.  "Assum- 
ing that  oxygen  absorption  is  normal  at  this  age,'*  they  say,  "the  quo- 
tients obtained  would  indicate  the  combustion  of  a  considerable  amount 
of  carbohydrate  (glycogen) »"  Since  Morris  has  published  his  sugar  an- 
alyses in  maternal  and  umbilical  bloods  and  has  shown  that  the  level  of 
the  blood  sugar  is  raised  in  both  by  a  severe  labor  or  by  the  use  of  an  anes- 
thetic, another  explanation  of  the  high  quotients  which  are  met  with  in  the 
early  hours  of  postnatal  life  has  been  presented.  Henceforth  it  will  be 
necessary  to  know  something  of  the  severity  of  labor  and  whether  the 
mother  was  given  an  anesthetic,  before  a  plentiful  supply  of  glycogen  in 
the  liver  of  the  newborn  all  ready  for  combustion  the  moment  the  cord  is 
tied,  can  be  inferred.    However,  it  is  possible  that  the  severe  labor  would 


XORMAL  PROCESSES  OF  ENERGY  METABOLISM  029 


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630  J0H2^  R.  MUELIN 

mobilize  glycogen  from  the  maternal  tissues  and  that  ether  administered 
would  mobilize  it  from  both  the  maternal  and  fetal  tissues,  so  that  the  um- 
bilical vein  would  get  a  contribution  from  both  directions.  Ilasselbalch^s 
insistence  upon  a  relationship  to  general  nutritive  condition  is  not  neccsr- 
sarily  discredited,  for  it  is  well-known  that  in  the  majority  of  instances 
a  large,  well-formed  infant  produces  a  more  difficult  labor  w^liich  itself, 
without  the  assistance  of  an  anesthetic,  would  in  all  probability  call  out 
enough  carbohydrate  into  the  circulation  to  raise  the  quotient  several 
points.  Premature  infants  also  produce  an  easy  labor,  and  this  fact  with 
absence  of  a  hyperglycemia  may  explain  the  impression  of  Ilasselbalch 
that  in  the  prematurely  born  infant  ''the  store  of  carbohydrate  is  very 
quickly  spent" 

Benedict  and  Talbot(a)(5)  did  not  observe  especially  high  quotients 
immediately  after  birth ;  for  the  technique  of  their  experiments  w^as  not  cal- 
culated to  separate  the  respiratory  quotients  into  individual  periods.  The 
authors  state,  however,  that  when  the  quotients  above  and  below  0.80  are 
compared,  it  is  found  '^that  up  to  the  eighth  hour  the  greater  number 
lie  above  0.80,  while  subsequent  to  the  tenth  hour  the  larger  proportion 
lie  below  this  value." 

All  the  modern  observ^ations  agree  in  showing  a  rapid  fall  in  the 
respiratory  quotient  toward  the  end  of  the  first  day.  Ilasselbalch  did  not 
repeat  his  observations  on  the  same  infant  except  in  immediately  succeed- 
ing periods;  but  even  these  second  periods  show  in  four  out  of  five  cases 
a  noticeable  fall.  Bailey  and  Murlin  made  observations  on  two  infants 
bom  three  hours  apart  on  the  same  day  and  placed  in  the  respiration  in- 
cubator at  six  hours  of  age.  The  obsen'ations  were  repeated  on  the  sec- 
ond, fourth,  fifth,  and  sixth  days  with  one  child,  and  on  the  second,  fourth, 
fifth,  and  eighth  with  the  other.  The  quotients  fell  to  0.67  in  both  cases 
on  the  second  day.  While  distrusting  the  exact  figures  obtained,  the  au- 
thors point  out  the  extreme  significance  of  the  indication,  confinned  on 
a  third  newborn  at  the  twenty-seventh  hour,  that  all  available  carboh3^drate 
has  been  utilized  by  this  time,  and  the  importance  of  supplying  artificially, 
if  need  be,  some  materials  to  protect  the  body  substances.  Mother^s  milk 
was  available  in  small  amount  for  both  infants  on  the  third  day,  but  the 
quotients  did  not  reach  the  level  usually  obtained  after  breast  feeding  of 
older  babies  until  the  sixth  day  in  one  instance  and  the  eighth  in  the 
other.  These  obsen'ations  were  confirmed  by  Benedict  and  Talbot  in 
their  long  series,  the  values  shown  in  Table  26  having  been  obtained  as 
averages  of  several  short  periods  for  each  infant. 

a.  The  Influence  of  Food  on  the  Respiratory  Quotient. — Milk  appears 
in  the  mother's  breast  usually  by  the  fourth  day,  and  by  the  fifth  day  the 
infant  receives  enough  to  prevent  further  loss  in  weight.  The  course 
of  the  average  respiratory  quotient  from  the  first  to  the  eighth 
days  reflects  the  adequacy  of  the  food  intake.     Unless  artificial  feeding 


XOKMAL  PROCESSES  OF  ENERGY  METABOLISM    631 

TABLE  26 
Resptbatory  Quotients  the  First  Eight  Days    (Benedict  and  Talbot) 


Day 

1 

2 

3 

4 

5 

6 

7 

0.81 
15 

8 

Respiratory  Quotient 

0.80 
74 

0.74 
64 

0.73 
62 

0.75 
51 

0.79 
41 

0.82 
22 

0.80 

Nurnbw  of  Cases    

9 

is  resorted  to,  the  modern  infant  is  doomed  to  almost  complete  starvation 
for  the  first  three  days,  although  it  is  clear,  even  from  the  average  R.  Q. 
in  the  observations  made  at  Boston,  that  glycogen  is  present  in  sufficient 
quantity  to  prevent  starvation  acidosis  the  first  day.  When  milk  comes 
in  sufficient  quantity  on  the  fourth  day,  the  average  respiratory  quotient 
responds  noticeably  and  on  the  fifth  and  sixth  days  mounts  to  a  level 
which  indicates  a  satisfactory  state  of  nutrition. 

The  question  has  often  arisen  whether  the  newborn  infant  is  capable 
at  once  of  digesting  and  metabolizing  a  sufficient  quantity  of  breast  milk 
even  if  it  were  present,  to  prevent  loss  of  weight.  The  answer  to  this 
question  must  be  sought  by  means  of  the  respiration  apparatus.  The  mat- 
ter will  be  discussed  in  its  quantitative  aspects  at  greater  length  beyond. 
Meantime,  it  may  be  noted  that  Hasselbalch  has  tested  the  capacity  of 
the  newborn  to  absorb  and  metabolize  grape  aiid  milk  sugar  and  that  per- 
fectly satisfactory  evidence  was  obtained  from  the  respiratory  quotient 
that  this  capacity  is  developed  by  the  end  of  the  second  day. 

Infants  bom  prematurely  may  have  a  high  R.  Q.  within  the  first  few 
hours  after  birth  but  by  the  fifteenth  hour  the  supply  of  glycogen,  or  tbe 
hyperglyca^mia  due  to  labor  or  anesthesia  or  both,  has  been  considerably 
reduced  and  the  child  may  be  already  on  a  nearly  pure  fat  metabolism. 
When  an  adult  mammal  already  well  nourished  is  given  even  a  small  quan- 
tity of  an  easily  absorbed  sugar,  the  effect  upon  the  R.  Q.  may  be  seen 
within  the  first  half  hour.  When,  on  the  other  hand,  fat  is  given  in  large 
amount,  the  effect  upon  the  quotient  may  not  be  seen  until  the  third  to 
sixth  hour.  We  may  expect  then  that  in  feeding  an  infant  with  milk, 
whether  mothcr^s  or  cow's  milk,  it  is  the  sugar  of  milk  which  is  burned 
first  and  the  fat  will  only  be  absorbed  in  sufficient  quantity  to  affect  the 
R.  Q.  after  several  hours. 

The  work  of  Hasselbalch  demonstrates  these  points  very  clearly.  After 
feeding  infants  2  and  4  days  of  age  with  breast  milk,  he  found  the  high- 
est quotient  (.92  and  .93)  11^  hours  after  the  meal.  In  one  case  ho  was 
able  to  show  that  an  experiment  begun  2  hours  after  a  feeding  gave  a 
quotient  4  points  lower  than  an  immediately  succeeding  period  begun  only 
one  hour  after  a  similar  feeding.  Apparently  in  Ilasselbalch's  experi- 
ments, as  in  those  of  Bailey  and  Murlin,  it  is  much  easier  to  secure  this 
rise  of  quotient  with  infants  ^ve  days  or  more  of  age  than  it  is  with 
those  of  2  days  or  less.     The  explanation  clearly  is  that  unless  artificial 


632  JOHiNT  K.  MUKLIIST 

nourishment  has  been  resorted  to,  the  infant's  tissues  are  depleted,  of 
glycogen  at  2  days  just  as  are  those  of  an  adult  after  several  days  of 
fasting,  and  anything  less  than  a  large  feeding  of  carbohydrate  is  held 
up  by  the  tissues  to  satisfy  their  craving  for  storage  glycogen. 

2.  Basal  Metabolism  in  the  Newborn. — Carpenter  and  Murlin  found 
the  metaboh'sm  of  the  newborn  taken  per  unit  of  weight  to  be  two  and  a 
half  times  that  of  the  mother  lying  in  bed  beside  the  child.  Later  observa- 
tions by  Benedict  and  Talbot  (&)  and  by  Bailey  and  Murlin  make  the  figure 
for  newborns  less  than  a  week  old  1.75  and  1.87  calories  respectively  per 
kilogram  and  hour  as  iagainst  1.0  calory  per  kilogram  and  hour  for  the 
normal  adult.  The  figure  given  by  Benedict  and  Talbot  is  the  average  of 
obsen^ations  on  nearly  one  hundred  subjects  which  ranged  from  two  and  a 
half  hours  to  seven  days  of  age,  and  had  an  average  age  of  two  days. 
That  given  by  Bailey  and  Murlin  is  the  average  of  twelve  hourly  periods 
on  four  infants  less  than  one  week  of  age,  during  which  the  infant  slept 
all  or  substantially  all  of  the  time.  On  the  basis  of  twenty-four  hours 
at  the  same  rate,  the  metabolism  would  be  42  calories  per  kilogram 
according  to  Benedict  and  Talbot,  or  45  calories  per  kilogram  and 
twenty-four  according  to  Bailey  and  Murlin.  It  should  be  noted,  however, 
that  the  periods  selected  for  this  average  represented  the  periods  of  unusual 
muscular  repose,  and  that  no  infant  would  ever  actually  maintain  a 
metabolism  so  low  for  an  entire  twenty-four  hour  period.  It  avoids  con- 
fusion, therefore,  to  report  all  results  of  metabolism  experiments  done  in 
short  periods  on  the  hourly  basis ;  for  it  is  obvious  that  when  a  child  sleeps 
quietly  for  the  entire  period,  as  it  did  in  most  instances  in  the  two  series 
of  experiments  referred  to,  the  metabolism  obtained  does  not  represent 
an  average  condition  for  the  entire  twenty-four  hours.  In  fact,  it  would 
be  next  to  impossible  to  find  a  short,  period  or  to  arrange  conditions  for 
one  which  could  be  said  to  represent  average  conditions  for  twenty-four 
hours.  Moreover,  a  child  does  not  metabolize  materials  in  periods  of 
twenty-four  hours  as  an  adult  may  be  said  on  certain  grounds  to  do.  If 
there  is  any  cycle  of  metabolism  in  the  newborn,  it  corresponds  to  the 
feeding  period. 

The  influence  of  weight  on  the  metabolism  per  unit  of  weight  is  well 
illustrated  by  the  table  on  page  633  from  Bailey  and  Murlin.  The 
metabolism  is  noticeably  higher  for  a  light-weight  baby  (W,  birth-weight 
6  lbs.)  than  for  a  heavy  baby  (B,  birth-weight  10  lbs.  3  oz.).  From 
considerations  which  will  be  presented  in  discussion  of  metabolism  of  older 
infants,  it  is  practically  certain  that  the  principal  factor  responsible  for 
such  a  difference  is  the  insulating  effect  of  subcutaneous  fat  or  of  the 
effect  of  fat  to  reduce  the  effective  radiating  surface. 

The  average  heat  production  of  all  of  the  infants  over'  4.00  kilos 
body  weight  and  over  one  day  of  age  in  Benedict  and  Talbot's(&)  Table  12 
(loc.  cit.  p.  95)  is  1.75  calories  per  kilogram  and  hour,  while  the  average 


ITOEMAL  PKOCESSES  OF  EISTERGY  METABOLISM    633 

TABLE  27 


Weight,  Kgm. 

Age,  Hours 

Cal.  per  Hour 

Cal.  per  Kgm. 
and  Hour 

Cal.  per  Sq. 

Meter  and  Hr, 

(Meeh) 

w 

2.9 
4.6 

2.82 
4.49 

2.75 
4.27 

2.75 

4.27 

Average 
Average 

6 
6 

31 
31 

80 
80 

104 
104 

5.649 
6.724 

6.255 
9.704 

5.972 
7.101 

5.252 
7.500 

5.782 
7.514 

1.94 
1.46 

2.22 
1.94 

2.18 
1.66 

1.83 
1.77 

2.04 
1.70 

23.67 

B 

20.43 

W 

B 

26.54 
26.87 

W 

25.57 

B 

22.67 

VV 

B 

21.85 
23.47 

VV 

24.43 

B 

23.36 

of  all  those  between  2.70  and  3.00  kilos  in  weight  and  within  the  same 
range  of  ages  is  2.00  calories  per  kilogram  and  hour.  The  observations  of 
Benedict  and  Talbot  are  thus  in  substantial  agi-eement  with  those  of 
Bailej  and  Murlin.  One  cannot  say,  however,  that  every  individual  case 
in  these  groups  as  compared  with  every  other  shows  a  metabolism  which  is 
inversely  proportional  to  weight.  Tlio  influence  of  body  weight  (fat)  can 
be  shown  best  by  contrasting  the  extremes. 

Within  the  age  of  one  week  the  metabolism  is  by  no  means  constant. 
The  average  of  31  cases  less  than  12  bours  of  age  is,  according  to  the  re- 
sults of  Benedict  and  Talbot,  1.59  calories  per  kilogram  and  hour,  while 
for  their  ten  infants  from  12  to  22  hours  of  age  it  is  1.87  calories.  Be- 
yond the  first  day  there  is  but  little  fluctuation  in  the  average.  Thus  for 
fourteen  infants  two  days  old  the  averag-e  is  1.86  calories  per  kilogram 
and  hour  and  for  thirteen  infants  four,  four  and  a  half,  and  five  days  of 
age,  the  average  is  1.85  calories.  It  is  evident  from  these  calculations 
that  the  lower  value  noted  above  for  Benedict  and  Talbot's  longer  series 
is  due  to  the  large  number  of  infants  less  than  12  hours  of  age  included 
in  their  obsei-vations.  Summing  up  all  the  modern  results,  it  may  be 
stated  categorically  that  the  metabolism  per  unit  of  weight  for  the  first 
twelve  hours  is  approximately  15  per  cent  lower  than  it  is  the  rest  of  the 
first  week. 

3.  Metabolism  of  the  Newborn  Infant  per  Unit  of  Body  Surface. — 
When  the  metabolism  per  unit  of  surface  area  of  the  newborn  is  compared 
with  that  of  the  adult,  account  must  once  more  be  taken  of  the  actual  age. 
The  average  for  the  first  two  weeks  may  be  illustrated  by  the  following 
table  from  Carpenter  and  Murlin  slightly  modified  by  Lusk(6).  Here  it 
is  seen  that  the  metabolism  .of  the  pregnant  mother  with  an  average  weight 
for  the  three  subjects  of  63  kilogTams  was  33.4  calories  per  square  meter 
of  body  surface  (Meeh's  formula).  After  parturition  the  average  weight 
was  53  kilogTams  and  the  heat  production  33.2  calories  per  square  meter. 


634 


jOH:Nr  E.  muklij^ 


TABLE  28 

Metabolism  Before  and  Ajter  Parturition.    The  IVIetabolism  of  the  Child  was 

Determined  by  Diffeiience 


Case  I: 

Before  parturition 

After  parturition   . 

Difference    

Cliild 

Case  II: 

Before  parturition 

After  parturition  . 

Difference    

Child 

Case  III: 

Before  parturition 

After  parturition   . 

Difference    

Child 

Average: 

Before  parturition 

After  parturition  . 


Weight 
in  Kg. 


63.0 

51.4 

11.6 

2.7 

58.0 

48.5 

9.5 

3.4 

69.1 

60.1 

9.0 

3.2 

63.4 
53.3 


Calories 
per  Hour 


60.7 

53.9 

6.8 

7.3 

64.7 

59.0 

5.7 

9.8 

70.6 

60.4 

10.2 

9.3 

65.3 
57.8 


Calories 

per   Sq.  M. 

(Meeh) 


31.4 
31.7 

30.5 

35.1 
36.2 

34.9 

34.0 
31.9 

34.8 

33.4 
33.2 


Calories 

per  Kg.  per 

Hour 


0.96 
1.05 

2.70 

1.11 
1.21* 

2.88 

1.02 
1.00 

2.90 

1.03 
1.09 


•  Child  cried  during  experiments. 


The  average  heat  production  for  women  between  20  and  50  years,  according 
to  Benedict  and  Emmes,  is  32.3  calories  per  square  meter.  !N'ow  the  still 
more  remarkable  fact  is  that  the  metabolism  of  the  child  (determined  by 
difference  between  the  metabolism  of  mother  and  child  taken  together  and 
mother  alone)  with  an  average  body  weight  of  3.10  kilos  is  33.4  calories 
per  square  meter  of  body  surface — exactly  the  same  as  that  of  the  mother 
whether  before  or  after  parturition.  A  more  striking  agreement  in  ac- 
cordance wdth  the  law^  of  surface  area  w^ould  indeed  be  difficult  to  find. 
A  woman  heavy  with  child,  the  same  woman  immediately  after  delivery, 
the  child  itself,  and  normal  non-pregnant  women  differing  enormously  in 
weight  and  showing  a  metabolism  per  unit  of  weight  differing  two  and  a 
half  times  have  the  same  metabolism  when  this  is  reckoned  on  the  basis  of 
surface.  The  agi-eement,  in  fact,  is  too  close  to  represent  the  exact  truth, 
except  for  the  circumstances  presented  by  chance  in  these  particular  ex- 
periments. We  now  know  from  the  further  work  of  Murlin  and  Hoobler 
as  well  as  that  of  Benedict  and  Talbot  that  the  exact  age  makes  a  measur- 
able difference  in ^ both  the  newborn  and  older  infants.  !N^evertheless  it 
holds  as  a  substantial  statement  of  the  facts  that  the  metabolism  of  the 
young  infant  (two  weeks  to  two  months  of  age)  on  the  basis  of  surface 
area  is  the  same  as  that  of  the  adult.  It  is  now  known  that  the  level  of 
metabolism  of  the  newborn  less  than  one  week  of  age  is  considerably  lower 
than  that  of  the  adult.  This  discovery  was  made  simultaneously  by  Bene- 
dict and  Talbot,  and  Bailey  and  Murlin,  though  it  was  emphasized  first 


KOEMAL  PKOCESSES  OF  EjS^EKGY  METABOLISM    635 

by  the  latter  autliors.  According  to  Meeh's  formula  the  basal  heat  pro- 
duction of  the  newborn  was  23.7  calories  per  square  meter  per  hour. 

Benedict  and  Talbot  interpret  their  results  on  all  their  infants  be- 
tween birth  and  one  week  of  age  as  showing  no  relation  between  body 
surface  and  metabolism.  Yet  when  two  extreme  gToups  like  those  men- 
tioned on  pages  632  and  633  are  selected  from  their  results,  it  is  found 
that  the  average  metabolism  per  unit  of  weight  diffei*s  12.5  per  cent,  while 
on  the  basis  of  surface  area  (Meeh\s  formula),  the  same  groups  show  a 
difference  of  less  than  3  per  cent,  namely  24.1  and  23.4  calories  per  square 
meter  per  hour. 

The  basal  metabolism  of  the  newborn  above  12  hours  of  age  while 
sleeping  quietly  at  a  comfortable  temperature  is  in  the  neighborhood  of 
23  or  24  calories  per  square  meter  of  surface,  in  contrast  with  that  of  the 
adult  which  is  in  the  neighborhood  of  32  or  33  calories.  In  other  "words, 
the  metabolism  of  the  newborn  is  nearly  one-third  less  than  that  of  the 
adult.  On  the  same  basis,  the  basal  metabolism  of  the  31  newborn  babies 
less  than  12  hours  of  age  in  Benedict  and  Talbot's  series  is  about  20 
calories  per  square  meter  per  hour  or  quite  40  per  cent  less  than  that  of 
the  adult.  Singularly  enough  this  same  level  of  metabolism  may  be 
reached  by  the  adult  after  twenty  days  of  fasting. 

4.  Influence  of  Sex  on  Basal  Metabolism  of  Infants. — From  the  sec- 
tions  immediately  preceding,  it  is  already  evident  that  sex  at  this  early  age 
exercises  little,  if  any,  specific  influence.  Further  examination  confirms 
this  impression.  Thus  the  gToup  of  31  infants  under  12  hours  of  age  in  the 
Boston  series  includes  17  males  and  14  females.  The  average  weight  of 
the  males  is  3.76  kilos  and  they  have  an  average  metabolism  per  kilo  and 
hour  of  1.53  calories.  The  average  weight  of  the  females  is  3.29  kilos  and 
they  have  an  average  metabolism  per  kilo  and  hour  of  1.61  calories.  The 
metabolism  of  the  larger  body  is  slightly  less  as  before.  The  two  groups, 
however,  have  exactly  the  same  metabolism  per  unit  of  surface. 

Carrying  the  comparison  to  older  groups,  wo  find  the  same  is  true  of 
all  infants  two  days  of  age.  There  are  seven  boys  and  seven  girls  of  this 
age  in  the  Boston  series.  The  average  metabolism  of  the  boys  is  1.85 
calories  per  kilogTam  and  hour,  while  that  of  the  girls  is  1.87  calories. 
The  average  metabolism  per  unit  of  surface  (Meeh)  is  23.5  calories  for 
the  boys  and  23.2  calories  for  the  girls.  Using  the  DuBois  height-weight 
formula  and  calculating  the  surface,  the  average  for  the  boys  is  30.7  calories 
and  for  the  girls  30.4  calories.  The  mean  percentage  deviation  from  the 
average  is  slighth'  less  for  both  gTOups  on  the  basis  of  the  Meeh  fonnula 
than  it  is  on  the  basis  of  weight  or  on  the  basis  of  the  surface  as  estimated 
by  the  DuBois  formula  (Table  29). 

Going  on  to  infants  4  to  5  days  of  age,  in  the  same  series,  we  find  the 
average  weight  of  the  boys  is  3.34  kilos,  that  of  the  girls  3.83.  The  basal 
heat  production  per  kilo  and  hour  of  the  former  is  1.88;  that  of  the  latter 


G36 


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1 

l^OEMAL  PROCESSES  OF  ETsTEEGY  METABOLISM    637 

1.83  calories.  On  the  basis  of  the  Meeb  formula  tbe  basal  metabolism  of 
the  boys  per  square  meter  of  surface  is  23.5  calories  and  that  of  the  girls 
23.2.  On  the  basis  of  the  DuBois  fonniila  the  metabolism  is  30.5  and  31.0 
calories  per  square  meter  per  hour  respectively.  The  mean  deviation  from 
the  average  is  again  less  for  the  Meeli  formula. 

In  the  statistical  analysis  of  the  basal  metabolism  of  the  entire  Bos- 
ton series,  Harris  and  Benedict  carried  the  comparison  somewhat  further. 
They  predicted  the  metabolism  of  girl  infants  from  constants  based  on 
the  boys,  and  determined  the  sign  and  magnitude  of  the  difference  be- 
tween observed  and  calculated  values.  Equations  employed  were  those  show- 
ing regression  of  basal  metabolism  on  stature  (body  length),  on  weight, 
and  on  body  surface  in  the  male  infants.  Subdividing  the  entire  senea 
of  female  infants  into  stature  groups,  it  was  found  that  out  of  six  groups 
three  showed  a  higher  metabolism  and  three  a  low^er  metabolism  than 
that  predicted  on  the  assumption  that  all  were  boys  of  like  height.  Clas- 
sifying for  surface  area,  out  of  seven  groups  four  showed  a  higher  metab- 
olism and  three  a  lower  than  predicted  on  the  assumption  that  they  were 
boys  with  the  surface  area  of  the  girls.  The  comparison  for  body  weight 
turned  out  the  same."  The  authors  conclude:  "As  far  as  our  data  go,. they 
indicate  that  on  the  average  there  is  no  sensible  difference  between  the 
heat  production  of  the  two  sexes  in  the  first  week  of  life." 
.  5.  Influence  of  Crying. — -Since  the  newborn  child  is  scarcely  able  to 
influence  metabolism  by  any  other  form  of  muscular  effort  than  crying, 
the  activity  factor  may  be  discussed  under  this  heading.  Bailey  and  Mur- 
lin  cited  among  their  results  the  case  of  a  child  ten  days  of  age  who  pro- 
duced 8.14  calories  per  hour  while  sleeping  quietly  throughout  the  period 
of  observation.  The  next  day,  while  crying  "most  of  the  time,"  i.  e.,  one 
hour,  she  produced  10.73  calories,  an  increase  of  31  per  cent,  Ilowland 
with  Lusk's  calorimeter  observed  an  increase  of  39  per  cent  in  an  infant 
7  months  of  age  for  a  one-hour  period  of  "struggling  and  crying."  Bene- 
dict and  Talbot  have  contrasted  in  one  of  their  tables  minimal  with  maxi- 
mal periods  of  activity  (including  crying)  for  93  infants,  and  deduce  an 
average  difference  of  65  per  cent,  the  individual  differences  ranging  from 
4  to  211  per  cent!  Unfortunately  65  out  of  the  93  maximal  penods  are 
"calculated  from  the  carbon  dioxid  produced  during  a  preliminary  period 
for  which  the  respiratory  quotient  was  not  determined."  Since  even  those 
periods  for  which  oxygen  as  well  as  carbon  dioxid  was  determined  often- 
times gave  "defective  respiratory  quotients  due  to  excessive  carbon  dioxid 
excretion  .  .  .  or  to  a  defect  in  the  measurement  of  the  oxygen,  particu- 
larly the  residual  oxygen,"  it  is  impossible  to  compare  Benedict  and  Tal- 
bot's results  with  those  of  Howland  or  Bailey  and  Murlin  whose  "crying" 
periods  like  their  basal  periods,  were  controlled  by  residual  analyses. 
From  a  practical  point  of  view,  however,  namely  the  effect  of  crying  upon 
the  energy  requirement  of  the  newborn,  the  several  authors  are  in  sub- 


638  JOHN  R  MUELIN 

stantial  agreeirient.  Por  an  infant  who  cries  no  more  than  the  average  nor- 
mal infant  probably  30  per  cent  increase  above  the  basal  would  more  than 
cover  the  energy  recpiirement  for  maintenance;  while  for  an  infant  who 
cries  "most  of  the  time*'  (admitting  considerable  latitude  in  the  use  of 
the  expression),  probably  40  per  cent  above  the  basal  would  be  more  than 
adequate;  for  it  is  certain  that  no  newborn  infant  can  continue  to  cry  at  a 
rate  sufficient  to  increase  the  metabolism  40  per  cent  for  more  than  a 
few  hours  out  of  the  twenty-four. 

6.  Influence  of  Food  and  External  Temperature. — Very  few  observa- 
tions have  been  made  indicating  that  the  food  of  the  newborn  has  any 
dynamic  effect.  Hasselbalch(a)  reports  two  observations  on  premature  in- 
fants in  which  he  surmises  that  the  increase  of  some  15  per  cent  in 
metabolism  the  second  period  is  due  to  the  "work  of  digestion."  "At 
any  rate/'  he  asserts,  "it  was  impossible  to  recognize  a  difference  in  the 
muscular  activity  of  the  infant."  Since  the  first  effect  of  hunger  is  to 
induce  muscular  activity  in  the  form  of  crying,  it  is  very  difficult  to  secure 
complete  muscular  repose  on  empty  stomach  so  as  to  have  a  basis  of  com- 
parison with  periods  following  the  ingestion  of  food.  In  Ilasselbalch's 
comparison  just  cited  both  periods  follow  the  feeding  and  the  more 
active  work  of  digestion  in  the  second  period  is  inferred  from  the 
higher  respiratory  quotient.  Coupled  with  the  difficulty  just  mentioned 
is  the  natural  reluctance  of  the  physician  to  give  the  newborn  a  large 
feeding.  In  fact,  it  is  quite  possible  that  the  stomach  of  the  child  at 
this  time  cannot  contain  enough  food  at  a  single  filling  to  raise  the  metab- 
olism sensibly. 

We  are  equally  without  convincing  evidence  that  external  temperature 
acting  independently  can  influence  metabolism  in  the  newborn.  Scherer 
reported  a  difference  of  23  per  cent  in  oxygen  absorption  by  the  infant 
between  what  he  called  summer  temperature  (16  to  26.8°  C.)  and  winter 
temperature  (9.5  to  16.2°  C).  But  there  was  no  control  of  muscular  ac- 
tivity, or  even  notes  regarding  crying.  Hasselbalch  conducted  his  ex- 
periments at  an  average  temperature  of  about  33°  C. ;  Bailey  and  Murlin 
maintained  a  temperature  of  27°  to  29°  C. ;  while  Benedict  and  Talbot 
kept  their  chamber  air  at  approximately  20°  C.  Hasselbalch  is  deeply  im- 
pressed with  the  fact  that  his  newborn  infants  (most  of  them  only  a  few 
hours  from  birth)  produced  only  270  c.c.  of  carbon  dioxid  per  kilogram  and 
hour  and  that  "this  is  not  essentially  higher  than  the  corresponding  figure 
for  a  grow^n  individual  in  absolute  repose."  From  the  connection  in  which 
the  author  alludes  to  this  comparison  one  might  infer  that  the  low  metab- 
olism which  he  mentions  was  due  to  the  absence  of  all  "chemical  regula- 
tion" since  the  temperature  w^as  "so  regulated  that  the  question  of  the 
feeble  heat  regiilation  of  the  infant  is  eliminated  as  far  as  possible."  Ee- 
sults  even  louver  than  this,  however,  may  be  seen  in  several  instances 
amongst  the  data  reported  in  the  more  recent  publications,  notwithstand- 


FORMAL  PROCESSES  OF  E:^rERGY  METABOLISM     639 

ing  the  lower  temperatures  employed.  A  careful  scrutiny  of  the  several 
tables  has  failed  to  reveal  any  relationship  between  external  temperature 
and  the  metabolism  recorded.  Doubtless  the  infants  in  the  several  series 
of  observations  were  wrapped  in  difi'crent  quantities  of  clothing  and  bed- 
ding necessary  to  maintain  an  environmental  temperature  high  enough 
to  induce  quiet  sleep  which  was  always  the  aim.  Since  the  notes  with 
reference  to  this  precaution  are  not  very  complete,  it  will  be  necessary 
to  give  special  attention  to  clothing  before  any  final  judgment  as  to  the 
influence  of  external  temperature  can  bo  rendered. 

In  conclusion  of  this  discussion  of  the  factors  which  may  influence 
heat  production  in  the  newborn,  emphasis  should  be  placed  once  more  upon 
the  fact  attested  by  several  observers  that  crying  is  the  only  normal  form 
of  activity  which  can  materially  raise  the  metabolism  above  the  basal  level. 
In  the  words  of  our  Danish  colleague,  "as  regards  the  amount  of  the 
metabolism,  ...  it  seems  impossible  for  me  to  conclude  anything  else 
from  the  tables  than  that  the  activity  of  the  infant  is  the  chief  determining 
factor."  Hasselbalch  goes  on  to  say  that  even  the  influence  of  age  has  not 
been  demonstrated  (in  the  newborn).  While  sanction  cannot  be  given 
to  this  statement  since  the  publication  of  Benedict  and  Talbot's  results 
(see  page  635),  emphatic  assent  can  be  given  to  his  estimate  of  the  mus- 
cular factor.  The  newborn  does  not  shiver.  He  responds,  however,  to  a 
drop  in  external  temperature,  as  he  does  to  hunger,  very  promptly,  by  cry- 
ing, and  since  this  form  of  exercise  is  almost  his  only  resort,  it  serves  at 
once  the  double  purpose  of  restoring  the  heat  production  to  an  equality 
with  heat  loss  and  of  calling  the  attention  of  his  nurse  to  his  unhappy 
plight.  The  importance  of  conserving  the  energy  resources  of  the  new- 
bom  infant  by  keeping  him  wann,  especially  before  his  natural  food  is 
forthcoming,  is  obvious. 

7.  Total  Energy  Requirement  of  the  Newborn. — Thus  far  we  have 
considered  the  basal  metabolism — i.  e.,  the  metabolism  of  the  sleeping 
infant — and  have  learned  that  body  weight  is  nearly,  if  not  quite,  as 
good  a  measure  as  body  surface,  and  that  length  of  body  (stature)  com^ 
bined  w^ith  surface  (or  weight)  gives  possibly  the  best  measure  now  avail- 
able. The  newborn  up  to  one  week  of  age  requires  for  maintenance  while 
asleep  1.87  calories  per  kilogram  and  hoiir  or  about  25  calories  p^r 
square  meter  of  body  surface  (]\rech).  On  the  24  hour  basis  this  becomes 
45  calories  per  kilogram  or  600  calories  per  square  meter  of  body  surface. 
The  formula  of  Benedict  and  Talbot(6)(L  X  12.65  X  10.3  (/(w)^),  i.  e., 
length  in  centimeters  times  a  constant  times  the  body  surface,  as  given  by 
Lissauer's  formula,  is  a  slightly  closer  approximation  to  the  average  needs. 
There  is  a  noi*mal  variation  from  this  standard  of  6  per  cent,  due  to  fac- 
tors (possibly  endocrine  index)  not  yet  understood. 

For  the  time  during  which  the  infant  is  awake  and  crying,  the  require- 
ment, as  nearly  as  it  can  l>e  estimated  to-day,  is  from  30  to  40  per  cent 


640  JOHN  K.  MUKLIN 

liigher.  Since,  however,  the  period  of  crying  continues  for  the  normal 
newborn  rarely  more  than  a  few  hours  at  most,  the  additional  allowance 
of  food  energy  should  not  be  computed  on  a  24-hour  basis,  but  an  attempt 
should  be  made  to  estimate  the  total  period  of  crying. 

The  energy  allowance  for  growth  cannot  yet  be  estimated  with  any 
accuracy.  In  general  it  may  be  stated  only  that  any  energy  left  over 
after  the  basal  and  activity  metabolism  are  provided  for  will  be  available 
for  growth,  since,  so  far  as  we  can  see  at  present,  no  allowance  is  necessary 
for  dynamic  action  or  for  fluctuations  of  external  temperature. 

It  would  appear  from  the  foregoing  that  an  energ}-  supply  of  2.5  cal- 
ories per  kilogi-am  per  hour  or  60  calories  per  kilogram  and  24  hours, 
will  amply  cover  the  maintenance  requirement  of  newborn  infants  who 
are  not  more  than  normally  active.  Any  intake  beyond  this  amount  may, 
it  is  presumed,  be  counted  upon  to  furnish  materials  for  growth.  Further 
study  of  the  "growth  quota^*  in  infants  of  this  age,  however,  is  very  much 
needed. 


G.    Energy  Metabolism  from  Two  Weeks 
to  One  Year  of  Age 

The  energy  metabolism  of  infants  over  two  weeks  of  age  has  been 
much  more  extensively  studied.  Beginning  with  the  fragmentary  ob- 
servations of  Forster  in  1877  down  to  and  including  1920,  not  less  than 
a  score  of  important  researches  have  been  published  on  the  normal  child. 
(Birk  and  Edelstein,  Howland(5),  Buhner  and  Heubner(a,  h,  c,), 
Schlossmann  and  Murschauser  {a,h,c,d)y  Bahrdt  and  Edelstein,  Frank 
and  Wolff,  Murlin  and  Hoobler,  Niemann (a^  c),  Bonniot,  Saint- Albin, 
Variot  and  Lavialle,  Hoobler(&)).  These  fall  into  two  groups  according 
to  the  method  of  observation  adopted.  The  earlier  researches  by  the  in- 
direct method  were  made  for  the  most  part  upon  a  few  individuals,  but 
these  were  studied  very  exhaustively  with  a  view  to  account  for  all  of  the 
food  ingested.  The  later  researches  by  the  indirect  method  and  all  the  ob- 
servations upon  normal  infants  by  the  direct  method  have  sought  rather  to 
establish  standards  of  metabolism  with  which  abnormal  or  i>athological 
cases  could  be  compared.  Consequently  a  considerable  number  of  sub- 
jects have  usually  been  employed.  Several  of  the  investigators  have  se- 
lected from  their  own  cases  those  whom  they  consider  normal.  In  the 
case  of  some  others  it  has  been  necessary  to  select  from  the  published  tables 
whom  the  authors  describe  as  of  normal  weight  for  age. 

1.  Respiratory  Quotient. — Very  little  need  be  added  to  what  was  said 
under  this  heading  for  the  newborn.  Carbohydrate  is  the  food  which  in- 
fluences the  quotient  most.  Soon  after  a  feeding  of  milk,  whether  breast 
or  cow's  milk,  the  quotient  will  be  found  higher  than  just  before,  provided 


:t;rOKMAL  PEOCESSES  of  EISTERGY  metabolism    641 

the  feedings  are; two  hours  or  more  apart,  and  if  easily  assimilable  sugars 
are  added  to  the  milk  the  quotient  \viU  he  even  higher.  For  example,  an 
infant  four  months  of  age  was  given  a  dextri  maltose  formula  and  the 
respiration  cxperiuients  were  begun  on  different  days  at  successively  longer 
intervals  from  feeding  with  the  following  results: 

Time  After  Feeding  It,  Q. 

18  minutes 0.79 

33         "  0.82 

1  hour  30  minutes  1.00 

From  this  point  the  quotient  usually  falls  progressively  (see  page 
G'U).  Benedict  and  Talbot's  (a,  b)  data  show  many  cases  like  the  fol- 
lowing : 


Case 

Time  After  Feeding 

R.Q. 

F.  B 

6  to     7V»  hours 
.           20  to  22 

25  to  27          " 

6  to     8 

18V>  to  21      " 
24  to  2QV2      " 

0  80 

R.  E 

0.78 
0.73 

0.82 
0.74 
0.72 

Schlossmann  and  Murschauser(d^),  however,  often  found  quotients  as  high 
as  0.84  and  0.85  as  much  as  18  to  20  hours  after  last  food.  I*^o  details  re- 
garding the  composition  of  the  food  taken  at  the  last  feeding  are  given. 

The  fact  that  the  respiratory  quotient  is  higher  soon  after  a  meal 
(and  progressively  falls  from  a  point  which  may  be  placed  at  1  to  2 ^^ 
hours  thereafter  depending  on  the  fonnula)  does  not  denote  accelerated  heat 
production,  for  it  will  be  remembered  that  carbon  dioxid  has  a  lower  heat 
value  when  the  quotient  is  high  than  when  it  is  low  (see  page  567), 

Another  reason  why  an  ordinary  feeding  of  milk  does  not  raise  the 
heat  production  in  an  infant  is  the  interesting  fact  first  recognized  by 
Buhner  that  protein  retained  for  growth  does  not  raise  the  heat  produc- 
tion. In  truth  one  can  say  that  any  foodstuff  retained  for  growth  does 
not  raise  the  heat  production.  It  is  only  when  a  surplussage  of  digestive 
products  enter  the  circulation  that  oxidation  of  them  is  accelerated  by 
adding  more  fuel  to  the  fire  or  by  stimulating  the  intracellular  processes. 
In  the  infant  or  any  other  stage  of  active  gi'owth  (pregnancy  or  convales- 
cence) the  materials  entering  the  circulation  are  retained  with  greater 
avidity  by  the  cells  and  therefore  are  not  exposed  to  the  destructive  oxida- 
tions to  the  same  extent  as  in  the  normal  adult.  IIoobler(&)  has  made 
this  point  as  regards  protein  an  object  of  special  study  in  an  infant,  with 
the  following  results : 


Protein  In- 
gested, Gms. 

Protein  De- 
stroyed, Gms. 

Protein  Added 
to  Body,  Gms. 

Calories  of 
Metabolism 

Period  I     

33.1 
43.3 

18.0 
18.0 

15.1 
24.4 

363 

Period  TI    

363 

642  JOHN  K.  MUKLIiT 

2.  Basal  Metabolism. — Three  different  observers  have  attempted  to 
secure  the  jnetabolism  of  the  infant  while  fasting.  Rubner  and  Ileubner 
'Compared  the  metabolism  of  a  breast-fed  infant  51/2  months  old  and 
weighing  nearly  ten  kilos  while  on  a  full  diet  four  days  with  his  metabol- 
ism on  the  fifth  day  when  he  received  only  tea  instead  of  the  breast 
milk.  The  metabolism  on  the  day  of  star\^ation  was  even  higher  than  the 
average  of  four  days  on  food. 

Two  objections  may  be  urged  against  this  experiment ;  First,  that 
no  graphic  record  was  obtained  to  prove  that  the  infant  was  just  as  quiet  on 
the  starvation  as  on  the  food  days.  It  is  almost  unbelievable  that  such 
should  be  the  case.  The  second  objection  is  that  caifein  is  known  to  in- 
crease metabolism  and  there  is  every  reason  to  believe  that  the  closely 
related  thein  might  have  a  similar  effect  especially  upon  an  unhabituated 
infant.  Howland(6)  tried  an  experiment  in  fasting  in  much  the  same  way 
with  an  infant  three  months  of  age,  and  weighing  4.65  kgm.,  giving  tea 
and  saccharin  instead  of  I/2  ^i^^  ^^^  ^  P^r  cent  milk  sugar  which  had 
been  the  regular  food.  The  result  was  the  same :  namely,  that  the  metabo- 
lism was  not  quite  as  low  oven  when  the  child  was  known  to  be  asleep  as 
while  sleeping  after  a  feeding.  The  first  objection  urged  against  Rubner 
and  Iluebner's  experiment  would  not,  therefore,  seem  to  apply,  although  a 
graphic  record  giving  proof  that  sleep  while  fasting  was  just  as  peaceful 
as  after  feeding  would  be  required  to  make  the  matter  wholly  convincing. 
The  second  objection  has  not  been  removed.  Schlossmann  and  Mur- 
schauser(a)  kept  careful  and  continuous  notation  of  the  repose  of  their  in- 
fants, and  determined  the  metabolism  repeatedly  on  the  three  different 
female  infants  from  87  to  180  days  of  age  18  hours  after  last  food.  All 
received  tea  and  saccharin  w^iich  the  authors  used  habitually  to  soothe 
their  subjects  to  sleep.  The  average  minimal  metabolism  of  the  three 
was  12.22  gm.  COo  and  11.02  gm.  Og  i>er  square  meter  (^Aleeh)  of  body 
surface  per  hour,  or  859  calories  per  square  meter  and  24  hours. 

It  will  be  apparent  from  this  recital  that  the  whole  question  of  basal 
metabolism  is  complicated  on  the  one  hand  by  the  difficulty  of  securing 
perfect  repose  without  any  immediately  preceding  meal  and  on  the  other 
hand  by  the  question  of  age.  'None  of  the  researches  yet  reported  have 
fulfilled  in  a  wholly  convincing  manner  the  conditions  now  recognized  as 
necessary  to  secure  the  absolute  basal  metabolism  of  infants.  We  must 
be  content  for  the  present,  therefore,  to  speak  of  the  lowest  metabolism 
obtainable  under  the  various  circumstances  as  the  "minimal  metabolism." 
As  landmarks  of  progress  in  this  direction,  the  brief  table  on  page  G43  ma^' 
be  borne  in  mind. 

It  is  somewhat  hazardous  to  compare  the  results  of  different  authors 
obtained  on  different  subjects  by  methods  which  are  not  strictly  alike;  but 
the  results  suggest,  if  they  do  not  prove,  that  the  stage  of  digestion  as  well 
as  the  age  of  the  infant  is  a  factor  which  must  be  reckoned  with  in  at- 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM    643 

tempting  to  arrive  at  truly  basal  conditions.    The  environing  temperature 
was  different  in  the  groups  of  cases  cited,  but  the  fact  that  quiet  sleep  was 

TABLE  30 

Average  AIimmal  Metabolism  of  Normal  T>-faxts 

(All  sleeping  or  nearly  qniet) 


Authors 

Condition 

Cases 
Averaged 

Age,   Months 

Calories  per 
Sq.  M.(Meeh) 
md  24  Hours 

Schlossmann   and    Mur- 
8chauser(a)     

Fasting  18 
hrs. 

3    (S,  P,  L) 

3-6 

859 

Benedict  and  Talbot  (a)    .... 

Tost-' 
Absorptive  (?) 

6    (E.F.,  E.R., 
A.S.,  R.A., 
N.D.,  B.F.) 

2-3 

809 

iVIurlin  and  Hoobler   

y.y  to  3  hrs. 
aiter   feeding 

4   (A.S.,  W.I., 
E.H.,  E.N.) 

2-3 

843 

Benedict  and  Talbot  (a)    

Post- 
Absorptive 

2  (E.G.,  P.S.) 

10   and   12 

983 

Murlin  and  Hoobler 

U  to  5  hrs. 
after  feeding 

2(C.M.,W.S.) 

lOV.   ^nd  12 

1104 

•  No  details  given  by  authors  for  three  of  these  infants. 

induced  may  be  accepted  as  proof  tliat  the  clothing  was  properly  adapted 
to  the  temperature  of  the  chamber. 

We  pass  now  to  a  consideration  of  the  two  factors  just  mentioned: 
namely,  (1)  the  dynamic  action  of  food,  and  (2)  the  influence  of  ago  upon 
the  metabolism. 

3.  Dynamic  Action  of  Foods  in  Infants. — It  will  be  seen  later  that 
the  average  energy  metabolism  of  the  sleeping  infant  from  two  months 
to  one  year  of  age  is  about  2^/^  times  that  of  the  adult  on  the  basis  of 
weight.  This  means  that  the  alimentary  tract  of  the  infant  must  be  at 
least  two  and  one-half  times  as  active  as  that  of  the  adult  in  order  to 
supply  to  the  circulation  the  materials  necessary  for  combustion.  Added 
to  this  is  the  requirement  for  growth.  It  might  be  expected  a-  priori,  there- 
fore, that  the  proportionately  more  rapid  streaming  of  materials  into 
the  blood  (see  page  005)  would  sot  np  a  greater  dynamic  effect  in  the  in- 
fant than  in  the  adult.  The  evidence  to  date,  however,  is  that  the  reverse 
is  true. 

Rubner  and  Heubner(&)  were  of  the  opinion  that  they  had  demon- 
strated a  dynamic  effect  of  cow^s  milk  when  they  foimd  in  their  second 
study  a  higher  heat  production  in  an  artificially-fed.  -infant  of  7%  months 
than  in  their  first  breast-fed  infant  of  nine  weeks.  Using  the  latter  as  a 
basal  experiment,  they  calculated  that  a  diet  of  cow's  milk  containing  41 
per  cent  more  than  the  maintenance  requirement  of  energy  had  raised  the 
metabolism  in  the  fomier  9.7  per  cent.  The  difference  in  the  ages  of 
the  two  infants  together  with  the  absence  of  certainty  that  the  second 


644: 


JOHI^  K.  MURLIN 


infant  was  not  more  active  than  the  first  wholly  invalidates  their  con- 
clusions. 

The  dynamic  effect  of  protein  in  the  metabolism  of  an  infant  was  first 
proved  by  Rowland  (&).  Adding  4  grams  of  nutrose  (containing  14.25 
per  cent  nitrogen)  to  each  of  three  previous  feedings  increased  the  metab- 
olism of  his  fii-st  subject,  three  months  of  age,  10  per  cent.  Adding  00 
grams  to  the  food  of  his  second  child  of  7  months  raised  the  metabolism 

26  per  cent. 

TABLE  31 

DiNAific  Effect  of  Protein  (Ilowland) 


Date 

Weight 

Food 

Calories  per  Hour 

1911 
Feb.  23 

4.32 
4.32 

%  Cow's  Milk,  5%  Milk 

Sugar 
Same,  +  30  gm.  Nutrose 
Difference  

15.35  Sleeping  entire  time 
19.31          "            "            « 

Feb.  25 

3.96  Cal.  or  26% 

Murlin  and  Hoobler  saw  a  similar  effect  from  changing  to  a  richer  protein 
foi-mula  the  diet  of  an  atrophic  infant  three  months  of  age.  The 
nitrogen  in  the  urine  rose  in  response  to  the  greater  intake  of  protein 
and  the  heat  production  was  increased  more  than  two  calories  per  hour. 
The  child  slept  throughout,  but  made  more  frequent  readjustment  move- 
ments after  the  high  protein  feeding.  Hoobler(6)  followed  up  this  sub- 
ject independently  and  demonstrated  a  much  higher  metabolism  by  feed- 
ing progressively  higher  and  higher  protein  formulas.  The  following 
comparison  of  the  periods  on  low  and  on  high  protein  diets  summarizes 
his  results  on  a  single  subject. 

TABLE  32 
DyxAMic  Effect  of  Protein  (Hoobler) 


Nr>  of 

Food 

Degree  of 
Repose 

Dikitribution  of 
Calories 

Calories  Produced 

Increase 

Hrs. 

Per  Hr. 

Per  Sq.  M. 
24  Hrs. 

Per  Cent 

5 

10 

Low  Prot. 
High  Prot. 

Sleeping 
Sleeping 

P,  12.2%;  F, 
26.47o;   CII, 

61.4% 
P,  40.2%;  F, 
18.f%;   CH, 

41.1% 

10.78 
12.74 

893 
1120 

25.4 

■ 

The  highest  d^Tiamic  effect  of  milk  protein  ever  recorded  was  obtained 
on  this  child  on  the  twelfth  day  of  the  special  feedings  when  the  amount  of 
protein  (in  the  form  of  albumin-milk)  in  the  21  hours  food  was  43.3  grams 
compared  with  9.9  gTams  in  the  basal  diet.  The  dynamic  effect  in  ab- 
solute terms  was  lOS  calories  for  the  24  hours,  or  42.4  per  cent! 

The  dynamic  action  of  fat  seems  to  be  proved  by  the  following  obser- 
vations made  by  Xiemann(a)  on  a  normal,  though  at  the  time  underweight, 


NORMAL  PEOCESSES  OF  ENERGY  METABOLISM    645 


child  four  weeks  of  age.  In  one  period  of  four  days  when  the  food  con- 
tained 127  calories  from  protein,  105  from  fat,  and  168  from  carbohy- 
drate, or  400  calories  in  all,  the  average  daily  metabolism  was  52^1  cal- 
ories or  1337  calories  per  square  meter  of  body  surface  (Meeh).  In  the 
following  period  of  five  days  the  food  contained  145  calories  from  pro- 
tein, 368  from  fat  and  177  from  carbohydrate  or  629  calories  in  all.  The 
heat  production  averaged  569  calories  per  day  or  1443  calories  per  square 
meter.  An  increase  of  70  per  cent  in  the  energy  intake  (largely  fat)  in- 
creased the  metabolism  10  per  cent.  Niemann  observed  a  similar  effect  of 
increasing  the  fat  in 
the  food  of  an  atrophic 
infant  22  weeks  old. 
HeHeson(6)  deter- 
mined the  resting  me- 
tabolism of  a  normal 
infant  five  months  old 
and  found  that  w^hen 
a  part  of  the  carbo- 
hydrate of  the  diet 
^vas  replaced  by  an 
isodynamic  amount  of 
fat  the  heat  produc- 
tion was  increased  8.3 
per  cent.  Schloss- 
mann made  a  similar 
substitution  in  kind 
though  not  in  amount 
and  obsen^ed  an  in- 
crease in  the  metab- 
olism of  fifteen  per 
cent. 

The  writer  is  not 
aware  of  any  experi- 
ment   establishing    the    dynamic    action    of    carbohydrate    in    infants. 

The  evidence  of  dynamic  action  thus  far  applies  only  to  surplus  food. 
There  is  no  satisfactory  evidence  that  an  ordinary  feeding  given  at  the 
time  when  the  infant  is  naturally  ready  for  it  raises  the  metabolism  at 
all.  In  the  first  place  the  difficulty  of  securing  perfect  repose  when  the 
infant  is  hungry  has  thus  far  foiled  all  efforts  to  get  a  clean-cut  contrast 
before  and  after  an  ordinary  feeding.  Although  Schlossman  states  in  one 
place  that  the  effect  of  a  meal  may  be  discerned  as  long  as  18  hours  after- 
ward, yet  as  already  noted  (page  642)  neither  Schlossman  and  Mur- 
schauser  nor  Rubner  and  Heubncr  nor  Howland  were  able  to  demonstrate 
a  low^er  metabolism  in  fasting.     Benedict  and  Talbot  likewise  assert  that 


2     3     4 

Metabolism    During 
(Talbot). 


9     10    II    12 

Year    of    Life 


646 


JOHN*  R.  MURLIN 


in  some  instances  the  heat  production  (based  on  carbon  dioxid)  in  their 
subjects  twenty-one  hours  after  food  was  slightly  "greater  even  in  periods 
of  conipletQ  muscular  repose"  than  immediately  after  food. 

4.  Influence  of  Age  on  Basal  Metabolism. — Basal  metabolism  is  the 
term  used  to  describe  the  fundamental  requirements  of  the  body  for  energy 
when  it  is  resting,  fasting,  and  kept  comfortably  warm.  It  is  the  lowest 
normal  metabolism.  With  the  infant  this  lowest  metabolism  will  always 
occur  during  sleep  and  at  that  distance  from  feeding  time  just  preceding 
the  point  w^here  hunger  becomes  so  acute  as  to  induce  crying  or  some  other 
form  of  activity. 

In  connection  with  the  dynamic  action  of  food  we  have  chosen  to 
speak  of  the  lowest  metabolism  yet  attained  as  the  minimal  rather  than  tho 
basal  metabolism ;  for  we  have  yet  to  learn  of  the  details  of  this  subject. 
However,  the  minimal  metabolism  ordinarily  seen  in  the  infant,  i.  e.,  the 
sleeping  metabolism  of  the  recently  fed  infant,  cannot  be  much  greater  than 
the  basal  metabolism  if  food  really  exercises  so  small  an  influence  on  total 
heat  production  as  it  seems  to.  We  shall  not  go  far  wrong  then  in  speak- 
ing of  the  minimal  metabolism  observed  in  infants  of  different  ages  as 
the  true  basal. 

Benedict  and  Talbot  first  demonstrated  the  influence  of  age  on  the 
basal  metabolism  per  unit  of  area,  although  not  recognizing  the  fact,  in 
the  following  table; 


TABLE  33 

Heat-Pboduction  per  Square  Meter  of  Body-Surface  (Meeh  Formula)  for  Normal 

Infants 


Bodv- 

Fleat  per  Sq. 

Subject 

Weight 

Without 

Clothing, 

Kg. 

Height, 
Cm. 

Age 

Experi- 
mental Days 

Periods 

Meter  of 

Bodv-Sur- 

face   (Meeh) 

Cals. 

M.  D 

3.99 

17     days 

2 

4 

656 

L.   L 

5.13 

57 

2y.i  mos. 

10 

13 

759 

B.  D 

4.90 

58 

2      mos. 

2 

4 

B02 

M.  C 

6.17 

63 

4      mos. 

3 

7 

837 

L.  R.  B.  ... 

5.99 

64 

4      mos. 

4 

11 

844 

E.  G 

9.37 

74 

10     mos. 

3 

5 

907 

R.  L 

7.58 

71 

8^/^  mos. 

5 

8 

991 

P.  W 

7.11 

64 

7      mos. 

2 

5 

998 

The  next  year  !Murlin  and  Hoobler  brought  together  their  own  data 
from  normal  infants  and  those  of  Benedict  and  Talbot  published  in  their 
second  paper  and  conclusively  showed  that  both  on  the  basis  of  surface 
area  and  weight  the  metabolism  of  infants  above  six  months  of  age  is  sig- 
nificantly higher  than  that  of  infants  four  months  and  less.  The  results 
are  condensed  in  the  followinc:  table : 


NORMxVL  PROCESSES  OF  ENERGY  METABOLISM    647 


TABLE  34 
Basal  Heat  Productiox  from  Two  ^foNTiis  to  0>e  Year  of  Age 


Months    

Cal.  per  Sq.  M.  and  Ilr.   (Meeh 
Cal.   per   K«,'ni.   per    Hr 


2 

34.7 
2.43 


3 

33.2 
2.29 


4 

3H.0 

2.4 


6 
40.2 
2.5G 


7 
41.G 
2.57 


9 
41.7 
2.36 


1011 
41.8 
2.34 


12 
46.4 
2.61 


H.    Energy  Metabolism  of  Children 
up  to  Puberty 

Logically,  as  we  now  see  very  clearly,  everything  starts  from  the  mini- 
mal or  mere  maintenance  requirement,  although  historically  the  order 
has  been  quite  different.  The  latest  and  in  many  respects  the  most  com- 
plete researches  have  been  made  upon  the  basal  metabolism.  It  is  proper, 
however,  to  see  how  much  had  been  learned  regarding  the  basal  needs 
from  earlier  investigations. 

The  Zuntz  school  headed  by  the  late  IN".  Zuntz  of  Berlin  had  long 
emphasized  the  necessity  of  eliminating  the  influence  of  muscular  activity 
and  of  food  if  results  upon  subjects  of  different  size  or  age  were  to  be  com- 
pared. ^Magnus-Levy  and  Falk,  followers  of  Zuntz,  employing  the  Well- 
known  method  of  Zuntz  and  Geppeii;  with  which  important  results  had  been 
obtained  on  the  influence  of  muscular  work  in  mountain  climbing,  in 
marching,  and  in  the  treadmill,  on  the  influence  of  altitude  and  on  the 
influence  of  digestion,  undertook  in  1899  an  investigation  on  the  influ- 
ence of  age  on  the  basal  metabolism.  The  subjects  ranged  from  2^^ 
years  to  old  age,  including  eleven  boys  and  nine  girls  under  fourteen 
years  of  age.  At  the  time  of  observation  the  subjects  were  all  in  the 
nilchtern  condition,  which  is  Zuntz's  term  for  the  absence  of  digestion,  i.  e., 
at  least  twelve  hours  since  taking  food,  or,  what  has  been  called  by  others, 
the  "post-absorptive  state."  The  subject  lay  upon  a  couch  and  suppressed 
all  muscular  contractions.  The  Zuntz  method  as  described  on  page  539 
permits  of  the  determination  of  oxygen  absorbed  as  well  as  of  CO2  elimi- 
nated. 

The  results  upon  the  group  of  children  mentioned  above  are  presented 
in  Table  35.  Tlie  respiratory  quotient  characteristic  of  the  lulchtern 
condition  in  children  is  well  illustrated  in  this  table.  The  average  is 
0.82  for  boys  and  0.84  for  girls.  With  adults  the  quotient  is  quite 
commonly  several  points  higher  for  the  reason  that  adults  do  not  consume 
their  store  of  glycogen  quite  so  rapidly.  This  is  in  accord  with  the  well 
known  fact  that  fasting  is  much  more  exhausting  for  children  than  for 
adults.  The  capacity  to  handle  carbohydrates  in  the  diet  is  the  basis 
of  the  craving  for  sweets  among  children.  The  arrangement  in  Table 
35,  following  that  of  the  authors  themselves,  is  acconling  to  weight  rather 
than  age.     It  is  apparent  at  once  that  the  metabolism  in  both  sex  groups 


648 


JOHF  E.  MURLIlsr 


TABLE  35 
The  Gaseouh  Exchange  of  Childrex  •   ( ^lagnus-Levy  and  Falk) 


Age, 
Yrs. 


Weight, 
Kgm. 


Height, 
Cm. 


O,  Consumed 


Per  Kgm. 

and  Hr., 

c.c. 


Per  Sq.  M. 

and  Hr. 
(Meeh)  liters 


R.  Q. 


Cal.  per  Sq. 
M.  and  Hr. 


BOYS 


2V2 

11.5 

? 

•585 

10.74 

0.83 

51.9 

6 

14.5 

110.0 

552 

10.92 

0.80 

52.4 

6 

18.4 

110.0 

457 

9.78 

0.80 

46.9 

7 

19.2 

112.0 

476 

10.32 

0.85 

50.2 

7 

20.8 

110.0 

478 

10.68 

0.83 

51.6 

9 

21.8 

115.0 

407 

9.24 

0.85 

44.9 

11 

26.5 

129.0 

374 

8.22 

0.80 

39.4 

10 

30.6     . 

131.0 

377 

8.52 

0.84 

41.3 

14 

36.1 

142.0 

313 

8.40 

0.84 

40.7 

14 

36.8 

141.5 

301 

8.10 

0.84 

39.3 

14 

43.0 

149.0 

308 

8.76 

0.81 

42.1 

GIRLS 


7 

15.3 

107.0 

490 

9.90 

0.81 

47.6 

6V2 

18.2 

? 

445 

9.48 

0.81 

45.6 

12 

24.0 

129.0 

338 

7.92 

0.92 

39.2 

12 

25.2 

128.0 

322 

7.68 

0.84 

37.2 

13 

31.0 

138.0 

332 

8.46 

0.89 

41.6 

14 

35.5 

143.0 

317 

8.46 

0.82 

40.8 

12 

40.2 

? 

295 

8.22 

0.78 

39.2 

U 

42.0 

149.0 

301 

8.52 

0.81 

41.0 

*  This  table  is  reconstructed  in  part  from  a  table  given  by  Tigerstedt  in  Nagel's 
"Handbuch  der  Physiologie,"  1909,  I,  p.  475,  and  in  part  from  a  table  in  Magnus-Levy's 
"Physiology  of  Metabolism,"  Van  Noorden's  Handbuch,  English  ed..  Vol.  I,  p.  268. 

decreases  as  age  and  weight  increase,  whether  it  is  estimated  on  the 
basis  of  a  unit  of  weight  or  a  unit  of  surface.  Comparing  the  basal 
metabolism  of  a  boy  and  a  girl,  on  the  basis  of  the  oxygen  absorption, 
with  adults  of  middle  age,  and  of  old  age  having  approximately  the  same 
body  weight  the  following  result  was  obtained. 


TABLE  36 

Gaseous  Exchaxgk  at  Different  Ages   (Magnus-Levy  and  Falk) 


Age 

Weight, 
Kg. 

Height, 
Cm. 

Absolute 

Amount 

oiO, 

Per  Kg. 

Relative  Amount  of 

0. 

per  Kilo. 

0,  per 
Sq.  M.  Sur- 
face 

Girl   

13 
49 
75 

15 
24 
71 

31.0 

31.6 

30.3   circ 

43.7 
43.2 
47.8 

138 
134 

1   140(?) 

152 

148 
164 

171.7 
156.6 

128.6 

216.6 
1S5.8 
163.2 

5.54 
4.96 

4.25 

4.97 
4.53 
3.42 

112 

100 

86 

110 

100 

75 

111 

Woman   

Old  Woman  . . 

Boy   

100 
84 

100 

Man    

Old  Man 

100 
78 

ISrORMAL  PROCESSES  OF  ENERGY  HETABOUSM    649 


CbIs. 


Na145(F)- 


They  conclude  that  children  produce  more  heat  not  merely  for  the 
reason  that  their  superficial  area  is  gi-eater  in  relation  to  tJieir  weight 
hut  more  also  on  account  of  the  increased  vital  energj'  characteristic  of 
youth. 

Sonden  and  Tiger stcdt  in  the  course  of  an  extensive  investigation  on 
the  metabolism  of  children  sitting  quietly  as  in  school,  which  will  he  pre* 
sented  later,  obtained  results  on  two  boys  11.2  and  12  years  of  age  re- 
spectively while  sleeping.  They  found  the  COg  elimination  on  the  basis  of 
surface  area  (Meeh)  52 
per  cent  higher  than  that 
of  adults  in  sleep.  While 
the  conditions  of  these 
experiments  did  not  ex- 
clude the  influence  of 
food  altogether,  they  ap- 
proached the  ti*ue  basal 
conditions  very  closely 
and  furnished  early  evi- 
dence of  a  variation  di- 
rectly caused  by  a  differ- 
ence in  age.  The  con- 
clusion of  these  authors 
agrees  with  that  of  Mag- 
nus-Levy and  Falk  that 
the  youthful  body  in  and 
of  itself  independently  of 
its  smaller  size  possesses 
a  more  active  metab- 
olism. 

1.  Basal  Metabolism 
of  Children  up  to  Pu- 
berty.— Among  the  sub- 
jects studied  at  intervals 
over  a  long  period  of  time 
by  Benedict  and  Talbot (c)  was  a  girl,  designated  in  their  series  as  Xo. 
145,  whose  record  extends  from  the  age  of  ^\e  months  to  the  age  of  tbree 
years  and  five  months.  In  all  she  was  placed  in  the  respiration  chamber 
on  thirty-one  different  days  and  the  observational  periods  of  approximately 
30  minutes  each  numbered  4  to  5  daily.  The  minimal  metabolism  is 
given  for  25  different  days  and  the  accompanying  chart  represents  19 
distinct  points  in  the  course  of  the  three  years  (Fig.  38). 

The  most  rapid  growth  (as  would  be  expected)  is  seen  in  the  first  half 
of  the  time,  namely  from  the  5th  to  the  21st  month.  During  this  time  the 
basal  metabolism,  calculated  to  24  hours  (called  "total  calories''  in  thQ 


Fig.  38.  Body-weight,  pulse-rate  and  basal  metab- 
olism per  24  hours  of  a  girl  from  5  months  to  41 
months  of  age    (Benedict  and  Talbot). 


650 


JOHX  K.  MURLIX 


chart)  rises  nearly  parallel  with  the  growth  in  weight,  after  which  the 
metabolism  rises  less  rapidly  than  the  weight.  It  is  evident  from  tlie  cun^e 
representing  metabolism  per  imit  of  weight,  however,  that  the  parallelism 
is  only  apparent  and  arises  from  the  fact  that  metabolism  and  weight  arc 
plotted  to  ordinates  which  are  not  strictly  proportional;  for  the  metab- 
olism per  kilogram  falls  from  the  beginning  instead  of  running  hori- 
zontally. The  level  at  five  months  is  60  calories  per  kilogram  and  at  24 
months  it  has  dropped  to  38  calories.  From  this  point  onward  the 
cun-e  is  horizontal  indicating  that  the  progress  in  growth  is  equal  to  the 
progress  in  basal  heat  production.    Charted  on  the  basis  of  a  unit  of  body 


C«tlL 

TOTAL  CALORIES  REFERWEO  TO  WEIGHT. 

BOYS. 

1400 

^ 

ia^J- 

1300 

^ 

1200 

. 

-^ 

1100 

. 

^ 

• 

1000 

X 

; 

000 

-^ 

^, 

800 

y 

k^' 

700 

^ 

X' 

«00 

V 

y- 

500 

■■/ 

/. 

400 

•r 

/:■ 

' 

300 

V 

/'•' 

200 

-  1 

/ 

100 

/ 

0 

it^9v< 

c 

e 

'     « 

>    u 

\  \ 

\       K 

>      » 

»      2 

3    i 

2     2 

4    i 

e    2 

8     a 

0     3 

2     3 

1      3 

&    3 

J      4 

3     4 

Fig.  30.     Basal  heat  production  of  boys  from  birth  to  puberty.     Total  calories  per  24 
hours  referred   to   weight    (Benedict   and   Talbot). 

surface  (DuBois'  linear  formula)  the  general  trend  again  is  downward — 
from  1086  calories  at  5  months  to  841  at  24  months  from  which  time  it 
rises  to  nearly  900  calories  per  square  meter  at  41  months.  Figure  39 
gives  the  progress  of  the  basal  metabolism  in  relation  to  weight  for  boys  and 
Fig.  40  the  same  for  girls  for  the  entire  series  of  children  studied.  The 
continuous  line  represents  the  average;  dots  individual  cases.  In  the 
first  of  these  charts  it  may  be  seen  that  the  basal  metabolism  in  boys  as 
determined  by  the  most  recent  obsen-ations  runs  from  a  little  less  than  100 
calories  daily  at  2  kilos  body  weight  to  1325  calories  at  42  kilos  or 
from  about  45  to  about  31  calories  per  kilogram.  With  girls  the  curve 
starts  at  a  slightly  lower  level  at  2  kilos  and  rises  to  1100  calories 
daily  at  32  kilos,  or  from  about  40  to  about  34  calories  per  kilo- 
gram. The  values  obtained  by  Benedict  and  Talbot  arc  lower  than 
those  obtained  by  any  previous  observers  except  01  in.    Curves  of  the  same 


Can. 
1500 

1400 

TOTAL  CALORIES  REFERRED  TO  WEIGHT. 

CIRL& 

nno 

, 

, 

1200 

."- 

HOC 

_..'• 

.-•'*'' 

1000 

' 

• 

900 

' 

^ 

^ 

• 

800 

>" 

<^ 

700 

. 

> 

^ 

600 

• 

.V 

.•MX) 

/f\ 

• 

400 

y 

/• 

' 

rMX) 

V 

/: 

200 

: 

<^- 

100 

/ 

0 

i 

< 

ikfl.. 

4    e 

€ 

\       K 

>      U 

I      V 

\    1 

)     u 

)      2 

9     2 

2    i 

4      26      28     30     3i»     34     36     38    40 

Fig.  40.     Basal  heat  protliiction  of  girls  from  birth  to  puberty.    Total  calories  per  24 
hours  referred  to  body  weight    (Benedict  and*  Talbot). 


1700 
leuO 

TOTAL  CALORIES  REFERRED 

TO  SURFACE. 

1 

30YS 

e 

1500 

9 

1400 

• 

'o 

o 

* 

0 

1300 

• 

• 

/ 

',/"  • 

1200 

\/ 

/^  ' 

1100 

: 

/ 

• 

1000 

k 

900 

^ 

/' 

. 

bOO 

y 

/: 

700 

•• 

/ 

/ 

f)00 

y 

^ 

600 

.'■/ 

Y.- 

400 

V 

Vi 

t 

300 

A 

' 

o-DL 

B0« 

BOIS 

(i9te 

(19U 

) 

200 

7 

r 

o-OL 

» 

100 

/ 

0 

.2 

Kj.rn... 

i        4 

.! 

>      .€ 

7 

.8 

9 

1.( 

)  1. 

t      1.2 

I     1. 

J      1. 

4      1. 

}  te 

Fig.  41.     Basal  heat  production  of  boys  from  birth  to  puberty.    Total  calories  per  24 
hours  referred  to  surface  area  (Benedict  and  Talbot). 

651  "^ 


652 


joh:^  r.  murlin 


general  character  are  obtained  when  the  total  basal  heat  production  cal- 
culated to  24  hours  is  referred  to  the  body  surface  (Figs.  41  and  42). 
The  surface  area  in  these  observations  was  calculated  from  numerous  ac- 
tual measurements  according  to  DiiBois  linear  fommla,  and  a  revision 
of  the  formula  of  Lissauer  is  proposed  by  derivation  of  the  con- 
stant, with  which  the  two-thirds  power  of  the  weight  should  be 
affected,  from  the  surface  as  measured.    The  authors  find  a  slightly  closer 

agreement  upon  this  basis 
than  upon  the  basis  of 
weight,  but  persist  in  their 
belief  that  there  is  no  causal 
relationship  between  body 
surface  and  heat  production. 
This  topic  has  been  suffi- 
ciently discussed  at  p.  598 
and  it  may  only  be  reiterated 
here,  that  the  vastly  better 
agreement  between  basal  heat 
production  and  body  surface 
than  between  this  physio- 
logical character  and  body 
weight,  as  between  individ- 
uals of  the  same  species  but 
of  widely  different  size,  re- 
mains as  a  challenge  to  dis- 
believers. The  factor  of  age 
must  be  taken  into  account 
as  now  is  definitely  estab- 
lished by  the  work  of  the 
several  authors  described 
above. 

Benedict  and  Talbot  (c) 
find  wide  variations  from  their  mean  cur\^es — from  20  to  64  calories  per 
kilogram  and  24  hours  for  boys  and  an  even  wider  range  for  girls ;  from 
650  to  1275  calories  per  square  meter  (DuBois  linear  formula  and 
Lissauer  formula  modified)  per  24  hours  for  boys,  and  from  600  to  1350 
for  girls.  The  widest  variation  on  both  bases  for  any  single  age  falls  in 
the  latter  half  of  the  first  year,  being  over  60  per  cent  for  boys  and  over 
65  per  cent  for  girls  on  the  basis  of  weight ;  and  in  the  neighborhood  of 
50  per  cent  for  both  sexes  on  the  basis  of  surface.  The  variability  upoi; 
the  basis  of  surface  is  noticeably  less  than  upon  the  basis  of  weight  for 
other  ages  also. 

2.  Influence  of  Sex  on  Basal  Metabolism. — Signs  of  sex  difference  in 
metabolism  appear  in  the  very  early  work  of  Andral  and  Gavarret  and 


1400 

rOTAL  CALORfES  REFERRED  TO  SURFACE. 

QtRLS 

1300 

• 

. 

1200 

/ 

1100 

/ 

/ 

1000 

y 

/ 

900 

'/. 

/^^ 

800 

/^ 

700 

>. 

^. 

V 

[^ 

600 

< 

V  / 

k; 

• 

600 

L-V 

/" 

400 

•  * 

/ 

' 

300 

;^ 

• 

, 

200 

J\ 

7- 

• 

100 

A 

0 

.  2 

sq.  m. 

.^  A 

i 

i    .( 

J   .- 

T       i 

J  k 

J   l( 

3   I 

1  X'i 

2  Id 

Fig.  42.  Basal  heat  production  of  girls 
from  birth  to  puberty,  total  calories  per  24 
hours  referred  to  surface  area  (Benedict  and 
Talbot). 


NORMAL  PROCESSES  OF  ENERGY  METABOLISM    653 

of  Scharling;  but  it  is  not  until  the  classic  investigation  of  Sonden  and 
Tigerstedt  that  definite  proof  is  furnished.  While  the  conditions  of  ex- 
perimentation were  not  those  recognized  to-day  as  essential  to  demon- 
strate a  basal  difference,  the  authors  are  very  positive  in  their  opinion  that 
under  like  conditions  in  the  young  the  CO2  output  both  per  kilogram  of 
weight  and  per  square  meter  of  surface  (^Eeeh)  is  considerably  greater  in 
males  than  in  females  (see  page  656).  The  average  difference  for  their 
age  series  (see  below,  Table  38)  is  as  140  :  100,  *'This  difference  appears 
to  vanish  gradually  with  increasing  age  until  in  old  age  it  disappears 
completely." 

DuBois(a)  first  drew  attention  to  a  probable  difference  of  actual  basal 


Cats* 
1500 

1300 

TOTAL  CALORIES  REFERRED  TO  WEIGHT. 

^ 

!I00 

'/'^ 

^ 

$)00 

.;:^ 

.-r>^ 

< 

700 

y> 

,.''^ 

^ 

500 

* 

^ 

^ 

BO 

YS 

300 

/ 

CIF 

.LS  — 

.100 

/ 

2kgs.  6 


10 


14 


18       ZZ        26       30       34       38      42 


Fig.  43.     Comparison  of  basal  heat  production  of  boys  and  girls  per  24  hours  referred 
to  body- weight  (Benedict  and  Talbot), 


metabolism  between  the  sexes  in  children  (Fig.  35,  p.  613)  upon  the  basis 
of  the  observations  of  Magnus- Levy  and  Falk,  who  did  not  themselves  rec- 
ognize such  a  difference.  Its  demonstration,  however,  is  due  to  Benedict 
and  Talbot  (c).  They  find  that  the  absence  of  a  sexual  difference  for  the 
very  young  infant  (p.  (>'j5),  '^pei-sists  until  about  the  weight  of  11  kgm., 
but  that  frequently  there  is  a  tendency  for  the  boys  to  have  a  somewhat 
higher  metabolism  (average)  tlian  girls  of  the  same  weight"  (Fig.  43). 
On  the  basis  of  surface  they  find  that  the  two  sexes  remain  at  essentially 
the  same  metabolism  (average)  until  the  surface  reaches  0.48  sq.  M. 
(DuBois).  ^'From  this  point  the  line  for  the  boys  rises  above  that  for 
girls  and  there  is  no  evidence  of  a  tendency  for  the  two  lines  to  cross 
later.'' 


654  JOHN  R  MUKLIN 

a.  Influence  of  Puberty. — Andral  and  Gavarret  maintained  that  with 

boys  the  carbon  dioxid  output  suddenly  increased  at  the  age  of  puberty, 

while  with  girls  it  just  as  suddenly  ceased  to  increase  at  this  critical  point. 

Sonden  and  Tigerstedt  give  the  following  comparison  of  the  total  CO2 

output  for  different  age  groups  using  that  of  a  man  57  years  of  age  as  100. 

9-12  years 98 

13-19      " 126 

22-25      ** Ill 

34-44      "  105 

The  combustion  in  the  body  of  male  individuals  from  13  to  19  years 
of  age  is  therefore  greater  than  that  of  younger  or  older  individuals  of 
the  same  sex.  This  coincides  with  the  period  of  most  rapid  growth  in 
length  (15th  year)  and  the  most  rapid  growth  in  weight  (16th  year). 

In  a  remarkable  series  of  observations  on  200  boys  ranging  from  9 
to  19  years  of  age  Olm(a)  thought  she  had  found,  in  agreement  with 
Sonden  and  Tigerstedt,  that  the  CO2  output  whether  as  total  elimination 
or  on  the  basis  of  body  surface  shows  a  distinct  elevation  for  the  age  of 
puberty  (14-16)  above  the  general  trend  of  the  metabiDlism  for  the  entire 
group.  Her  table  given  on  p.  655,  however,  does  not  appear  to  bear  out 
this  conclusion. 

The  first  work  carried  out  on  the  same  youths  just  before  and  just  after 
the  attainment  of  sexual  maturity  was  that  of  Olmstead,  Barr  and  DuBois. 
Eight  normal  boys  were  studied  in  the  respiration  calorimeter  when  they 
were  twelve  and  thirteen  years  of  age  and  again  two  years  later  when  they 
foui-teen  and  fifteen  years  of  age.  On  both  occasions  the  boys  were  placed 
in  the  respiration  chamber  four  or  five  hours  after  a  very  light  breakfast, 
which  has  been  shown  with  adults  to  leave  the  basal  metabolism  unaffected, 
and  were  observed  for  two  or  three  consecutive  hourly  periods  while  lying 
quietly,  but  for  the  most  part  awake.  In  the  first  series  of  observations 
the  basal  metabolism  was  found  to  be  25  per  cent  higher  than  the  adult 
level  per  unit  of  surface  (linear  fommla),  while  in  the  second  after 
puberty  had  been  definitely  established  in  four  of  the  eight  subjects  the 
metabolism  was  on  the  average  only  11  per  cent  higher  than  the  adult  level. 
Benedict  and  Talbot  very  properly  criticise  these  observations  as  failing 
to  establish  definitely  by  a  sufficient  number  of  observations  the  true  basal, 
and  point  out  that  if  the  quieter  periods  of  the  first  series  be  selected  the 
metabolism  is  very  close  to  that  found  in  the  second  series.  It  might  be 
urged  further  that  there  were  at  the  time  of  DuBois^  observations  scarcely 
a  sufficient  number  of  basal  experiments  in  the  literature  at  ages  preceding 
and  following  the  ages  of  his  subjects  to  warrant  the  inference  of  a  distinct 
rise  in  metabolism  of  the  prepubescent  age  above  that  of  adjacent  ages. 
Benedict  and  Talbot  in  a  few  scattered  observations  on  boys  and  girls  of 
prepubescent  age  find  no  such  increase  but  they  admit  that  their  experi- 
ments are  not  yet  sufficient  in  number  to  warrant  a  definite  conclusion. 

3.  The  Influence  of  Muscular  Activity  in  Children. — The  extensive 


l^ORMAL  PROCESSES  OF  ENERGY  METABOLISM     655 

observations  of  Sondeii  and  Tigerstedt  at  Stoekliolm,  of  Rubner(^)  at  Ber- 
lin and  of  V.  Willebrand  at  Helsina:fors  in  contrast  with  the  very  low  if  not 
actually  minimal  values  obtained  by  Magnus-Levy  and  Falk  at  Berlin,  by 
Olin  at  Ilelsingfors  and  by  the  Boston  workei*s,  furnish  some  very  interest- 
ing, though  as  yet  very  incomplete,  data  on  the  effects  of  moderate  mus- 
cular activity. 

The  resting  and  post-absoi*ptive  rate  established  by  Magnus-Levy  and 
Falk  have  been  discussed  above  and  while  the  average  line  established  by 
them  lies  considerably  above  that  of  Benedict  and  Talbot,  their  results  lie 
within  the  range  of  variability  given  by  the  latter  authors.  So  also  do 
those  of  Olin,  notwithstanding  that  her  subjects  were  studied  in  the  sit- 
ting position.  They  were  placed  in  the  apparatus  individually,  usually 
in  the  morning  after  a  light  breakfast.  The  results  are  summarized  in 
the  following  table. 

TABLE  37 
Metabolism  of  Boys  Sitting  Very  Still  (Olin) 


No.  of 
Subjects 

Average  Age 

Average 
Height 

Bodr    Surface 
(Meeh) 
sq.  M, 

CO,  per 
Kgm.  and  Hr. 

Heat    Produc- 
tion  per  Sq. 
yU  and  Hr.* 

4 

9 

35.9 

1.299 

0.425 

34.1  Cal. 

15 

10 

31.4 

1.217 

0.505 

37.9    " 

14 

11 

36.1 

1..327 

0.492 

39.3    '* 

27 

12 

38.1 

1.396 

0.372 

37.5    " 

20 

13 

43.1 

1.573 

0.452 

35.7    " 

22 

14 

49.6 

1.720 

0.425 

35.3    " 

19 

15 

52.9 

1.805 

0.412 

35.3    " 

18 

16 

69.2 

1.948 

0.399 

35.0    " 

9 

17 

55.4 

1.804 

0.385 

33.5    " 

4 

18 

65.6 

2.086 

0.359 

32.8    ** 

Assuming  a  R.  Q.  of  0.85  i.  e.,  Heat- value  of  CO,  of  5.721  Cal.  per  liter. 


In  calculating  the  surface  area  by  Meeh^s  fonnula  the  constant  12.205 
w^as  used  by  Olin  for  boys  under  13  and  12.81:7  for  boys  over  that  age. 
The  heat  production  in  relation  to  surface  area  calculated  by  the  writer 
upon  the  assumption  of  a  R.  Q.  of  0.85  are  very  close  to  those  ordinarily 
obtained  upon  adult  subjects  under  tlie  conditions  usually  accepted  as 
basal  (see  page  (510 ).  It  has  recently  been  shown  that  a  person  propped 
up  in  a  semi-reclining  position  may  have  a  metabolism  even  lower  than 
when  lying  flat  in  bed.  These  results  by  Olin  seem  to  signify  that  young 
persons  may  be  induced  to  sit  quietly  enough  to  exhibit  a  metabolism  even 
lower  ( ?)  than  when  lying  down.  It  w^ould  seem  that  Olin^s  subjects 
must  have  been  supported  in  such  a  position  as  to  require  no  muscular 
tension  and  that,  as  in  the  semi-reclining  position  in  a  steamer  chair,  the 
diminished  pressure  of  the  abdominal  organs  upon  the  diaphragm  may 
have  lessened  the  muscular  effort  of  breathing.  The  results  should  prob- 
ably be  regarded  as  representing  tiiily  basal  conditions. 


656 


JOHN  K.  MUELIN" 


In  stroug  contrast  with  these  are  the  figures  obtained  by  Sonden  and 
Tigerstedt  upon  gi'oups  of  6  boys. and  girls  of  approximately  the  same  age. 
The  authors  state  that  their  purpose  was  to  obtain  data  which  would  be 
of  value  in  deteraiining  the  ventilation  requirements  of  public  assembly 
halls  and  especially  school  rooms.  Their  subjects  were  required  to  sit  as 
still  as  they  would  in  school,  but  were  permitted  to  handle  and  read  books 
and  at  times  to  nibble  candies  and  fruits.    Their  results  follow : 

TABLE  38 
Metabolism  of  Childrex  Sitting  as  ix  School  (Sonden  and  Tigerstedt) 


Average  Age 


Years 


Months 


Average  Weight 


CO3  per  Kgm. 
and  Hour 


Calories  per  Sq. 

M.    (Meeh)   and 

Hr.* 


BOYS 


7 

10 

20.1 

1.149 

73.1 

9 

7 

27.5 

1.207 

83.1 

10 

6 

30.2 

1.106 

78.6 

11 

5 

31.6 

1.063 

76.7 

12 

6 

34.1 

0.997 

72.1 

13 

10 

44.5 

1.000 

75.0 

14 

6 

45.3 

0.960 

74.2 

GIRLS 


7 

10 

21.8 

1.133 

74.1 

9 

11 

26.6 

0.850 

67.8 

11 

2 

31.0 

0.845 

60.6 

12 

2 

36.2 

0.743 

56.1 

13 

4 

39.5 

0.696 

51.4 

14 

0 

44.3 

0.661 

50.7 

15 

2 

48.6 

0.562 

44.5 

*  In  view  of  the  fact  that  the  children  of  this  series  were  permitted  to  eat  candy 
and  fruit  at  times  while  in  the  respiration,  chamber  a  R.  Q.  of  0.90  is  assumed, 
i.e.,  the  CO,  is  given  a  heat  value  of  5.471  Cals.  per  liter. 

The  heat  production  here  is  calculated  upon  the  assumption  of  a  R.  Q. 
of  0.90  employing  the  values  for  CO2  given  by  the  authors  upon  the  basis 
of  a  square  meter  of  surface.  The  results  are  nearly  double  those  obtained 
by  Olin.  Benedict  and  Talbot  have  calculated  the  heat  production  per 
kilo  and  24  hours  of  these  subjects  on  the  assumption  of  a  E.  Q.  of  0.90 
and  these  values  are  shown  for  comparison  upon  a  chart  (Fig.  44)  pre- 
pared by  them  to  exhibit  the  basal  metabolism  according  to  several  authors. 
The  average  distance  of  the  individual  points  designated  as  the  "active 
subjects  of  Sonden  and  Tigerstedt"  above  the  continuous  line  representing 
the  average  basal  may  be  taken  as  approximating  the  activity  metabolism 
occasioned  by  sitting  at  a  desk  reading  a  book  and  making  such  minor 
movements  as  a  well-behaved  child  in  school  would  make  during  study 
periods.  This  amounts  to  fully  30  calories  per  kilogram  and  24  hours. 
Table  38  shows  a  very  marked  difference  between  boys  and  girls  which  is 


ISrOKMAL  PROCESSES  OF  ENERGY  METABOLISM    657 

even  greater  than  the  difference  in  basal  metabolism  between  boys  and 
girls  (Fig.  43)  of  the  same  age.  This  is  due  to  the  greater  degree  of 
composure  readily  induced  in  girls  of  the  adolescent  age. 


Cell 
6€ 

64 

eo 

56 
52 
48 
44 
40 
36 
32 
28 


1. 

CALORIES  PER  KILO.  REFERRED  TO  AGE. 

BOY& 

T 

* 

( 

4 

c 

< 

f 

\ 

"■■■\ 

\, 

V 

.• 

■^ 

"-^ 

^ 

• 

^^ 

• 

• 

o 

a 

■^ 

J 

<f.  s 
x-S 

>CHARUNG 
ONO^N  AND  T 

GERi 

TED- 

o- DUBOIS  0916) 
a  -  DU  BOIS  0918) 

■--i-J 

•  •» 

3AGN 

1 

US-L 

EVY  / 

1 

kND  F 

ALK 

A-  MURLIN  AND  HOOBLER 

1     1     1     1     1 

p 

24 
Yrt.     1 


12      13 


15     IS 


Fig.  44.  Basal  heat  production  of  boys  from  birth  to  puberty  (continuous  line 
according;  to  Benedict  and  Talbot),  x  x  x  x  Active  cases  of  Sondea  and  Tigerstedt. 
Total  Calories  per  kilogram  referred  to  age. 


Sonden  and  Tigerstedt  give  the  following  values  for  two  of  their  boys 
during  sleep : 

Boy  of  11  yrs.  3  mos. — 14.09  gm.  COo  per  sq.  M  (Meeh)  and  hour. 
u       **    1 9    **  1^  78    '^         "        "      '*     **  *'        '* 

From  which  we  may  derive  the  following  heat  production  on  the  assump- 
tion of  a  R.  Q.  of  0.8S: 

Boy  of  11  yrs.  3  mos- — ^35.1  cal.  per  Sq.  M.  and  Hr. 

u      u    -iC)     ii  04  Q    (c      a       a      cc      u       a 

Boys  of  the  same  age  in  school  showed  a  heat  production  of  fully  twice  as 
much  (Table  38).  ^ 

Von  Willebrand's  observations  were  made  upon  boys  from  9  to  14 
years  of  age  in  the  apparatus  used  by  Olin.  They  were  confined  for  the 
entire  24  hours,  taking  all  three  meals  in  tlie  apparatus.  Tlie^'  went  to 
bed  at  8  to  9  P.  ^I.  and  rose  in  the  morning  about  6  o'clock.  In  some 
instances  the  subjects  slept  for  a  short  time  during  the  day.  The  differ- 
ence between  waking  and  sleeping  metabolism  for  four  individuals  is 
shown  in  the  following  table  somewhat  modified  from  one  given  by 
Benedict  and  Tallx)t(r), 


658  JOHN  R.  MUIlLi:^' 

TABLE  39 
Metabolism  of  Bovs  Awake  and  Sleeping   (Von  Willebrand) 


Name 

Age,  Years 

Body  Weight,  . 
*Kgm. 

Cal.  per  Sq.  M.*  and  liour 
Awake          |          Asleep 

Wikko 

Viktor    

Julius    

Silo    

9 
10 
13 
14 

2.5.9 
30.8 
34.1 
36.5 

57.8 
40.0 
47.6 
38.9 

27.3 
22.0 
24.9 
20.4 

^Meeh's  formula  using  12.205  for  the  first  two  boys  and  12.847  for  the  second  two. 
Heat  is  calculated  from  the  COj  assuming  an  R.  Q.  of  0.83. 

Eubner's  experiments  were  made  upon  two  brothers,  one  fat  and  one 
thin,  the  sons  of  parents  of  slender  means  and  therefore  not  likely  to  be 
overfed.  They  were  confined  for  about  22  out  of  the  24  hours  in  the 
respiration  chamber,  ate  and  slept  there  and  during  waking  hours  were 
pennitted  to  move  about,  even  walking  some.  The  following  summary  of 
the  results  are  given  by  Lusk(7i). 

TABLE  40 
Metabolism  of  a  Fat  and  Thin  Boy  (Rubner,  after  Lusk) 


Age, 
lears 

Weight, 
Kgm. 

Heat  Production 

Per   Sq.  M. 
24  Hrs. 

(Meeh) 
per  Hr. 

Total  for 
24  Hrs. 

Total  Kgm. 
and  24  Hrs. 

Fat  boy 
Thin  boy 

10 
11 

41 
26 

1786.1 
1352.1 

43.6 
52.0 

1.321 
1290 

55.0 
53.7 

The  last  column  may  be  compared  with  the  results  of  v.  Willebrand 
(Table  30)  and  those  of  Sondon  and  Tigerstedt  (Table  38). 

A  most  interesting  phase  of  the  activity  metabolism  in  children,  name- 
ly, the  muscular  efficiency  as  compared  with  adults,  has  never  been  studied. 
Nor  has  any  attempt  been  made  to  estimate  the  actual  energy  expenditure 
of  an  active  child  for  the  entire  24  hours.  How  much  the  values  just  given 
for  boys  who  were  permitted  to  move  about  to  a  limited  extent  in  the 
respiration  chamber  falls  short  of  the  actual  daily  requirements  with  its 
large  quota  for  growth  may  be  gained  from  the  following  chart  taken 
from  Lusk (;)  (Fig.  45). 

I.    Energy  Metabolism  of  Old  Age 

In  modern  times  the  energy  metabolism  of  old  age  has  been  studied  by 
three  sets  of  observers.  Magnus-Levy  and  Falk  studied  by  moans  of  the 
Zuntz-Geppert  method  five  old  men  and  seven  old  women.  One  of 
tlieir  tables  has  been  i-eproduced  on  page  648  where  comparison  is  made 
between  the  metabolism  of  a  bov  and  a  girl  and  of  middle  aged  subjects 


NORMAL  PROCESSES  OF  EXERGY  METABOTJCSM     650 

nf  approximately  tho  same  body  weiglit  with  two  of  their  aged  subjects. 
A  lib  and  DuBois  determined  the  basal  metabolism  of  six  old  mea 
between  the  ages  of  75  and  85  years.  The  authors  describe  their  subjects 
as  ^*in  good  condition  and  fairly  well  nourished,  though  on  plain  and  some- 
what scanty  diets.  Considering  their  ages,  they  were  in  good  health, 
]h(jugh  most  of  them  suffered  from  arteriosclerosis,  chronic  interstitial 
nephritis  and  emphysema,  which  ^normally'  accompany  advanced  years." 


50 
CALS. 

4500 
4P00 

JiQOO 
2,500 
2pOO 
1500 


500 


34  73  95     12     14  5     t6      19     ?0-5    22      25     27      30     33      35     40     45      50  KG 

5gS6a8738   82B   89i     9&l     106     n2     M7      Ig2    >?7    »33     l37    142     148     155     160  CM. 


it    I         2         3        4         S        6         7         0        9        10       It        12       13       14       I5VR$. 
teS'^i^Z'S"  29.5"  2'\r  32"  3' 6"    38'    VlO'    4"      4*2"  4*4-   4-6-    4'8"  4' lO"  5'r    5'3"fT.|.IM 
75  16  21      27      32     36     41      45    495  545    60     67     72     60     88     99     III    LBS. 

Fig.   45.     Metabolism  in   calories  per  dav  of  boys  from  birth   to  15  years  of  age. 

(After  Lusk.)' 


The  average  basal  heat  production  was  35.1  calories  per  square  meter 
(linear  formula)  per  hour,  which  is  12  per  cent  below  the  average  for 
men  between  the  ages  of  20  and  50.  The  respiratory  quotients  lay  be- 
tween 77  and  86,  the  average  being  81.  Since  these  subjects  had  been 
on  rather  meager  fare  and  were  kept  in  the  metabolism  ward  of  Bellevuq 
Hospital  for  several  days  before  the  tests  were  made,  the  low  metabolism 
and  rather  low  quotients  are  in  part  accounted  for  by  these  factors.  How- 
over,  since  these  conditions  accord  with  the  usual  routine  of  life  for  sub- 
jects of  very  advanced  ago  the  metabolism  findings  are  such  as  would  ordi- 
narilv  obtain. 


ceo  JOHN  R.  MUELIN 

From  the  Nutrition  Laboratory  at  Boston  are  available  a  few  scat- 
tered data  on  the  basal  metabolism  of  old  people.  For  example,  Benedict 
(/)  in  a  discussion  of  the  factors  affecting  basal  metabolism  includes  in 
one  of  his  tables  one  man  63  and  one  woman  74  years  of  age  and  notes 
that  a  person  *'of  advanced  years  has  a  still  lower  metabolism  than  the 
person  in  middle  life." 

Magnus-Levy  obsen-es  in  explanation  of  the  low  metabolism  of  old  age 
that  *'the  cells  of  the  body  lose  their  thermodynamic  powers  with  old 
age''  and  cites  the  older  observations  of  Andral  and  Gavarret,  Son- 
den  and  Tigerstedt  and  his  own  work  with  Falk  in  support  of 
the  view  that  an  old  man  utilizes  less  food,  not  only  because  his  output 
of  work  is  less,  but  also  because  his  cells  generate  less  heat  during  rest. 
Whatever  special  causes  may  underlie  the  onset  of  senility  physiological 
eld  age  can  only  be  said  to  exist  when  the  involution  of  the  various  organs 
takes  place  gradually  and  at  a  proportional  rate.  In  such  changes  is  found 
sufficient  cause  for  the  decreasing  metabolism.  How  low  the  hour-glass 
must  run  before  the  processes  of  oxidation  must  cease  or  what  level 
of  heat  production  marks  the  ultra-minimum  for  the  suppoii:  of  respira- 
tion and  circulation  has  not  yet  been  disclosed.  "And  his  days  were 
ended  and  lie  died,  for  he  was  old  and  weary  of  life." 


SECTION  VI 


Bacterial   Metabolism,  Normal    and    Abnormal,   Within 

the   Body Arthur  Isaac  Kendall 

Introduction — The  Significance  of  Bacterial  Metabolism — Bacterial  Metab- 
olism— General  Relations  Between  Surface  and  Volume  of  Bacteria  and 
the  General  Energy'  Requirements  of  Bacteria — The  Influence  of  Sap- 
rophytism,  and  Pathogenism  upon  Bacterial  ^letabolism — Chemical  Re- 
quirements for  Bacterial  Development — The  General  Nature  of  the  Prod- 
ucts of  Bacterial  Growth,  Arising  from  the  Utilization  of  Proteins  and 
of  Carbohydrates  for  Energy — Toxin,  Indol  and  Enzyme  Formation — 
The  Specificity  of  Action  of  Pathogenic  Bacteria  and  Its  Relation  to 
Proteins  and  Carbohydrates — Quantitative  Measures  of  Bacterial  Metab- 
olism, the  Effects  of  Utilizable  Carbohydrates  upon  General  ^letabolism, 
and  the  Elementary  Composition  of  the  Bacterial  Cell — The  Chemistry  of 
Bacterial  Metabolism — General  Reactions:  The  Formation  of  Phenols, 
Indol  and  Indican,  Amins — Reactions  Illustrative  of  the  Decomposition 
of  Proteins  by  Bacteria — The  Effects  of  Utilizable  Carbohydrate  upon 
the  Formation  of  Phenols,  Indol  and  Amins — The  Physiological  Action 
of  the  Aromatic  Amins — rSummary — Intestinal  Bacteriology — General 
History  and  Development — The  Intestinal  Bacteria  of  Normal  Nurslings 
— Adolescent  and  Adult  Intestinal  Bacteriology — Sour  Milk  Therapy  and 
Bacterial  Metabolism — Exogenous  Intestinal  Infections — Summary  and 
Conclusions. 


Bacterial  Metabolism,  Normal  and 
Abnormal,  Within  the  Body 

ARTHUR  ISAAC  KENDALL 

CniCAGO 

A.    Introduction:    The  Significance  of 
Bacterial  Metabolism 

That  remarkable  chapter  in  the  history  of  the  development  of  the 
Science  of  ]\redicine  which  treats  of  the  relations  of  microorganisms  to 
the  causation  of  specific  disease  in  man  has  exposed  an  entirely  new  and 
extraordinarily  fertile  field  for  study  and  for  speculation. 

The  fir.-^t  two  decades  of  this  era  were  gi'eatly  enriched  by  the  isolation 
and  identification  of  microbes  which  were  shown  to  be  etiological  agents 
in  some  of  the  most  formidable  infections  of  mankind.  The  second  decade 
of  this  period  also  witnessed  the  beginnings  of  specific  bactei'ial  therapy. 
The  brilliant  investigations  of  Von  Behring.  Kitasato,  Roux,  Yersin, 
Smith  and  others,  upon  the  soluble  toxins  of  diphtheria  and  tetanus 
bacilli,  and  the  preparation  of  their  specific  antitoxins,"  seemed  to  prepare 
the  way  for  a  universal  antitoxic  therapy  which  should  be  efiicacious  in  all 
disorders  of  microbic  causation.^ 

Time  has  shown,  however,  that  antitoxic  therapy  is  limited  to  a  very 
few  specific  diseases.  The  development  of  the  field  of  Immunology  by 
Ehrlich,  Metchnikoff,  Bordet  and  their  followers,  and  the  elucidation  of 
the  nature  of  the  complex  reciprocal  relationships  between  host  and  para- 
site, which  comprise  the  phenomena  of  infection  and  of  resistance  to  infec- 
tion have  shown  the  basis  for  antitoxic  therapy  very  clearly,  and  the 
limitations  which  surround  it.  These  studies  also  indicate  very  definitely 
that  entirely  new  procedures  must  be  established  to  combat  those  micro- 
organisms for  whose  pernicious  activities  no  antitoxins  can  be  prepared. 

The  third  decade  of  medical  bacteriology  has  been  endowed  with 
greatly  improved  methods  of  culture.  These  have  led  to  the  discovery  of 
many  incitants  of  infection  that  had  eluded  the  earlier  attempts  at  isola- 
tion.    The  rapid  development  of  the  Science  of  Serology,  and  the  defini- 

*Von  Behring:     Die  Blutserum-therapie,  Leipzig,  1S92. 

663 


664  ARTHUR  ISAAC  KENDALL 

tion  of  the  limits  surrounding  the  uses  of  vaccines  for  therapeutic  pur- 
poses, are  also  sig-nificant  events  of  this  decade.  The  preparation  of 
specific  serums,  begun  in  this  period,  represents  as  jet  an  immature  phase 
of  bacteriotherapy,  but  it  is  a  most  promising-  field  for  further  study. 

ProgTCss  up  to  the  present  time  in  medical  bacteriology,  therefore,  has 
been  chiefly  along  diagnostic  lines,  both  with  reference  to  the  isolation  and 
identification  of  the  etiological  agents  of  specific  microbic  diseases,  and 
with  reference  to  the  recognition  of  serological  reactions  in  infected  indi- 
viduals. Indeed,  with  the  exception  of  those  few  hacteria  to  whose  soluble 
toxins  specific  antitoxins  have  been  prepared,  the  advances  in  the  ameli- 
orative and  curative  aspects  of  medical  bacteriology  have  been  disappoint- 
ingly limited.    Yet  this  is  the  most  important  field  of  all. 

It  is  quite  apparent  that  a  shifting  of  the  point  of  attack  m.ust  precede 
further  advances.  Diagnostic,  or  morphologic,  bacteriology  must  give 
place  to  dynamic  or  chemical  bacteriology.  "It  is  what  bacteria  do  rather 
than  what  bacteria  are  that  conmiands  our  attention,  since  our  interest 
centers  in  the  host  rather  than  the  parasite,^'  as  Theobald  Smith  has  so 
aptly  said.  The  application  of  biochemical  methods  to  the  elucidation  of 
conditions  which  surround  the  preparation  of  soluble  toxins,  and  which, 
therefore,  permit  of  the  generation  of  potent  antitoxins  is  a  striking 
example  of  the  correctness  of  this  dynamic  principle:  Those  same  phe- 
nomena which  influence  the  iormation  of  toxin  in  cultures  of  diphtheria 
bacilli  play  a  very  important  part  in  determining  the  nature  of  the 
significant  products  formed  by  other  pathogenic  bacteria. 

It  is  not  without  significance  that  those  very  procedures  which  Esclier- 
ich  and  the  long  list  of  bacteriologists  following  him  have  found  useful, 
and  even  essential -for  the  identification  of  microbes  have  their  origin  and 
explanation  in  these  bacteriochemical  studies  of  the  mode  of  action  of 
bacteria.  In  this  regard,  bacteriology  merges  imperceptibly  into  the  fields 
of  protein  and  carbohydrate  chemistry. 

Also,  the  explanation  for  the  striking  alternations  of  bacterial  types 
in  the  alimentary  canal  in  response  to  dietary  stimuli,  and  for  the  con- 
ditions which  surround  the  production  of  endogenous,  physiologically  ac- 
tive bacterial  putrefaction  products,  depends  upon  the  same  biochemical 
principle  of  bacterial  metabolism.  The  amelioration,  or  even  the  rectifica- 
tion, of  exogenous  and  endogenous  disturbances  or  infections  of  microbic 
causation  in  the  alimentary  canal  can  be  accomplished  through  the  simple 
and  direct  application  of  the  same  metabolic  principle.  A  new  science,  that 
of  bacteriochemistry,  is  gradually  forging  into  prominence.  A  new  field 
in  medical  bacteriology  is  developing.  In  this  new  field,  certain  funda- 
mental principles  underlying  the  metabolism  of  bacteria,  are  being  ex- 
ploited in  the  direct  interest  of  the  host.  The  nature  of  these  principles, 
their  limitations,  their  relation  to  bacteria,  and  to  bacterial  infections  of 
man,  are  discussed  in  the  following  pages. 


BACTERIAL  METABOLIS^L  WITHIX  THE  BODY      665 

B.    Bacterial  Metabolism 

1.     General  Relations  Between  Surface  and  Volume 

of  Bacteria  and  the  General   Energy 

Requirements  of  Bacteria 

Bacteria  in  common  with  all  living  things  exhibit  two  distinct  phases 
in  their  life  historj — the  anabolic  or  structural  phase,  and  the  katabolic  or 
energy  phase.  Of  these,  while  no  absolutely  sharp  line  of  demarcation 
can  always  be  determined,  the  manifestations  and  significance  of  the  latter 
phase  are  by  far  the  more  conspicuous,  inasmuch  as  the  amount  of  material 
transformed  into  energy  and  heat  far  exceeds  that  entering  into  the  body 
of  the  organism  and  the  replacements  of  structural  wear  and  tear,  and 
losses  incidental  to  the  formation  of  enzymes  and  other  essential  nitrogen- 
ous secretions  and  excretions. 

The  bacteria  differ  quantitatively  from  the  gi-eat  majority  of  plants 
and  animals  in  their  dispro}X)rtionately  large  ratio  between  surface  and 
volume.  An  ordinary  typlioid  bacillus,  for  example,  has  a  volume  of 
approximately  0.000000002  cubic  millimeter.  The  surface  area  of  a 
bacterium  of  this  size  is  nearly  0.00001  square  millimeter.  Inasmuch 
as  the  energy  requirement  of  organisms  in  general  varies  with  the  surface 
area  rather  than  with  the  volume  (Du  Bois),  it  is  not  surprising  to  find 
that  bacteria  bring  about  transfonnations  of  nutritive  material  for  meta- 
bolic requirements  considerably  greater  than  their  minute  size  would 
appear  to  permit  of  at  first  sight.- 

Bacterial  cells  exhibit  no  morphologically  definable  nucleus,^  and  the 
complex  phenomena  attending  nuclear  division,  so  characteristic  of  more 
highly  organized  cellular  structures,  is  not  a  feature  of  bacterial  multi- 
plication. Hence,  reproduction  among  bacteria  is  mechanically  an  ap- 
parently simple  process.  It  takes  place  by  direct  transverse  fission,  the 
resulting  parent  and  daughter  cells  being  of  approximately  equal  size. 

The  rate  of  increase  among  bacteria  is  a  geometrical  progi-essioh  which 
in  favorable  mediums  is  theoretically  maintained  imtil  the  accumulation 
of  waste  products  and  other  environmental  factors  imposes  a  restraint 
upon  the  process. 

Among  the  more  rapidly  growing  organisms,  as  for  example  the  cholera 
vibrio,   successive  generations  may  appear  at  intervals  as  frequent  as 

'A  man  of  average  figure,  200  cm.  long  and  weighing  100  kg.,  would  have  a  surface 
area  of  about  2.36  square  meters.  It  will  be  seen  that  the  ratio  between  weight  [or 
volume]  and  surface  in  this  instance  is  much  more  nearly  equal  than  that  of  the 
bacteria. 

'  Bacterial  cells  are,  however,  rich  in  nuclear  material.  The  chemical  basis  for 
nuclei  probably  is  quite  uniformly  distributed  throughout  the  entire  cell. 


666  ARTHUR  ISAAC  KENDALL 

every  fifteen  minutes.  The  theoretical  descendants  of  a  sino-le  microhe 
after  four  hours  of  unrestrained  growth  would  number  almost  thirty-three 
thousand.  Their  combined  volumes  would  be  approximately  0.000066 
cubic  millimeterj'^  but  their  united  surface  areas  woidd  be  nearly  0.33 
square  millimeter.  It  is  obvious  that  the  amount  of  structural  substance 
essential  for  the  thirty-three  thousand  cholera  vibrios  would  be  little  in- 
deed; the  quantity  of  material  necessary  to  provide  the  requisite  energy 
for  these  organisms  is* relatively  very  large. 

The  rapidity  of  reproduction  among  bacteria,  therefore,  furnishes  an 
additional  explanation  of  the  magnitude  of  transformation  of  nutritive 
material,  which  is  such  a  conspicuous  feature  of  bacterial  gi-owth.  Prom 
this  viewpoint,  the  activities  of  bacteria  appear  to  lie  within  the  realm  of 
colloidal  chemistry — the  chemistry  of  sui*face  relations. 

The  relations  between  surface  and  volume  of  bacterial  cells  as  an- 
explanation  of  the  magnitude  of  bacterial  metabolism  cannot  be  empha- 
sized to  the  exclusion  of  the  specific  activities  of  individual  species  or 
types  of  bacteria,  howex^er.  Bacillus  proteus  and  Bacillus  typhosus,  for 
example,  are  of  nearly  equal  dimensions  and  multiply  at  nearly  the  same 
rate.  Nevertheless,  the  former  is  far  more  energetic,  under  apparently 
parallel  conditions,  in  its  chemical  transformations  to  obtain  the  elements 
requisite  for  energy  than  the  latter,^  The  fact  remains,  however,  that  in 
general,  bacteria  effect  changes  in  their  chemical  environment,  both  in 
time  and  amount,  gieatly  exceeding  that  to  be  expected  from  such  minute 
organisms,  and  the  significant  aspect  of  this  activity  is  that  associated  with 
the  energy  phase  rather  than  the  structui-al  phase  of  their  metabolism. 


2.    The  Influence  of  Saprophytism,  Parasitism,  and 
Patho^enism  upon  Bacterial  Metabolism 

From  the  viewpoint  of  mankind,  bacteria  may  be  classed  for  con- 
venience as  of  three  principal  gTOups  (Smith,  Kendall («))  :  First,  sapro- 
phytic bacteria,  living  upon  dead  organic  material,  and  usually  without 
significance  in  a  pathogenic  way.  Their  function  in  ^N^ature  is  to  bring 
about  deep-seated  changes  in  dead  organic  matter,  returning  the  essential 
elements,  as  nitrogen,  to  the  vegetable  kingdom  as  fully  mineralized  com- 
pounds ready  for  resynthesis  into  proteins  and  other  necessary  organic 
compounds,  by  chlorophyll-bearing  plants.  Secondly,  parasitic  bacteria, 
which  live  upon  the  body  of  the  host  or  in  channels  or  cavities  in  free 
communication  with  the  exterior  of  the  body  of  the  host.  Usually  such 
organisms  are  endowed  with  the  power  of  multiplying  within  the  tissues, 

*  The  cholera  vibrio  is  approximately  equal  in  size  to  the  typhoid  bacillus. 
"In   general,    it   may   be    stated   that   non-pathogenic   bacteria   are   more   active 
chemically  than  pathogenic  bacteria. 


T5ACTEKIAL  METABOLISM  WITHIX  THE  BODY      667 

in  the  pi-esence  of  opposition  from  the  various  bactericidal  forces  of  the 
host,  but. they  lack  the  power  of  independent  invasiveness.  They  are  '^op- 
portiini'^ts''  with  respect  to  pathogenicity  and  they  are  usually  secondary 
invaders  because  they  require  some  break  in  the  continuity  of  the  skin  or 
mucous  membranes  to  permit  of  their  entrance  to  underlyin*^  tissues.  Such 
an  orjianism  is  the  Streptococcus.  Parasitic  bacteria  do  not  ordinarily 
incite  epidemics,  because  they  have  not  i>erfected  a  mechanism  for  escape 
from  the  tissues,  and  as  a  general  rule  their  excursion  into  the  tissues 
results  in  relatively  non-specific  inflammatory  processes,  rather  than  well- 
defined  anatomical  lesions.^  Recovery  from  an  invasion  of  organisms  of 
the  opportunist  type  does  not  ordinarily  appear  to  result  in  a  well-defined 
specific  immunity,  thus  again  affording  a  contrast  to  bacteria  of  the  pro- 
gressively pathogenic  type. 

Finally,  the  members  of  a  small  but  formidable  group  of  bacteria  aro 
progressively  pathogenic,  that  is  to  say,  they  appear  to  possess  the  power 
of  independent  invasiveness  of  the  body,  if  they  reach  a  suitable  jxjrtal  of 
entry  in  sufficient  numbers.  After  invasion  they  multiply  for  a  period  of 
time  within  the  tissues  of  the  body  in  the  presence  of  the  opposition  offered 
by  the  various  non-specific  lines  of  defense.  They  have  individually  per- 
fected, finally,  well-defined  mechanisms  of  escape  from  the  tissues  to 
channels  in  communication  with  the  outside  world,  thus  providing  for 
escape  to  other,  susceptible  hosts,  and  the  perpetuation  of  the  species. 

The  typhoid  bacillus  may  be  cited  as  illustrative:  The  organism  must 
reach  the  small  intestine  of  a  susceptible  individual,  penetrate  the  mucosa, 
and  enter  the  circulation.  It  grows  in  the  tissues  and,  after  a  period  of 
time,  reenters  the  intestines  from  the  gall  bladder  from  which  it  escapes 
to  the  environment  in  increased  numbers,  or  it  escapes  from  the  urinary 
bladder  to  the  outside  world. 

Thus,  it  is  possible  to  distingtiish  a  '^cycle  of  parasitism"  and  a  "cycle 
of  pathogenism."  The  essential  factors  of  the  former  are — first,  for  the 
parasitic  microbe  to  reach  the  surface  of  a  suitable  host,  or  to  reach  chan- 
nels or  cavities  in  free  communication  with  the  outside  w^orld;  secondly, 
for  the  microbe  to  multiply  there,  and,  thirdly,  to  escape  to  other,  suitable 
hosts,  thus  insuring  the  perpetuation  of  the  species.  Penetration  of  the 
tissues  and  growth  therein  is  not  a  part  of  this  cycle — the  microbe  cannot 
escape  to  the  outside,  as  a  general  rule,  and  perishes,  although  it  may 
overwhelm  the  host  in  so  doing.  Parasitic  organisms,  therefore,  are  not 
progressively  pathogenic.  The  pathogenic  cycle  is  somewhat  more  com- 
plex. The  organism  must  reach  a  suitable  portal  of  entry  to  the  under- 
lying tissues  of  the  host,  actually  penetrate  into  the  underlying  tissues  and 
grow  therein  in  the  face  of  non-specific  and'  specific  opposition.    Finally, 

'Thus,  the  lesions  caused  by  progressively  pathogenic  bacteria,  as  the  tubercle, 
typhoid,  or  syphilis  microbes,  are' fairly  distinctive  and  characteristic  in  structure  and 
distribution,  contrasting  sharply  in  this  respect  with  the  non-specific  inflammations  in- 
duced by  streptococci  or  other  pyogenic  microbes. 


668  AETHUR  ISAAC  KEN^DALL 

the  organism  must  escape  from  the  tissues  in  significant  numhers  to  chan- 
nels in  communication  with  the  outside  world,  and  eventually  reach  other, 
suitable  hosts.  Such  organisms  incite  specific  epidemics.  They  are  pro- 
gressively pathogenic  from  host  to  host. 

It  is  a  striking  fact  that  the  evolution  of  bacteria  from  saproph3i:ic 
types  through  parasitic  to  pathogenic  types  has  been  attended  by  a  marked 
decrease  in  the  chemical  activities  of  the  microbes.  For  example,  the  con- 
trast in  chemical  activity  between  the  powerfully  proteolytic  members 
of  the  saproph;y1:ic  hay  bacillus  gi'oup,  which  are  without  virulence, 
through  the  ordinary  skin  Staphylococcus  to  the  exquisitely  fastidious 
!\[eningococcu3  is  only  equaled  by  the  increased  pathogenicity  of  these 
latter  organisms.  Generally  speaking,  intense  chemical  activity  appears 
to  be  incompatible  with  pathogenicity  (Kendall). 

The  facts  adduced  thus  far  relate  to  general  properties  of  bacteria  j 
they  furnish  little  or  no  information  relative  to  the  specificity  of  bacteria 
and  of  bacterial  action.  Bacteria,  in  the  last  analysis,  are  "living  chem- 
ical reagents,"  as  Professor  Folin  once  characterized  them,  and  the 
specificity  of  bacterial  action  is  largely,  if  not  almost  wholly,  a  problem 
of  the  chemistry  of  their  interchange  with  their  environment. 

The  ultimate  chemistry  of  bacterial  action,  particularly  that  relating 
to  the  pathogenic  organisms,  is  as  yet  unsolved.  The  formula?  for  diph- 
theria and  tetanus  toxins,  the  nature  of  the  poisons  of  the  typhoid  and 
dysentery  bacilli,  are  problems  for  the  bacteriological  chemists  of  the 
future  to  solve.  ^N'evei'theless,  all  bacteria  of  interest  or  of  importance  to 
man  exhibit  certain  rather  general  relationships  with  respect  to  their 
energy  requirements,  which  are  of  interest  and  of  increasing  importance 
in  the  solution  of  certain  problems  of  medicine.  A  discussion  of  these  re- 
lationships will  necessitate  a  survey  of  the  general  phenomena  of  bacterial 
nutrition. 

3.    Chemical  Requirements  for  Bacterial  Development: 

a — For  Structure.        b — For  Energy. 

The  cytoplasm  of  bacteria  contains  nitrogen,  carbon,  hydrogen  and 
oxygen,  together  with  other  elements  in  lesser  amounts,  in  about  the  same 
proportions  as  those  found  in  other  living  cells.  The  phosphoric  acid 
content  is  higher  than  that  found  in  the  cells  of  a  majority  of  higher 
plants  or  animals,  however.*^  It  is  obvious  that  the  growth  of  bacteria  in 
the  abstract  depends  upon  the  availability  of  these  elements,  together  with 
those  of  lesser  occurrence,  in  proper  amounts  and  in  proper  combinations. 
For  purposes  of  discussion,  attention  will  be  directed  specifically  toward 

'  Thus,  the  ash  of  Bacillus  xerosis  contains  34  per  cent  of  phosphorus  calculated 
as  phosphoric  acid,  the  tubercle  bacillus  55  per  cent,  the  cholera  vibrio  about  45  per  cent. 


BACTERIA  I.   METABOLISM   WITHIN  THE  BODY      609 

nitrogen,  as  an  eleiuent  of  great  stnietural  significance,  and  carbon,  of 
peculiar  inipoi-tancu  as  the  basis  of  the  energy  phase  of  bacterial 
metabolism. 

a.  Structural  Chemical  Requirements. — J>acteria  can  not  multiply 
in  non-nitrogcnuiis  media,  and  the  organisms  of  interest  and  significance 
to  man  derive  their  iiitrog-en  requirements  from  nitrogen  in  combination 
with  carbon,  hydioa^^i  and  oxygen  of  the  amino-acid  complexes — poly- 
peptids,  peptones,  or  proteins.  The  more  fastidious  organisms,  as  the 
Gonococcus  and  Meningococcus,  require,  or  at  least  develop  best  in,  media 
containing  protein  but  little  altered  from  the  state  in  which  it  exists  in 
the  human  or  aninuil  body.  Others  grow  very  well  indeed  in  media  con- 
taining less  highly  organized  nitrogen,  as  for  example  that  of  peptone. 
None  will  grow  in  the  absence  of  this  element ;  hence,  it  may  be  regarded 
as  an  essential  structural  element.  Nitrogen  has  no  energy  value,  however, 
for  parasitic  or  pathogenic  microbes. 

b.  Energy  Chemical  Requirements. — Bacteria  derive  their  energy 
from  the  oxidization  r;f  carbon,  in  the  last  analysis,  and  the  state  of  com- 
bination of  this  element  with  others — particularly  oxygen  and  hydrogen 
[as  well  as  nitrog-en  in  proteins  and  protein  derivatives] — determines  to  a 
very  considerable  degree  the  nature  of  the  products  of  specific  bacterial 
metabolism.  The  iiiHuence  of  associative  elements  lipon  bacterial  metab- 
olism and  even  the  specificity  of  bacterial  action,  from  the  viewpoint  of 
energy,  is  shown  in  the  following  well  authenticated  series  of  illustrations: 


4,     The   General   Nature  of  the    Products  of   Bacterial 

Growth,  Arising  from  the  Utilization  of  Proteins 

and  of  Carbohydrates  for  Energy — Toxin, 

Indol  and  Enzyme  Formation. 

Diphtheria  Toxin. — It  is  well  known  that  the  soluble  or  exotoxin  of 
the  diphtheria  bacillus  is  the  s}>ecific  product  which  makes  this  organism 
formidable  to  man.  Diphtlicria  toxin  is  also  excreted  incidentally  to  the 
growth  of  the  microbe  in  plain  nutritive  broth,  wdiich  consists  essentially 
of  a  neutral  mixture  of  peptone,  meat  extractives,  salts  and  water.  In 
such  a  medium,  the  diphtheria  bacillus  develops  rapidly  and  wathin  a 
week  or  ten  days  the  filtrate  of  this  culture  medium,  freed  from  all  bacteria 
or  other  particulate  matter,  is  extremely  toxic  for  guinea  pigs.  Indeed, 
0.025  cubic  centimeter  of  such  bacteria-free  broth  frequently  kills  250 
gram  giiinea  pigs  A\'ithin  four  days  with  very  definite  specific  symptoms 
and  lesions. 

Contrast  this  Inuhly  toxic  broth  with  that  resulting  from  the  gi'owth 
of  the  same  organism  under  precisely  the  same  conditions  in  the  same 


670  ARTHUR  ISAAC  KENDALL 

medium  to  which  has  been  added  merely  a  minimum  of  0.5  per  cent  of 
gkieose.  Here  the  broth  is  acid  in  reaction  in  place  of  slightly  alkaline, 
but  otherwise  it  appears  to  be  the  same  (Van  Turenhout,  Smith,  Kendall). 
Injected  into  f^iinea  pig's,  however,  the  glucose  broth  is  found  to  be  wholly 
without  toxicity.  The  simple  addition  of  a  small  amount  of  glucose  has 
completely  changed  the  character  of  the  products  formed  as  the  result  of 
the  growth  of  the  diphtheria  bacillus.  Lactic  and  other  acids  are  foi-med 
under  these  conditions,  but  no  soluble  toxin. 

Indol  Formation. — The  amount  of  indican  excreted  in  the  urine  has 
long  been  regarded  by  some  observers  (Combe,  Bahr)  as  an  index  of  the 
intensity  of  that  obscure  clinical  condition  spoken  of  as  "auto-intoxica- 
tion." Irrespective  of  the  clinical  significance  of  urinaiy  indican,  how- 
ever, the  parent  substance  is  indol  (Kendall),  an  aromatic  residue  of  the 
amino  acid  tryptophan.  In  man,  indol  is  produced  from  tryptophan  in 
the  intestinal  tract  by  the  action  of  Bacillus  coli.  Bacillus  proteus,  and  to  a 
lesser  extent  by  other  facultative  proteolytic  organisms,  acting  in  the 
absence  of  utilizable  carbohydrates.  The  absorption  of  indol  from  the  ali- 
mentai-;^'  canal,  its  oxidization  in  the  liver,  and  its  excretion  and  sig- 
nificance are  discussed  later. 

The  production  of  indol  from  tryptophan  by  cultures  of  B.  coli,  Bacil- 
lus proteus,  the  cholera  vibrio  or  other  bacteria  can  be  obsei-ved  readily 
in  the  test  tube;  the  conditions  favoring  or  preventing  its  formation  are 
easily  controlled.  Indol  appears  within  twenty-four  to  forty-eight  hours  in 
ordinary  sugar-free  nutrient  broth  containing  tryptophan,  such  as  that  in 
w^hich  the  diphtheria  bacillus  produces  toxin.  Precisely  as  the  addition  of 
glucose  to  plain  nutrient  broth  prevented  the  fonnation  of  diphtheria  toxin 
by  the  diphtheria  bacillus,  so  that  addition  of  glucose  to  such  broth  pre- 
vents the  formation  of  indol  by  the  colon  bacillus.  Bacillus  proteus  and  the 
cholera  vibrio.  In  place  of  indol  and  other  products  of  putrefaction,  which 
appear  in  sugar-free  media- of  the  kind  described,  the  addition  of  glucose 
so  changes  the  products  of  metalx)lism  of  these  organisms  that  only  organic 
acids — as  lactic  and  acetic — are  formed,  together  with  carbon  dioxid  and 
hydrogen;  in  other  words,  the  substitution  of  utilizable  carbohydrate  for 
protein  as  a  source  of  energ}'  alters  completely  the  nature  of  the  products 
formed. 

The  Formation  of  Protein-Liquefying  Enzymes. — Bacillus  proteus, 
the  cholera  vibrio,  and  several  other  parasitic  and,  less  commonly,  patho- 
genic bacteria,  form  soluble  enzymes,  much  like  trypsin  in  their  protein- 
digestive  power,  in  sugar-free  media.  These  enzymes  may  be  obtained  in  a 
reactive  state,  quite  free  from  bacteria,  by  filtering  the  latter  away  (Fuhr- 
mann).  The  germ-free  filtrate  is  strongly  proteolytic  for  a  variety  of 
proteins,  including  gelatin,  breaking  the  complex  molecule  into  amino 
acids  and  po-lypeptids. 

The  addition  of  glucose  to  cultures  of  the  cholera  vibrio  or  Bacillus 


EACTERIx\L  METABOLISM  WITHIN  THE  BODY      671 

pioteus  prior  to  inoculation  [to  the  extent  of  0.5  per  cent  or  more]  will 
so  alter  the  products  of  growth  that  the  soluble  proteolytic  enzyme  and  all 
other  evidences  of  proteolytic  and  putrefactive  activity  are  no  longer 
detectable  in  the  cultui'e  medium  (Kendall  and  Walker).  On  the  con- 
trary, lactic  and  other  acids  indicative  of  the  fermentation  of  carbo- 
hydrates are  formed.  Here  again  the  addition  of  glucose  in  a  minimal 
amount  of  0.5  per  cent  has  completely  altered  the  products  of  growth.  In 
other  words,  from  the  illustrations  cited,  small  amounts  of  glucose  pre- 
vented the  formation  of  toxin  in  cultures  of  the  diphtheria  bacillus,  of 
indol  in  cultures  of  Bacillus  coli  and  Bacillus  proteus,  and  of  a.  soluble 
proteolytic  enzyme  in  cultures  of  the  cholera  vibrio  and  Bacillus  proteus. 
If  space  permitted,  examples  of  the  sparing  action  of  utilizable  carbo- 
hydrate for  protein  as  sources  of  energy  might  be  cited  from  all  fields  of 
bacterial  activity,  but  those  herewith  presented  are  illustrative.  Ad- 
ditional observations  of  specific  interest  are  discussed  in  appropriate 
sections. 

It  is  worthy  of  note  that  a  minimum  of  0.5  per  cent  of  glucose  was 
specified  in  each  instance.  Experience  has  shown  that  the  diphtheria 
bacillus  can  utilize  from  0.1  to  0.3  per  cent  of  glucose  without  producing 
enough  fermentation  acid  and  other  products  of  the  cleavage  of  glucose  to 
inhibit  its  further  growth  (Theobald  Smith).  Under  these  conditions 
no  toxin  is  demonstrable  until  the  sugar  [glucose]  has  disappeared.  Then 
toxin  begins  to  form. 

Bacillus  coli  and  Bacillus  proteus  do  not  form  indol  in  culture  media 
until  the  utilizable  sugar  is  used  up.  If  the  amount  of  sugar  is  somewhat 
less  than  0.5  per  cent,  the  products  of  fermentation  incidental  to  the 
utilization  of  it  for  energy  do  not  inhibit  the  subsequent  development  of 
the  colon  or  proteus  bacilli,  and  the  formation  of  indol  proceeds  after 
the  glucose  is  fennented. 

Similarly,  relatively  small  amounts  of  glucose  or  other  utilizable  car- 
bohydrate, somewhat  less  than  0.5  per  cent — the  limit  of  tolerance  varies 
somewhat  with  the  strain  of  the  organism — prevent  the  formation  of  pro- 
teolytic enzymes  by  cholera,  proteus  and  other  bacilli.  When  the  carbo- 
hydrate is  used  up,  however,  provided  the  conditions  due  indirectly  to  the 
accumulation  of  products  of  fermentation  are  not  too  unfavorable,  the 
organisms  attack  the  protein  constituents  of  the  medium  for  their  energy, 
and  the  proteolytic  enzyme  makes  a  belated  appearance.  It  should  be 
emphasized  that  the  presence  of  glucose,  or  other  utilizable  carbohydrate 
in  cultures  of  cholera,  proteus,  or  other  bacteria,  which  form  a  soluble 
proteolytic  enzyme,  prevents  the  formation  of  the  enzyme  in  the  reactive 
state.  ^N^either  glucose  nor  any  other  carbohydrate  prevents  the  action  of 
the  mature,  reactive  proteolytic  enzyme  when  it  has  been  elaborated  (Ken- 
dall and  Walker(6)).  In  other  words,  when  the  enzyme  is  formed  in  an 
active  state,  as  for  example  in  sugar-free  media,  this  bacteria-free  enzyme 


G72  ARTHUR  ISAAC  KENDALL 

will  act  quite  as  readily  upon  protein  media  containing  glucose  as  upon 
protein  media  from  wLich  glucose  is  absent. 

The  foregoing  illustrations  typify  a  very  general  property  of  bacteria, 
and  of  other  living  things  for  that  matter,  with  resi>ect  to  metabolism. 
It  has  long  been  a  physiological  dictum  that  '^carhohydrate  spai-es  body 
protein"  (lIoweIl(«))^  meaning  by  that  that  an  animal  requires  a  definite, 
if  minimal,  amount  of  dietary  protein  to  maintain  the  nitrogen  equilibrium 
of  the  adult  organism.  This  minimal  amount  of  nitrogen  is  indispensable 
for  the  repair  of  structural  wear  and  tear,  and  for  the  replacement  of 
nitrogenous  losses  in  secretions,  enz^-mes  and  other  nitrogen-containing  sub- 
stances, which  are  of  necessity  constantly  lost  to  the  body.  The  fuel  or 
energy-  requirement  of  the  organism,  on  the  contrary,  amounting  to  many 
times  the  minimal  nitrogen  requirement,  can  be  met  by  the  feeding  of 
non-nitrogenous  food,  as  carbohydrate  and,  to  a  lesser  degree,  organic 
acids  or  fat. 

Bacterial  nutrition  presents  the  same  fundamental  phenomena  of 
structural  and  energy  requirements.  The  former  absolutely  requires 
nitrogen  as  one  element  in  its  make-up,  whereas  the  latter  may  be  satisfied 
by  non-nitrogenous  organic  substances.  Of  these,  the  carbohydrates  as  a 
class  are  of  paramount  importance,  although  of  varying  degrees  according 
to  specific  characteristics  of  the  organisms  under  investigation.  Precisely 
as  saprophytic  bacteria  were  found  to  be  more  energetic  cleavers  of  protein 
than  parasitic  and  pathogenic  bacteria,  so  the  saprophytic  types  are  some- 
what more  energetic  cleavers,  both  in  kind  and  amount,  of  carbohydrate 
than  the  pathogenic  types.  Hence,  a  majority  of  the  progressively  patho- 
genic bacteria,  as  typhoid,  dysentery,  diphtheria  and  many  others,  utilize 
the  hexoses  [especially  glucose],  but  fail  to  utilize  the  bioses,  as  lactose  and 
saccharose.  The  pathogenic  bacteria  produce  less  deep  seated  changes 
even  in  the  hexoses  than  do  the  saprophytic  types.  In  general,  the 
changes  induced  by  the  former  result  in  the  formation  of  lactic  and  acetic 
acids,  whereas  the  latter  frequently  oxidize  a  not  inconsiderable  portion  of 
the  hexose  to  carbon  dioxid  and  hydrogen. 

Returning  to  the  conditions  prevailing  in  cultures  of  diphtheria,  colon 
and  cholera  orgarisms  referred  to  above,  it  will  be  found  that  plain  or 
sugar-free  media  offer  to  bacteria  protein  and  protein  derivatives  [pep- 
tone, polypeptids  and  amino  acids],  as  the  sole  source  of  structure  and  of 
energy.  The  gluccise  met^lia  offer  precisely  the  same  protein  and  protein 
derivatives  for  structure — non-nitrogenous  substances  are  not  suitable  for 
structure,  generally  speaking — and,  in  addition,  a  choice  between  this 
protein  or  protein  derivative  and  carbohydrate  for  energy.  To  sum- 
marize: 

The  marked  difference  discernible  between  the  significant  products 
formed  by  bacteria  in  non-saccharine  media,  where  both  structure  and 
energy  requirements  are  of  necessity  obtained  from  the  nitrogenous  protein 


BACTEKIAL  METABOLISM  WITHIN  THE  BODY      673 

derivatives,  and  the  absence  of  such  significant  products  [toxin,  indol  or 
enxyme]  in  the  glucose-nitrogenous  media  indicates  the  importance  of  the 
source  of  energy  as  a  determining  factor  in  directing  tlie  type  of  action 
of  the  microbe. 


5.    The   Specificity   of    Action  of    Pathogenic   Bacteria 
and  Its  Relation  to  Proteins  and  Carbohydrates 

From  what  has  been  stated  previously,  it  would  appear  that  pathogenic 
and  parasitic  bacteria  produce  significant  or  specific  nitrogenous  waste 
products  incidental  to  their  utilization  of  protein  or  protein  derivatives 
for  energy.  Thus,  diphtheria,  typhoid,  dysentery,  cholera,  paratyphoid,- 
glanders,  colon,  proteus,  and  many  other  pathogenic  microbes  produce 
specific  toxins  or  other  characteristic  nitrogenous  products  in  protein  en- 
vironments from  which  utilizable  carbohydrates  are  excluded. 

On  the  contrary,  when  in  addition  to  protein  utilizable  carbohydrates 
are  also  available  as  sources  of  energy,  these  same  organisms  act  upon  the 
latter  instead  of  the  former,  and  produce  therefrom  acidic  products,  chiefly 
lactic  and,  to  a  lesser  extent,  acetic  acid. 

In  other  words,  the  simple  addition  of  glucose  to  cultures  of  patho- 
genic bacteria,  other  conditions  remaining  the  same,  brings  about  a  strik- 
ing alteration  of  the  nature  of  their  metabolic  products.  In  place  of  toxins, 
phenols,  «katol,  and  other  protein  derivatives,  specific  or  characteristic 
of  each  individual  microbe,  all  produce  innocuous  lactic  and  acetic  acids. 
These  foraiidable  incitants  of  disease  in  man  have  become  potentially 
lactic  acid  bacteria.  Grown  in  glucose  media,  therefore,  the  diphtheria, 
typhoid,  cholera  and  other  pathogenic  bacteria  become  the  qualitative 
equivalents  of  the  Bulgarian  lactic  acid  bacillus.® 

Stated  difl:erently,  it  may  be  said  that  the  specificity  of  action  of  the 
vast  majority  of  bacteria  pathogenic  for  man  is  dependent  upon  their 
utilization  of  protein  for  energy  (Kendall). 

Fats  play  a  very  minor  part  in  the  metabolism  of  pathogenic  bacteria, 
other  than  those  of  the  acid-fast  gToup,  which  includes  the  tubercle  and 
leprosy  bacilli.  The  effects  of  utilizable  fats  are  comparable  to  the  carbo- 
hydrates rather  than  the  proteins,  however,  so  far  as  their  energy  rela- 
tionships are  concernede 

The  toxicity  of  the  cellular  substance  of  bacteria  is  not  considered  in 
this  connection,  nor  is  it  relevant.  Available  evidence  indicates  that  the 
cytoplasm  of  non-pathogenic  bacteria,  as  for  example  Bacillus  prodigiosus, 
may  be  many  fold  more  deadly  to  animals  than  that  of  such  formidable 

•It  is  obvious  that  a  continuous  supply  of  utilizable  carbohydrate  must  be  avail- 
able; when  the  sugar  is  used  up,  provided  the  orfranisms  are  not  killed  bj^  the  products 
resulting  from  fermentation,  they  will  at  once  attack  the  protein  again  and  generate 
their  specific  protein  decomposition  products. 


674  AKTHTJE  ISAAC  KE]N'DALL 

incitants  of  disease  as  diphtheria,  anthrax,  or  typhoid  hacilli  (Vaughan). 
The  effects  of  carbohydrates  and  proteins  upon  the  composition  of  the 
c^-toplasm  of  bacteria  is  discussed  in  the  following  section. 


6.     Quantitative  Measures  of  Bacterial  Metabolism,  the 

Effects  of  Utilizable  Carbohydrates  upon  General 

Metabolism,  and  the  Elementary  Composition 

of  the  Bacterial  Cell. 

It  is  very  evident  that  there  are  far-reaching  theoretical  and  practical 
applications  of  the  theory  that  the  "specificity  of  action  of  the  vast 
majority  of  bacteria  depends  upon  their  utilization  of  protein  or  protein 
derivatives  for  energy."  The  application  of  the  theory  to  the  domain  of 
medicine  is  closely  associated  with  the  corollary  thereof,  namely,  that  the 
"great  majority  of  pathogenic  bacteria  become  potentially  lactic  acid 
bacteria  when  they  are  gi'owing  in  an  environment  containing  carbo- 
hydrates or  other  non-nitrogenous  compounds  from  which  they  can  obtain 
their  energy." 

So  sweeping  an  assertion  would  appear  to  require  more  than  qualitative 
evidence  for  its  consideration  or  acceptance.  Fortunately,  such  evidence 
is  available  from  several  sources. 

The  chemical  basis  for  the  proof  of  the  theory  of  the  sparing  action  of 
utilizable  carbohydrate  awaited  the  development  of  methods  for  the  study 
of  metabolism  which  were  applicable  to  bacterial  cultures.  Qualitative 
evidence  has  long  been  known,  even  though  it  was  not  appreciated  for  its 
full  significance. 

The  very  exact  micro  methods  of  urine  analysis,  developed  and  per- 
fected by  Folin  and  his  associates  (Folin(rf)),  have  been  found  applicable 
to  the  study  of  nitrogenous  metabolism  in  cultures  of  bacteria  (Kendall 
and  Farmer).  The  analytical  data  obtained  are  as  precise  as  any  obtain- 
able for  corresponding  metabolic  studies  upon  man  or  animals.  Indeed, 
in  some  respects  they  are  of  greater  precision,  inasmuch  as  tlie  total  nitro- 
genous changes  induced  by  various  bacteria  under  varying  cultural  con- 
ditions are  always  reproducible,  since  there  is  neither  gain  nor  loss  of 
nitrogen  during  the  experiment. 

The  quantitative  studies  of  bacterial  metabolism  were  carried  out  in 
precisely  the  same  manner  as  a  corresponding  metabolic  study  upon  man 
or  upon  an  experimental  animal.  Broadly  speaking,  the  significance  of 
the  results  is  the  same  for  bacteria  in  either  case.  The  results  of  these 
quantitative  metabolic  studiers  appear  to  be  very  clear  cut  and  definite; 
they  bear  out  exactly  what  has  been  indicated  by  qualitative  observations, 
namely,  that  utilizable  carbohydrate  added  to  protein  culture  media  does 


BACTERIAL  METABOLIS^I  WITHi:s'^  THE  BODY      675 

shield  the  nitrogenous  constituents  from  utilization  for  energy.  These  ex- 
periments also  demonstrate  the  very  considerable  amounts  of  acid — chiefly 
lactic  and  acetic — which  appear  concomitantly  with  the  utilization  of  the 
carbohydrate  for  energy.  In  this  respect,  the  sugar-protein  cultures  con- 
trast strikingly  with  the  purely  protein  cultures,  which  become  more  or 
less  alkaline,  due  to  the  gradual  accumulation  of  basic,  nitrogenous  waste 
products  arising  from  the  combustion  of  the  nitrogenous  constituents  of 
the  non-saccharine  media.  The  nitrogenous  waste  products  arising  from 
the  utilization  of  protein  for  structural  requirements  and  structui*al  re- 
placements, although  relatively  small  in  amount,  were  also  clearly  indi- 
cated in  these  quantitative  analytical  studies. 

A  word  of  explanation  of  the  analogy  between  the  metabolic  waste 
products  of  man  and  of  bacteria  will  be  required  to  indicate  the  parallelism 
between  human  [multicellular]  nitrogenous  nietabolism  and  bacterial 
[unicellular]  metabolism. 

It  will  be  remembered  that  the  principal  end  product  of  the  physio- 
logical metabolism  of  the  proteins  of  the  food  and  the  tissues  in  man.  is 
excreted  through  the  kidneys  into  the  urine  as  urea.  Urea  is  derived,  in 
the  last  analysis,  largely  or  chiefly  from  the  deamination  of  amino  acids: 
the  ammonia  liberated  is  changed,  principally  in  the  liver,  to  urea. 

Ammonia  has  no  energy  value  and  whenever  amino  acids  [protein  or 
protein  derivatives]  are  used  in  the  body  for  energy,  for  transformation 
into  glucose,  or  glycerin,  or  for  storage  as  glycogen  or  fats,  the  anamonia 
is  discarded  and  changed  to  urea,  unless  a  deficit  of  alkali  leads  to  its 
combination  with  acids  that  must  be  excreted  through  the  kidneys.  The 
excretion  of  urea  is  markedly  increased  when  a  purely  protein  diet  is 
provided,  and  it  is  greatly  reduced  when  the  energy  requirements  of  the 
body  are  provided  for  by  a  caibohydrate  regimen,  supplying,  however, 
sufficient  protein  for  structural  and  replacement  needs. 

This  urea  may  be  regarded,  therefore,  as  of  exogenous  and  of  en- 
dogenous origin  (Folin),  the  former  being  influenced  largely  by  an 
excess  of  protein  above  the  structural  requirements,  the  latter  more  spe- 
cifically associated  with  structural  changes  in  the  tissues  and  organs.  The 
exogeiicus  urea  is  greatly  influenced  by  the  nature  of  the  diet,  being  in- 
creased when  the  energy  requirement  of  the  body  is  obtained  chiefly  by 
the  oxidization  of  proteins  and  reduced  when  the  energy  needs  are  de- 
rived largely  from  dietary  carbohydrate  and  fat.  The  endogenous  urea 
is  less  variable  under  proper  dietary  conditions. 

Similarly,  bacteria  deaminizo  amino  acids  prior  to  their  utilization 
of  the  remainder  of  the  amino  acid  molecule  for  energy.  Also,  a  small 
amount  of  ammonia  is  apparently  produced  from  the  utilization  of  some 
nitrogenous  substance  for  the  structural  needs  of  the  bacterial  cell.  Bac- 
teria have  no  livers;  therefore,  so  far  as  is  known,  they  do  not  excrete 
urea  (Kendall  and  Walker).     Ammonia,  which  has  an  analogous  origin 


676  AKTHUR  ISAAC  KEJN^DALL 

in  man  and  in  bacteria,  is  "bacterial  urea,"  and  as  such  it  is  tho  best 
available  measure  of  nitrogenous  metabolism. 

The  "endogenous^^  ammonia  is  recognizable  when  bacteria  derive  their 
energy  solely  from  carbohydrates,  in  a  protein-carbohydrat(?  medium.  It 
is  of  course  masked  in  a  purely  protein  medium  where  deamination  of 
protein  occurs  prior  to  the  combustion  of  the  protein  for  energy,  as  well 
as  from  the  structural  nitrogenous  changes. 

The  following  analytical  data  are  illustrative  of  the  nitrogenous  metab- 
olism of  several  saprophytic,  parasitic,  and  pathogenic  bacteria,  under 
parallel  conditions: 

Briefly,  the  conditions  of  experiment  are  as  follow^s:  Plain,  nutrient, 
sugar-free  broth,  and  glucose  broth  respectively,  which  differ  only  in 
that  the  latter  is  reenforced  with  one  per  cent  of  glucose,  are  inocu- 
lated with  the  same  organism  under  exactly  similar  conditions,  incubated 
side  by  side,  and  examined  at  the  same  time  for  changes  in  titratable 
acidity  and  nitrogenous  changes,  particularly  ammonia  formation.  Am- 
monia formation  is  an  index  of  deamination,  associated  chiefly  ^vith  the 
utilization  of  the  non-nitrogenous  residue  of  the  amino  acid  complex  for 
energy.  In  media  containing  glucose  in  addition  to  the  protein  derivatives, 
the  energy  requirement  is  obtained  largely  at  the  expense  of  the  non- 
nitrogenous  carbohydrate,  wdiich  of  course  does  not  undergo  deamination 
prior  to  its  energy  transformation.  Under  these  conditions  the  sparing 
action  of  glucose  [carbohydrate]  for  protein  is  obviously  manifest(xl  by 
a  greater  or  lesser  reduction  in  the  amount  of  ammonia  formed  [deamina- 
tion]  in  contrast  to  the  amount  observed  in  the  corresponding  glucose- 
free  medium.     - 

The  table  on  following  page  also  shows  the  relatively  lesser  nitrogen 
change  in  media  induced  by  pathogenic  bacteria  than  that  characteristic  of 
the  saprophytic  types — as,  for  example,  between  Bacillus  dyscnteria^  and 
Bacillus  mesentericus.  This  is  in  harmony  with  the  observation  cited 
above  that  pathogenic  organisms,  generally  speaking,  are  less  active  chemi- 
cally than  the  ordinary  saprophytic  types  (Kendall,  Sears). 

Explanation:  In  general,  it  will  be  seen  that  all  the  bacteria  studied 
become  alkaline  in  reaction  and  form  considerable  amounts  of  ammonia 
in  sugar-free  broth.  Among  the  products  foi-med,  but  not  indicated  in 
the  table,  are  diphtheria  toxin  by  the  diphtheria  bacillus,  indol  by 
Bacillus  proteus  and  Bacillus  coli,  a  soluble  proteolytic  enzyme  by  Bacillus 
mesentericus,  Bacillus  proteus  and  Staphylococcus  aureus,  and  a  soluble 
hemolysin  by  Streptococcus  hemolyticus. 

In  the  glucose  medium,  all  the  bacteria  produce  a  relatively  strong 
acid  reaction  [chiefly  lactic  and  acetic  acids]  and  relatively  slight  amounts 
of  ammonia,  indicating  that  the  major  reaction  is  upon  the  glucose  in 
place  of  the  protein.  Neither  toxin,  enzyme,  hemolysin  nor  indol  is 
to  be  found  among  the  products  produced  from  glucose  by  the  organisms. 


BACTERIAL  METABOLISM  WITHm  THE  BODY      677 


Ten- Day  Observations 
Organism : 


B.  dysenterise  Shiga 

B.  dysenteriu?  Flexner   .  . . 

B.  diphtheriae 

B.  typhosus    

B.  paratyphosus  alpha  ... 
B.  paratyphosus  beta  . . . . 

B.  coli 

B.  proteus 

B.  mesentericus  

Streptococcus  hemolyticus 
Staphylococcus  aureus  . .  . 


Sugar-Free  Broth 


Reaction:       Ammonia 


—  0.30 

—  0.25 

—  0.50 

—  0.45 

—  0.20 
_0.60 

—  1.00 

—  2.00 

—  0.70 
4-0.70 

—  0.75 


4.20 
4.50 
3.10 
5.40 
6.30 
7.50 
+  24.40 
+  58.40 
+  38.50 
-f  1.40 
+  38.70 


+ 
+ 


Olucoae  Broth 


Reaction 


+  2.80 
-f  2.45 
4-  2.80 
+  3.10 
+  3.40 
-A-  3.75 
+  4.90 
+  3.55 
+  1.50 
+  3.50 
+  3.75 


Ammonia: 


+  0.70 
+  0.70 
+  1.05 
+  0.60 
+  1.20 
+  1.40 
+  1.05 
+  1.40 
+  2.80 
+  0.70 
+  0.70 


Legend : 

Reaction, 


Ammonia, 


—  indicates   the   amount   of   alkalinity   developed   in   terms   of   normal 

alkalai  per  100  cubic  centimeters  of  culture. 
+  indicates  the  amoiint  of  acidity  developed,  in  terms  of  normal  acid 

pef  100  cubic  centimeters  of  culture,  compared  with  suitable  controls. 

The  figures  indicate  the  number  of  milligrams  of  nitrogen  as  ammonia 

developed  in  100  cubic  centimeters  of  media,  compared  with  suitable 

controls. 


These  qualitative  and  quantitative  observations,  illustrative  of  the 
sparing  action  of  utilizable  carbohydrate  for  protein  as  a  source  of  en- 
ergy, together  with  the  significance  of  thia^  sparing  action  in  terms  of 
important  products  arising  from  the  use  of  protein,  and  their  replace- 
ment by  innocuous  compounds  when  carbohydrate  is  available,  leads 
logically  to  the  generalization  that  "the  significance  of  the  action  of 
pathogenic  bacteria,  so  far  as  is  known,  depends  upon  their  utilization  of 
protein  for  energy."  When  carbohydrate  is  used  for  energy,  the  organisms 
are  potentially  lactic  acid  bacteria  in  terms  of  their  reaction  products 
(Kendall). 

The  endotoxins,  so-called,  of  bacteria  are  not  considered  in  this  dis- 
cussion, which  deals  with  the  products  of  growth.  It  appears  to  be  a 
fact,  however,  that  carbohydrate  influences  the  comixjsition  of  bacteria  in 
a  striking  manner.  Thus,  Cramer  has  analyzed  tlie  dried  substance  of 
bacteria  grown  upon  ordinary  nutj'ient  agar,  and  upon  glucose  agar  of 
otherwise  the  same  composition,  with  the  following  results,  expressed 
in  percentages: 


Sugar-Free  Agar 

Glucose  Agar 

ORGANISM: 

Nitrogen 

Alcohol- 
ether  ex- 
tractives 

Ash 

Nitrogen 

Alcohol 
ether  ex- 
tractives 

Ash 

Pfeiflfer  bacillus 

Bacillus  H-28  

Pneuniobacillus    

Rhinoscleroma    bacillus 

66.6 
73.1 
71.7 
68.4 

17.7 
16.0 
10.3 
11.1 

12.56 
11.42 
13.94 
13.45 

53.7 
59.0 
63.3 
62.1     , 

24.0 
18.4 
22.7 
20.0 

9.13 

9.20 
7.88 
9.44 

678  AKTHUR  ISAAC  KENDALL 

It  will  be  seen  that  bacteria  grown  on  glucose  agar  contain  nearly 
twenty  per  cent  less  nitrogen,  and  materially  more  extractives  than  those 
grown  on  media  with  the  same  nitrogenous  constituents  but  without  the 
glucose.     The  significance  of  this  difference  is  yet  to  be  determined. 

Inasmuch  as  the  immunizing  processes  are  apparently  inseparable  from 
nitrogenous  substances,  however,  there  may  be  some  relations!)  ip  between 
a  maximum  nitrogen  content  of  bacteria  and  their  antigenic  potency, 
which  may  play  a  part  in  the  large  field  of  I)acterial  vaccines.  In  this 
connection,  the  reciprocal  variation  of  nitrogen  and  lipoids,  clearly  sug- 
gested in  the  table,  may  also  be  of  significance  inasmuch  as  solubility 
and  anti-complementary  properties  of  bacteria  appear  to  be  related  to 
the  lipoidal  content  of  bacterial  bodies  (Warden).  Whatever  the  sig- 
nificance of  the  composition  of  bacteria  may  be,  it  may  be  stated  con- 
fidently that  the  entire  series  of  phenomena  outlined  above — relating  to 
the  sparing  action  of  utilizable  carbohydrates  for  protein  in  the  energy 
manifestations  of  bacteria  and  their  effects  upon  the  composition  of  bac- 
teria even — is  of  material  importance  in  determining  the  nature  and 
extent  of  bacterial  action. 


C.    The  Chemistry  of  Bacterial  Metabolism 
1.    General  Statements 

The  chemistry  of  bacterial  metabolism  naturally  is  divided  into  two 
rather  distinct  phases — the  anabolic,  or  structural,  phase,  which  in  point 
of  time  occurs  first,  and  the  katabolic,  or  energy  phase,  which  follows  the 
maturation  of  the  bacterial  cell.^  The  latter  exceeds  the  foi-mer,  lx>th 
with  respect  to  the  amount  of  material  transformed  and  in  resj^ect  to 
the  significance  of  the  products  resulting  from  the  utilization  of  the 
various  substances  for  energy. 

Generally  speaking,  the  structural  or  anabolic  phase  consists  of  a 
series  of  hydrogenic  condensations  whereby  simpler  nitrogenous  sub- 
stances, as  amino  acids  or  polypeptids,  are  built  into  specific  proteins; 
where  glycerin  and  fatty  acids  are  synthesized  to  fats,  and,  in  association 
with  phosphorus,  into  nucleins;  and  where  glycogen-like  bodies  are  ap- 
parently synthesized  from  glucose. ^^    This  phase  of  bacterial  development 

•  It  is  almost  ciertain  that  a  certain  amounf  of  interchange  referable  to  the  anabolic 

{)hase  must  take  place  throughout  the  period  of  vegetative  activity  of  the  cell.  The 
osses  associated  with  the  formation  of  enzymes  and  other  essential  excretions  belong 
in  this  group. 

"Considerable  evidence  has  accumulated  indicating  the  possibility  of  a  mutual 
transformation  of  glycerin,  alanin  and  glucose  through  pyruvic  acid  into  the  three 
great  types  of  proteins,  carbohydrates,  and  fats. 


BACTEELVL  METABOLISM  WITHIN^  THE  BODY      679 

is  quite  similar  to  that  of  all  living  cells.  The  amount  of  material  re- 
quired to  meet  the  structural  requirements  of  bacteria,  and  to  replace 
losses  incidental  to  the  formation  of  soluble  enzymes  and  other  elements, 
is  very  little.  Usually,  also,  the  structural  waste  incidental  to  the  elabora- 
tion of  the  bacterial  substance  is  inconspicuous  in  amount  and  reactivity. 

The  cytoplasm  of  the  bacterial  cell  is  always  more  or  less  poisonous 
when  it  is  liberated  within -the  tissues  of  an  animal  or  man,  that  of  the 
saprophytic  types  of  bacteria  being  quite  as  reactive  on  the  whole  in  this 
regard  as  that  of  the  very  virulent  organisms,  as  Bacillus  diphtheria? 
(Vaughan).  The  significance  of  bacterial  infection,  however,  is  asso- 
ciated primarily  with  the  growth  of  bacteria  in  the  tissues,  or  with  the 
absorption  into  the  tissues  of  products  incidental  to  their  growth.  In 
other  words,  the  energy  phase  of  bacterial  metabolism  is  in  all  probability 
of  the  greatest  importance  from  the  viewpoint  of  microbic  infection  and 
microbic  intoxication.  ^ 

The  products  arising  from  the  transformation  of  nutritive  substances 
into  energy  by  bacteria  are  of  two  principal  types — nitrogen-containing, 
or  derivatives  thereof,  and  non-nitrogenous.  The  foiTner  arise  from  pro- 
teins or  protein  derivatives,  the  latter  from  carbohydrates,  less  commonly 
from  fats,^^ 

The  composition  of  the  highly  complex  nitrogenous  bacterial  toxins,  as, 
for  example,  that  of  the  diphtheria  bacillus,  is  unknown,  although  it  may 
be  separated  from  solution  by  protein  precipitants,  and  it  appears  to 
have  some  points  of  resemblance  to  that  group  of  the  proteins  known  as 
the  globulins.  Erom  the  viewpoint  of  the  present  discussion,  diphtheria 
toxin,  and  the  soluble  bacterial  toxins  in  general,  may  be  defined  as  soluble 
products  of  unknown  but  complex  composition,  containing  nitrogen,  aris- 
ing from  the  utilization  of  proteins  or  protein  derivatives  for  energy  by 
specific  bacteria. 

In  general,  the  measurable  changes  induced  in  the  nitrogenous  con- 
stituents of  culture  media  by  the  gi-eat  majority  of  pathogenic  microbes, 
as  deamitiation,  or  changes  in  amino  nitrogen,  are  quantitatively  the 
same.  (See  table  page  677.)  The  nitrogenous  metabolism  of  bacteria 
which  produce  soluble  toxins,  as  the  diphtheria,  tetanus,  and  Shiga  bacilli, 
is  comparable  in  magnitude  and  general  characteristics  to  that  of  such 
pathogenic  bacteria  as  the  tj^phoid  bacillus,  in  whose  cultures  soluble, 
specific  toxins  have  not  been  detected. 

The  qualitative- changes  induced  by  these  same  organisms  upon  ni- 
trogenous [protein]  substances  are,  on  the  contrary,  quite  unknown.  The 
elucidation  of  the  chemical  structure  of  toxins  and  other  harmful  nitro- 
gen-containing products  of  the  transfonnation  of  protein,  or  protein  de- 
rivatives, is  a  problem  for  the  bacterio-chemist  of  the  future  to  solve. 

"There  is  some  evidence  that  lecithin  and  similar  phosphatids  may  be  decom- 
posed by  bacterial  action  with  the  liberation  of  physiologically  active  substances. 


680  .      AKTHUR  ISAAC  KENDALL 

As  knowledge  of  bacteriology  has  increased,  attention  has  been  di- 
rected to  the  method  of  fcnuation  and  mode  of  physiological  action  of 
bacterial  products,  derived  from  protein,  from  poly[>eptids,  or  even  amino 
acids,  other  than  soluble  toxins.  Some  of  these  substances,  as  indol,  are 
regarded  by  certain  observers  to  be  indicative  *of  that  condition  spoken  of 
as  auto-intoxication  (Combe,  Bahi').  Others,  as  betaimidazole  ethylamine, 
possess  physiological  activity  even  in  minute  amounts,  which  may  have 
pathological  significance.  Between  these  two  general  groups  of  substances 
in  all  probability  lie  the  specific  products  of  the  typhoid  bacillus,  glanders, 
paratyphoid,  and  many  others,  which  are  perhaps  neither  as  highly  or- 
ganized chemically  as  the  soluble  toxins  of  the  diphtheria  or  tetanus 
bacilli,  nor  as  simple  as  the  amins  derived  from  the  aromatic  amino 
acids.  * 

2.    General  Reactions:    The  Formation  of  Phenols, 
Indol  and  Indican,  Amins 

The  types  of  reactions  through  which  proteins  are  transformed  by 
bacteria  into  simpler  compounds  incidental  to  their  utilization  for  energy 
are  fairly  ^vell  established,  and  inasmuch  as  certain  substances  of  clinical 
importance  are  formed  in  this  nrianner,  they  have  a  real  importance  in 
any  discussion  of  bacterial  action.  It  is  to  be  remembered  that  each 
kind  oi  organism  utilizes  protein  or  protein  derivatives  somewhat  dif- 
ferently and  characteristically,  but  in  general  one  or  more  of  the  fol- 
lowing reactions  are  involved,  either  successively  or  simultaneously  in 
the  katabolism  of  proteins: 

1.  RCHo.CHXHo.COOH  +  Ha  =-  E.Cn2.CIL,.C00H  +  NH3. 

Reductive  deamination  of  an  amino  acid  to  a  fatty  acid  with 
the  same  number  of  carbon  atoms. 

2.  R.CH,.CIIXII.,.COOH  +  IIoO  =  K.CHo.CHOILCOOH  +  NH,. 

Ilydrolytic  deamination  of  amino  acid  to  an  oxyacid  with  the 
same  number  of  carbon  atoms.  Lactic  acid  may  be  formed 
from  alanin  by  this  process. 

3.  R.CHo.CHNIL.COOH  +  O  -  R.CH2.CO.COOH  +  i^^H,. 

Deamination  and  simultaneous  formation  of  an  alpha  ketonic 
acid.     [Pyruvic  acid  transformation.] 

4.  R.CHo.CHmio.COOH  +  02=  Il.CH2.COOn  +  COo  +  Nil,. 

Deamination  of  amino  acid  and  simultaneous  oxidization,  re- 
sulting in  a  fatty  acid  with  one  less  carbon  atom. 

r>.     R.CHo.CHo.COOH >  R.CHo.CII,  +  CO.. 

Carboxylic  decomposition  of  fatty  acid  with  the  formation 
of  a  fattv  acid  containinfl:  one  less  carbon  atom. 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      681 

Ca.     R.CH2.CHNH0.COOH ^  R.CH2.  CHI2NH2  -J7  CO2. 

Carboxylic  decomposition  of  amino  acid  with  the  formation 
of  an  amin, 

or 

6b.     R.CH2.CHNH2.COOH  +  IL.  =  R.CHXH2XH2  +  H.COOH 

Decarboxylation  with  the  formation  of  formic  acid,  and  an 
amin. 
H.COOH  =-  CO2  +  H2 

Formic  acid,  under  the  action  of  formiase,  may  be  decom- 
posed into  carbon  dioxid  and  hydrogen. 


3.    Reactions  Illustrative  of  the  Decomposition  of 
Proteins  by  Bacteria 

a.  The  Decomposition  of  Tyrosin. — Organisms  like  Bacillus  pro- 
tens  act  upon  proteins  in  solution,  first  by  an  extracellular  cleavage  of 
the  protein  to  polypeptids,  and  probably  peptones  by  the  soluble  pro- 
teolytic enzymes  they  secrete,  then  decomposing  the  polypeptids  intra- 
cellularly,  according  to  the  reactions  indicated.  [In  the  alimentary  canal 
of  man,  it  is  probable  that  the  digestive  enzymes  are  largely  responsible 
for  the  initial  cleavage  of  the  protein  molecule.  The  subsequent  steps, 
giving  rise  to  products  not  formed  by  the  activity  of  gastro-intestinal 
enzymes,  as  indol,  are  the  result  of  intracellular  digestion  of  the  protein 
fragments  by  bacteria.^-] 

The  following  steps  in  the  decomposition  of  tyrosin  to  paracresol  and 
phenol  indicate  the  theoretical  progress  of  the  decomposition  of  this  amino 
acid  to  compounds,  as  paracresol  and  phenol,  which  have  no  available 
energy  for  the  organism.  In  this  state  they  are  eliminated  from  the 
bacterial  cell  and  appear  in  the  culture  medium,  or  in  the  alimentary 
canal. 

Tyrosin  Paraoxyphenyl  propionic  acid 

OH  OH 


CH2CimH2COOH  +H2=    CHoCHoCOOH     +  K^H, 

"The  formation  of  protein-liquefying  enzymes  and  the  production  of  indol  do  not 
take  place  in  cultures  of  Bacillus  proteus  containing  utilizablc  carbohydrate. 


682 


AKTHUR  ISAAC  KENDALL 


OH 


Paraoxyphenyl  acetic  acid 
OH 


'    CH2CH2COOH     +  30  =^     CH2COOH    +  H2O  -f-  COj 


OH 


Paracresol 
OH 


4. 


CH.COOH 


OH 


+  30  = 


+  CO2 

Pdraoxjbenzoic  acid 
OH 


COOH 


OH 


Phenol 
OH 


5. 


COOH 


+  C0, 


b.  Tryptophan  Decomposition. — Similarly,  tryptophan  undergoes  de- 
composition through  a  variety  of  intermediary  products,  some  of  which,  as 
indol  acetic  acid,  claimed  by  Herter  to  be  the  urinary  pigment  urorosein, 
skatol,  and  indol,  are  of  some  physiological  and  possibly  pathological  sig- 
nificance. Bacilhis  coli  and  Bacillus  proteus  are  the  common  producers  of 
indol  in  the  intestinal  tract.  [It  may  be  repeated  here  that  utilizable 
carbohydrate  will  prevent  the  formation  of  indol  and  skatol.] 


Tryptophan 

ch2Ch:n^H2COOH  +  H2 


Indol  propionic  acid 

A  CH2CH2C00H  +  :nh< 


KA 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      683 

Betaethyl  indc^ 
CH2CH2COOH     ^         /^  V1CH2CII3  +  COo 


CH2CH3  +  30 


Indol  acetic  acid  (urorosein) 
CH2COOH  +  HgO 


CH.COOH 


Betaindol  formic  acid 

^    A.    COOH  +  H2O 


+  C0, 


Indol  is  formed  in  the  greatest  amounts  in  those  cases  where  intestinal 
putrefaction  is  actively  taking  place.  Obstniction  of  the  small  intestine 
is  a  very  potent  factor  in  promoting  excessive  amounts  (Combe).  Slug- 
gish peristalsis  with  the  attendant  relatively  slow  absorption  of  the 
products  of  protein  digestion  provides  conditions  favoring  an  ove^gro^v1h 
of  Bacillus  coli  and  other  indol-forming  bacteria. 

Gelatin,  which  is  deficient  in  tryptophan  [and  other  aromatic  amino 

acids]   does  not  play  a  part  in  indicanuria.     The  toxicity  of  indol  ap' 

►  pears  to  be  slight,  and  it  is  lessened  when  indol  is  oxidized  and  is  paired 

with  sulphuric  acid  (Herter).     Amounts  administered  by  mouth  to  0.2 

gram,  however,  appear  to  cause  headache,  malaise  and  lassitude. 

Defective  oxidization  in  the  liver  may  lead  to  a  low  gi-ade  indol 
toxemia.  Herter  and  Wakemiin  found  tl>at  surviving  liver  acts  upon 
indol  in  such  a  manner  that  it  camiot  be  recovered  by  distillation  of  the 
organ.     The  kidney  and  muscle  ai*e  unable  to  ^x  indol  in  this  manner. 


684  AKTHUR  ISAAC  KENDALL 

The  daily  excretion  of  indican  varies  ^'eatlj,  both  in  the  period  of  life 
and  with  the  individual.  Xurslings  practically  never  excrete  indican 
(Soldin).  Adults  secrete  up  to  10-12  milligrams  daily  without  symp- 
toms (Folin  and  Denis). 

Indol  acetic  acid,  resulting  fro?n  an  oxidative  deamination  of  tryp- 
tophan, is  said  by  Ilerter  to  be  the  mother  substance  of  the  urinary  pi«»-- 
ment,  urorosein.  Indol  is  absorbed  from  the  intestinal  tract  and  oxidized 
in  the  body,  chiefly  apparently  in  the  liver,  to  indoxyl; 


and  excreted  as  the  sodium  or  potassium  salt,  indoxyl  sodium  [potas- 
sium], sulphonate,  or  indican.  It  is  also  excreted  under  certain  conditions 
paired  with  glycuronic  acid. 

OXa 
/ 

-  OS  -^  o  = 

I! 

Indoxyl  sodium  sulphonate 

Phenyl  alanin  undergoes  decomposition  similar  to  tyrosin,  finally 
being  absorbed  from  the  alimentary  canal  and  paired  with  glycuronic  acid 
or  with  sulphuric  acid.  In  the  latter  event,  it  becomeSj  together  with 
indican,  phenol  and  paracresol,  the  principal  ethereal  sulphates  of  the 
urine.  Phenol,^^  and  paracresol,  resulting  from  the  bacterial  degradation 
of  phenyl  alanin  and  tyrosin,  are  excreted  in  considerable  amounts  as 
ethereal  sulphates.  Folin  and  Denis  state  that  as  much  as  0.2  to  0.3 
gram  of  phenol  may  be  excreted  through  the  urine  daily  by  apparently 
normal  adults.  None  of  the  substances  excreted  as  ethereal  sulphates 
appear  to  be  very  toxic,  although  long  continued  formation  of  them  in 
the  alimentary  canal  may  be  associated  wnth  severe  disturbances.  At  the 
present  time  it  may  be  stated  that  the  formation  of  the  mother  substance? 
of  the  urinary  ethereal  sulphates  is  an  indication  of  bacterial  decompo- 
sition of  the  products  of  gastro-intestinal  digestion  of  proteins;     This 

"  It  is  worthy  of  note  that  the  body  rids  itself  of  phenol,  cresol,  and  indol  [products 
arising  from  the  bacterial  putrefaction  of  protein]  together  with  sulphuric  acid,  which 
arises  from  the  oxidization  of  the  sulphur  of  protein,  as  non-poisonous  ethereal  sul- 
phates. This  combination  of  noxious  products  of  protein  degradation,  with  a  mininml 
withdrawal  of  sodium  or  potassium  would  appear  to  be  a  not  unimportant  method  of 
elimination  of  a  fixed  acid  (sulphuric  acid),  without  impairing  to  any  marked  degree 
the  alkalai  reserve  of  the  body. 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      685 

takes  place  chiefly  in  the  small  intestine.  A  change  of  diet,  restricting 
protein  and  furaishing  a  large  part  of  the  caloric  i-equirement  above  that 
associated  with  a  reasonable  level  of  nitrogen  equilibrium,  by  carbohy- 
drate and  fat,  usually  will  lead  to  a  reduction  of  protein  putrefaction 
through  the  sparing  action  of  utilizable  carbohydrate  for  protein  in  the 
metabolism  of  the  intestinal  bacteria. 


4.    The  Effects  of  Utilizable  Carbohydrate  upon  the 
Formation  of  Phenols,  Indol  and  Amins 

Simple  decarboxylization  of  aromatic  amino  acids  gives  rise  to  amins, 
some  of  which  are  of  significance  from^their  physiological  action.  Thus, 
ornithin,  NH2.CH2.CH2.CHo.CHXH2.COOn,  is  changed  by  mixtures  ol 
bacteria  acting  upon  protein  into  putrescin  or  tetramethylenediamin, 

NH2.CH2.CH2.CH.2CHKH2C6OH     -^ 

CH2CH2CH2CH2  +  CO2 


I^H,  NH 


and  lysin  similarly  is  decarboxylized  to  cadaverin : 

lSrH2CH2.CH2.CH2.CH2.CHNH2.COOH-> 

CH2CH0CH2CII2CII2  +  CO2, 

NH2  ^  NH2 

or  pentamethylenediamin. 

Putrescin  and  cadaverin  were  about  the  first  of  the  group  of  sub- 
stances, frequently  called  ptomains,  to  be  isolated  and  identified.  It  is 
probable  that  sepsin  (Fraenkel)  also  belongs  to  this  class  of  diamins. 
The  clinical  significance  of  cadaverin  and  putrescin  is  not  clear.  These 
substances  have  been  frequently  detected  and  occasionally  isolated  from 
cases  of  cystinurea  (Spiegel).  The  information  available  at  present  is 
insufficient  to  explain  the  relationship,  however, — if,  indeed,  any  exists. 

Sepsin  is  said  by  some  to  be  a  capillary  poison  (Barger). 

Tyrosin  is  changed  by  the  loss  of  the  carboxyl  group  to  tyramin 
or  par  a  oxy  phenyl  ethylamin. 

OH  OH 


+  CO2 
CH2.CHNH2.COOH  +  Ho  CIL.CH0NH2. 


686  AKTHUE  ISAAC  KENDALL 

Barger  and  Walpole  have  detected  tyramin  in  meat  that  lias  been 
allowed  to  putrefy  spontaneously.  It  appears  to  be  a  physiologically  active 
substance  that  is  formed  in  small  quantities  when  ordinary  putrefactive 
organisms  are  allowed  to  act  upon  protein  in  the  absence  of  utilizable 
carbohydrates.  Such  a  condition  appears  to  be  present  in  the  alimentary 
tract  of  man  not  infrequently.  When  tyramin  is  injected  intravenously  in 
small  amounts  into  dogs,  it  raises  the  blood  pressure  rapidly  and  decidedly. 
The  same  authoi^  have  shown  that  this  substance  is  also  an  important 
pressor  constituent  in  some  ergot  preparations. 

Phenylethylamin,  derived  very  probably  from  phenyl  alanin,  as 
paraoxyphenyl  ethylamin  is  derived  from  tyrosin,  i^  perhaps  a  pressor 
base,  although  convincing  data  upon  this  point  is  wanting. 

Similarly,  histidin,  through  the  loss  of  the  carboxyl  group,  becomes  the 
powerfully  reactive  histamin,  or  beta  imidazole  ethylamin. 


H 


H 

/ 

C  — N 

1          )^       ^-" 

H 

HON 

1         Nc-H  +  CO^ 

1                   '' 
C-rN      . 

I 

CH^.CHNIL.COOH 

0  — N 
I 

Ackermann  has  detected  histamin  among  the  products  resulting  from 
the  decomposition  of  histidin  by  bacterial  action.  Somewhat  later,  Ber- 
thelot  and  Bertrand  described  their  Bacillus  aminophilus  intcstindis,  an 
intestinal  parasite  belonging  to  the  Mucosus  capsulatus  group,  which  they 
believed  to  be  the  causative  agent  in  the  production  of  histamin  in  the 
alimentary  canal.  About  the  same  time,  Mellanby  and  Twort  isolated  an 
organism,  apparently  closely  related  to,  if  not  identical  with,  Bacillus 
coli,  which  effects  the  same  transformation.  The  year  before,  Barger  and 
Dale  had  isolated  histamin  from  the  intestinal  wall.  Koessler  and 
Hanke  have  shown  recently  that  Bacillus  coli  will  produce  histamin  from 
histidin  in  cultures  of  this  organism. 

Ij;  is  significant  that  both  Berthelot  and  Bertrand  and  Mellanby  and 
Twort  have  found  that  the  amin  is  not  produced  in  acid  solutions.  A 
survey  of  the  experiments  suggests  strongly  that  the  acid  which  is  present 
in  such  cases  is  derived  from  the  fermentation  of  glucose.  Histamin 
is  best  isolated  from  '^putrefying"  mixtures.  In  this  connection,  the  ob- 
servation of  Garcia  that  glucose  added  to  putrefying  horseHesh  reduces 
the  yield  of  diamins  very  materially  is  significant.  It  would  appear 
that  utilizable  carbohydrates  interfere  with  the  utilization  of  the  protein 
or  prdtein  derivatives  for  energy,  precisely  as  is  the  case  with  other  putre- 
faction products  described  above. 


BACTERIAL  METABOLISM  WITIIIIsT  THE  BODY      687 

Histamin  is  a  very  reactive  compound.  According  to  Vaughan,  one- 
half  milligi-am  injected  into  a  guinea  pig  will  cause  death  very  soon.  The 
symptoms  elicited  suggest  in  a  striking  manner  those  characteristic  of 
anaphylactic  shock.  There  is  a. strong  contracture  of  smooth  muscle  fiher, 
including  that  of  the  bronchial  musculature.  The  latter  narrows  the 
lumen  of  the  bronchi  to  a  very  small  opening,  which  in  connection  with 
the  somewhat  tortuous  course  of  the  respiratory  tract,  leads  to  asphyxia- 
tion. There  is  also  noticed  a  rapid  fall  of  body  temperature.  According 
to  the  observations  of  Dale  and  Laidlaw,  however,  the  coagulability  of 
the  blood  in  such  cases  is  practically  unaltered,  which  is  a  point  of  dif- 
ference between  this  syndrome  and  that  of  anaphylaxis  induced  in  a 
sensitized  animal  with  the  homologous  protein. 

It  would  appear  from  available  evidence  that  the  formation  of  the 
aromatic  amins,  phenyl  ethylamin,  paraoxyphenyl  ethylamin,  beta  indol 
ethylamin,  and  beta  imidazole  ethylamin,  under  ordinary  intestinal  con- 
ditions, is  chiefly  the  result  of  the  activities  of  the  colon-proteus-mucosus 
capsulatus  group  of  bacilli.  It  is  probable  that  these  amins  do  not  form 
in  detectable  quantities  when  the  proportion  of  carbohydrate  to  protein  of 
the  food  is  suificient,  with  existing  alimentary  conditions  of  absorption,  to 
provide  at  least  a  minimal  amount  of  sugar  at  the  intestinal  levels  where 
these  organisms  ordinarily  are  found.  A  sour  milk  diet  is  supposed  to 
restrict  or  prevent  the  formation  of  amins,  and  of  other  putrefactive  prod- 
ucts as  well.  It  should  be  remembered  that  a  sour  milk  diet  is  one  re- 
stricted in  protein,  which  of  course  reduces  the  amount  of  protein  from 
which  the  parent  amino  acids  are  derived: ^^  The  carbohydrate  content  of  a 
typical  sour  milk  diet  is  decidedly  increased  in  proportion  to  the  protein. 
This  furnishes  a  readily  utilizable  source  of  energy  for  the  bacteria  of  the 
alimentary  canal,  and  thereby  switches  their  metabolism  from  the  protein 
constituents.  Under  these  conditions,  lactic  and  acetic  acids  are  produced 
largely,  in  place  of  the  amins  and  other  putrefactive  products. 


5.    The   Physiological   Action  of   the  Aromatic  Amins 

Generally  speaking,  the  amins  containing  the  benzene  nucleus,  phenyl 
ethylamin,  paraoxyphenyl  ethylamin,  and  indol  ethylamin  cause  an  in- 
crease of  blood  pressure  upon  injection,  paraoxyphenylamin  being  the 
most  powerful  of  this  gToup.  "There  is  some  theoretical  ground  for  asso- 
ciating the  symptoms  induced  in  experimental  animals  with  a  direct 
stimulating  action  of  the  sympathetic  system.  Barger  and  Dale,  in  study- 
ing this  relationship,  have  made  use  of  the  term  "sympathomimetic," 
which  seems  to  be  appropriate. 

"Gelatin  contains  much  less  of  the  aromatic  amino  acids  than  the  true  proteins. 
It  can  not  replace  protein  in  the  diet,  but  may  be  of  some  value  for  temporary  dietary 
reduction  in  these  compounds. 


688  ARTHUR  ISAAC  KENDALL 

Beta  imidazole  ethylamin  depresses  the  blood  pressure  upon  injec- 
tion, thus  differing  from  the  amins  with  benzene  nuclei. 

Continued   fonnation   of   these   arortiatic   amins   is   probably   taking 
place  within  the  alimentary  canal  in  those  whose  diet  is  rich  in  protein,  - 
or  whose  peristalsis  is  sluggish,  and  in  whom  therefore  there  must  be  a  - 
protein  residuum  at  levels  where  the  colon  and  proteus  oi-gariisins  can 
grow.    Such  individuals  would  appear  to  have  the  bacterio-chemical  basis 
for  increased  blood  pressure  and  other  symptoms  indicative  of  the  phar-* 
macological  action  of  these  drugs.     Usually  such  is  not  the  case. 

When  the  liver  is  functioning  well,  it  appears  to  possess  the  ability 
of  changing  the  aromatic  amins,  which  are  brought  to  it  from  the  intes- 
tinal vessels,  through  a  process  of  direct,  oxidative  deamination  to  cor- 
responding fatty  acid  derivatives. 

Thus,  tyramin  is  changed  to  paraoxyphenyl  acetic  acid: 

OH  OH  . 

+  02=  Q  H-NHa 

CH2CHo:^^H2  CH2.C00H 

Tyramin  Paraoxyphenyl  acetic  acid, 

and  indol  ethylamin  is  changed  to  indol  acetic  acid,  thus: 
CH2CH0NH2  A,  CHoCOOH 

•  Indol  ethylamin  Indol  acetic  acid  (urorosein) 

Er^vins  and  Laidlaw  have  actually  shown  by  perfusion  experiments 
that  indol  ethylamin  and  tyramin  are  changed  respectively  to  indol  acetic 
acid  and  to  paraoxyphenyl  acetic  acid.  This  suggests  that  the  normal 
condition  is  one  in  which  the  amounts  of  aromatic  amins  absorbed  from 
the  intestinal  contents  and  carried  with  the  portal  blood  to  the  liver,  are 
oxidized,  and  thus  rendered  adynamic  in  that  organ.^^  Defective  oxida- 
tion powers,  or  a  flood  of  aromatic  amins  too  great  for  the  liver  to 
handle,  would  lead  to  the  escape  of  the  unaltered  amins  into  the  general 
circulation,  where  they  might  well  lead  to  increased  blood  pressure  and 
associated  symptoms. 

The  preliminary  studies  of  Woolley  and  iN'ewburgh  upon  the  effects 

^'Folin  and  Denis  have  apparently  found  that  the  oxidization  jand  subsequent  pair- 
ing of  phenols  is  less  quantitative  than  had  been  supposed. 


BACTERIAL  METxVBOLISM  WITHIjST  THE  BODY"^  689 

of  injecting  indol  into  the  circulation  of  animals  suggest  that  the  escape 
of  unoxidizcd  putrefactive  products,  such  as  indol  or  aromatic  amin.--, 
from  the  liver  to  the  general  circulation  is  more  frequently  a  causative 
factor  in  the  production  of  symptoms  than  a  mere  overproduction  and 
absorption  of  these  substances  from  the  alimentary  canal,  when  the  liver 
is  functioning  normally. 

It  is  conceivable,  although  evidence  upon  this  point  is  not  available, 
that  the  epithelial  or  underlying  cells  of  the  intestinal  tract  may  possess 
to  a  degree  the  power  of  oxidizing  or  altering  these  aromatic  amines  and 
other  putrefaction  products. 

Attention  is  directed  at  this  point  to  the  important  studies  of  Si- 
monds  upon  the  effects  of  carbohydrate  in  liver  poisoning.  He  says, 
"The  administration  of  sugar  will  prove  to  be  an  important  therapeutic 
measure  in  phosphorus  and  chloroform  poisoning, — in  human  beings,  in 
acute  yellow  atrophy  and  possibly  in  eclampsia."  It  would  appear  from 
his  experiments  and  observations  that  inasmuch  as  liver  enzymic  activ- 
ity is  strengthened,  even  when  specific  poisoning  has  taken  place,  that  a 
similar  procedure  would  be  of  material  benefit  when  the  liver  is  permit- 
ting the  escape  of  unoxidized  putrefactive  products  into  the  general  cir- 
culation. The  administration  of  carbohydrate,  it  seems,  is  at  once  good 
physiology,  good  biochemistry,  and  good  bacteriology. 

•     Summary 

Evidence  has  been  presented  that  the  bacterial  decomposition  of  pro- 
teins or  protein  derivatives  for  energy  may  result  in  the  production  of 
specific,  soluble  toxins,  aromatic,  physiologically  active  amins,  putrefac- 
tive products,  such  as  indol  or  skatol,  and  of  unknown  products  which  are 
harmful  in  varying  degTces  to  man.  In  a  majority  of  instances,  these 
various  products,  which  are  specific  for  the  specific  organisms,  do  not  form 
in  the  presence  of  utilizable  carbohydrates.  In  the  latter  event,  practi- 
cally all  the^e  bacteria  are  potentially  sour  milk  bacteria  so  far  as  their 
products  of  gTOwth  are  concerned,  forming  lactic  and  acetic  acids  in  place 
of  specific  products  of  protein  degi-adation. 

^fany  of  these  protein  products  of  bacterial  formation  are,  or  may  be, 
found  in  the  alimentary  canaL  It  is  obvious  that  a  correlation  may  exist 
between  alimentation,  intestinal  bacteria,  health,  and  chronic  or  acute 
disease,  furthermore,  the  close  connection  between  the  nature  of  the. 
food  and  the  character  of  the  products  pi'oduced  in  the  test  tube  may 
have  a  corresponding  relationship  in  the  human  alimentary  canal,  inas- 
nuich  as  the  two  reacting  agents — food  and  microbes — are  fundamentally 
the  same  in  both  instances.  The  striking  parallelism  between  diet  and 
bacteria  is  shown  in  the  changes  in  intestinal  bacteria  which  follow  ma- 
terial changes  in  diet. 


690  ARTHUR  ISAAC  KEXDALL 

D,    Intestinal  Bacteriology 
General    History  and   Development 

The  earliest  conviucin^i^  studies  of  the  bacteria  of  the  alimentary  canal 
were  those  of  Theodore  Escherich  upon  the  intestinal  flora  of  nurslings. 
This  talented  observer  isolated  and  described  many  of  the  more  common 
and  important  noraial  microbes  of  the  intestinal  tract,  inventing  methods 
for  their  recognition  which  are  in  use  in  modified  form  to-day.  He  tried 
to  correlate  their  physiological  processes  with  normal  and  abnormal  intes- 
tinal conditions,  as  well.  This  work  is  of  special  merit,  not  only  for  its 
detailed  information,  but  also  for  the  broad  viewpoint  from  which  the 
work  was  conducted. 

Comparatively  little  attention  was  paid  to  the  work  of  Escherich  for 
several  years  after  its  publication.  The  discovery  of  the  cholera  vibrio 
by  Koch,  in  1883,  followed  by  that  of  the  typhoid  bacillus  by  Gaffky  in 
1884,  focussed  attention  upon  the  disease-producing  intestinal  bacteria  to 
the  virtual  exclusion  of  the  normal  organisms  and  their  relations.  What- 
ever progTCss  was  made  in  the  study  of  the  non-pathogenic  types  was 
directly  associated  with  methods  for  their  detection  and  differentiation 
from  the  pathogenic  microbes.  Intestinal  bacteriology,  in  common  with 
the  entire  field  of  microbiology^,  became  a  purely  diagnostic  science.  This 
extensive  interest  in  diagnostic  intestinal  bacteriology  has  been  extremely 
fruitful,  however.  The  microbes  which  are  causative  agents  in  practically 
all  the  acute  intestinal  infections  of  exogenous  origin  are  now  well  known, 
and  the  domain  of  preventive  medicine  has  profited  greatly  through  the  ac- 
cumulated information  relating  to  the  cycles  of  infection  of  these 
bacteria. 

Escherich  was  unable  to  isolate  the  predominating  organisms  of  the 
normal  nursling  feces,  although  he  recognized  them  morphologically  and 
realized  that  he  was  unsuccessful  in  this  direction.  It  remained  for 
Tissier  to  accomplish  this  difficult  task,  and  with  his  studies  of  IBacillus 
bifidus  communis,  the  way  was  cleared  for  satisfactory  studies  of  the  in- 
testinal bacteria  from  birth  to  adult  life. 

The  discovery  of  paratyphoid  bacilli  by  Salmon  and  Smith,  Gartner, 
and  Brion  and  Kayser,  and  their  significance  by  Achard  and  Bensaud^ 
and  of  the  dysentery  bacilli  by  Shiga  and  Flexner,  practically  com- 
pleted the  list  of  bacilli  which  induce  extensive  epidemic  intestinal  disease 
in  man. 

Attention  was  then  of  necessity  directed  to  the  endogenous  intestinal 
organisms.  Advances  were  made  in  two  principal  directions — the  isolation 
of  bacteria  from  the  normal  intestinal  contents  and  their  identification, 
and,  secondly,  the  study  of  intestinal  microbes  at  different  xx>riods  of 


BACTERIAL  METABOLISM  WITHI]S'  THE  BODY       691 

life.  The  former  studies,  which  culminated  in  the  compreliensive  mono- 
graph by  Ford,  showed  quite  clearly  that  the  normal  organisms  were 
quite  closely  related  to  the  coli,  proteus  and  niesentoricus  groups.  This 
is  suggestive  in  that  the  normal  bacilli  of  the  alimentary  canal  which 
exhibit  chemical  characteristics  common  to  the  colon-proteus-mesentericus 
types  remain  dominant  throughout  adult  life.^^  Observations  by  the  au- 
thor upon  the  residual  intestinal  flora  of  a  man  who  starved  for  thirty-one 
days  supports  this  view. 

The  other  line  of  study  considered  more  specifically  the  relations  which 
exist  between  the  normal  or  abnoi*mal  chemical  peculiarities  of  intestinal 
processes  of  microbic  causation,  and  the  activities  of  specific  bacteria. 
The  comprehensive  monograph  of  Herter,  sumjuarizing  his  extensive  con- 
tributions to  the.  field  of  excessive  bacterial  activity  in  the  alimentary 
canal,  epitomizes  the  information  upon  this  phase  of  the  subject.  Herter 
also  clearly  recognized  that  the  injection  of  lactic  acid  bacilli  into  the  small 
intestine  of  dogs  reduced  the  excretion  of  ethereal  sulphates  in  the  urine, 
while  Bacillus  coli  and  Bacillus  proteus  appeared  to  increase  intestinal 
putrefaction,  thus  foreshadowing  the  "lactic  acid  therapy''  which  Metch- 
nikoff  so  forcefully  presented  in  his  work  upon  the  prolongation  of 
life.  About  this  time  Sittler  studied  and  summarized  the  corresponding 
information  with  respect  to  the  nuj*sling. 

During  this  period  of  approximately  twenty-five  years  there  was  an 
ever-increasing  precision  of  methods,  both  chemical  and  bacteriological, 
and  the  last  decade  has  witnessed  the  application  of  these  procedures  to 
the  studv  of  bacterial  metabolism  under  various  conditions.  As  a  result 
of  the  application  of  these  more  refined  methods  to  the  study  of  bac- 
teriological activities,  a  new  viewpoint  has  presented  itself.  Many  of 
the  conflicting  statements  and  observations  which  had  embarrassed  earlier 
investigators  have  been  reconciled,  aJid  a  fairly  definite  unification  of 
the  phenomena  underlying  bacterial  chemistry  has  led  to  renewed  interest 
in  the  highly  important  field  of  bacterio therapy. 

Some  of  the  more  important  relations  of  bacteriochemistry  to  bac- 
terial metabolism  in  the  alimentary  canal  follow.  o" 
•                                                                    '._  '  ■ 

1.    The  Intestinal   Bacteria  of   Normal   Nurslings 

The  Relation  Between  Diet  and  Microbic  Response. — The  entire  ali- 
mentary canal  of  the  newly  bora  babe  is  sterile  under  normal  conditions, 
and  the  first  bacteria  appear  in  the  intestinal  tract  several  hours  after  birth 
(Escherich).  This  earliest  infection  of  the  alimentary  canal  is  by  ad- 
ventitious organisms  derived  from  the  environment  of  the  infant.  The 
kinds  of  microbes  found  at  this  time  are  those  which  have  gained  en* 

*«  This  applies  only  to  adults,  Tlie  flora  of  nurslings  is  quite  different  and  distinct 
with  reference  to  the  type  of  bacteria  and  their  characteristics. 


692  ARTHUK  ISAAC  KENDALL 

trance  through  the  mouth  to  the  alinientai-y  canal  from  various  sources, 
and  their  numbers — up  to  the  tliird  day  of  life — are  determined  chiefly 
by  their  ability  to  grow  in  the  fetal  intestinal  detritus,  and  the  cholostrum. 
In  temperate  /.ones^  the  initial  microbic  growth  is  usually  more  luxuriant 
in   summer  than  in  winter. 

On  or  about  the  third  day  after  birth,  the  nature  and  appearance  of 
the  alimentary  microbic  flora  im<lergoes  a  clearly  discei-nible  change 
(Tissier).  The  variety  of  forms  and  dissimilarity  of  staining  reactions 
which  characterize  the  postfetal  flora  give  way  to  the  dominance  of  a 
rather  long,  slender  bacillus  with  slightly  tapered  ends  which  rapidly 
supplants  the  adventitious  types.  This  is  Bacillus  bifidus  (Tissier),  a 
lactic-acid-producing  bacterium,  characteristic  of  the  intestinal  and  fecal 
floras  of  a  great  majority  of  normal  nui-slings.  It  is  worthy  of  comment 
that  Bacillus  bifidus  becomes  prominent  synchronously  with  the  full  flow 
of  the  breast  milk.  Breast  milk,  it  will  be  remembered,  contains  more 
than  six  per  cent  of  lactose,  and  scarcely  one  and  a  half  per  cent  of 
protein.  In  addition  to  Bacillus  bifidus,  other  bacteria  in  nmch  smaller 
numbers  are  found  normally, — Micrococcus  ovalis.  Bacillus  acidophilus, 
and  even  fewer  members  of  the  colon  and  lactis  aerogenes  groups  [the 
feces  stained  by  Gram's  at  this  time  are  strongly  positive].  The  author 
has  found  that  these  organisms  without  exception  can  gTOw  extremely 
well  in  mediums  rich  in  lactose,  and  they  all  produce  considerable  amounts 
of  lactic  acid.  The  combined  acidity  arising  from  the  utilization  of 
lactose  for  energy  by  these  bacteria  is  the  principal  source  of  the  acid 
reaction  characteristic  of  the  noi-mal  intestinal  contents  and  feces  of  the 
nursling.  Lactic  acid,  in  the  concentration  normally  present  in  the 
intestinal  tract,  restrains  the  gTOwth  of  endogenous  proteolytic  bacteria, 
and  it  also  restricts  the  development  of  exogenous,  pathogenic  microbes 
which  gain  entrance  to  the  tissues  through  the  alimentary  canal.^'^ 

When,  for  any  cause,  as  for  example  decreased  peristalsis,  the  lactose 
is  absorbed  in  the  higher  levels  of  the  tract,  a  purely  protein  residuum 
is  left  in  the  lower  levels  of  the  small  intestine,  and  in  the  large  intestine. 
Under  these  conditions,  the  habitat  of  the  obligate  acidogenic  bacteria 
is  restricted,  and  they  are  greatly  reduced  in  number  and  in  activity. 
This  follows  through  their  inability  to  gi-ow  well  in  a  residuum  in  which 
protein  derivatives  are  their  only   source  of  energy. 

The  immediate  effect  is  a  greater  or  lesser  reduction  in  the  amount 
of  lactic  acid  ^^  formed  in  the  intestines,   and  in  consequence  of  this 

"In  this  connection,  the  observations  of  the  ^Medical  ResearclL  Committee  that 
dysentery  bacilli  may  be  isolated  from  dejections  having  a  neutral  or  slightly  alkaline 
reaction,' for  days  after  they  are  excreted,  are  of  interest.  It  was  found  tliat  dysentery 
bacilli  could  not  be  isolated  from  the  same  stools  having  an  artificially  induced  acid 
reaction  (lactic  acid),  approximately  that  of  the  normal  nursling  movement,  even  after 
a  few  hours. 

"All  the  lactic  acid  bacilli  appear  to  produce  some  acetic  and  formic  acid  together 
with  minute  amounts  of  similar  volatile  decomposition  products  of  the  fermentation  of 


BACTERIAL  ^HETABOLIS^^E  WITHIX  THE  BODY      693 

reduction  the  principal  obstruction  to  the  development  of  endogenous  pro- 
teolytic bacteria,  as  Bacillus  proteus  and  Bacillus  mesentericus,  is  re- 
moved, or  ^^  least  greatly  reduced.  Also,  the  absence  of  lactose  and  other 
utilizable  carbohydrate  at  the  level  of  the  tract  where  Bacillus  coli  and 
relatetl  forms  are  iiio^t  numerous  forces  these  organisms  to  become  pro- 
teolytic in  place  of  fermentative.  The  net  result  is  an  immediate  increase 
in  proteolytic  activity,  and  a  decided  extension  of  the  proteolytic  zone. 

Indol  and  other  decomposition  products  resulting  from  the  utilization 
of  protein  for  energy  are  formed  in  increasing  amounts  from  the  in- 
testinal contents,  and, these  may  be  absorbed  from  the  tract  and  excreted 
as  aromatic  sulphates  or  glycuronates  into  the  urine.  Peristalsis  may 
be,  and  frequently  is,  further  reduced  by  this  process,  which  tends  to 
become  therefore  of  the  magnitude  of  a  vicious  cycle. 

The  biological  basis  for  successful  invasion  of  the  intestinal  tissues 
by  exogenous  microbes  is  probably  created  or  at  least  augmented  hereby, 
because  available  evidence  indicates  that  intestinal  invasion  is  more  read- 
ily accomplished  when  the  proteolytic  activities  of  bacteria  exceed,  or 
replace,  the  normal  fermentative  processes. ^^ 

Bacteriologically  considered,  therefore,  the  normal  nursling  intestinal 
flora  reacts  with  breast  milk  in  the  alimentary  canal  in  a  manner  analogous 
to  the  natural  souring  of  milk  outside  the  body.  Both  are  essentially 
preservative  processes.  Milk  soured  by  lactic  acid  bacilli  does  not  readily 
undergo  putrefactive  changes  which  render  it  unfit  for  human  consump- 
tion. Similarly,  the  nomial  intestinal  contents  of  the  normal  nursling 
do  not  appear  to  undergo  putrefaction. 

The  lactic  acid,  representing  some  decomposition  of  lactose,  has  fuel 
value  for  the  body ;  hence,  it  is  not  an  entire  loss  in  terms  of  the  original 
caloric  value  of  the  milk.  In  this  respect,  it  is  in  sharp  contrast  with 
the  products  arising  from  the  degradation  of  proteins  of  milk  by  bac- 
teria which  do  not  ferment  lactose.  Such  putrefactive  products  as  are 
known  are  either  useless,  or  more  or  less  harmful  to  the  human  body 
when  absorbed  from  the  alimentary  canal. 

It  would  appear  therefore  that  a  natural  relationship  exists  between 
the  nature  of  the  diet  of  the  nursling  and  the  character  of  the  products 
formed  in  the  intestinal  tract  wdiicli  are  qualitatively  those  fo)*raed  in  the 
natural  or  artificially  induced  souring  of  milk  outside  of  the  body.  The 
bacteria  concerned  are  chemically,  but  not  specifically,  the  same.  Intes- 
tinal conditions  are  unlike  those  outside  of  the  body.     This  is  true  not 

the  lactose,  and  to  a  much  lesser  degree  from  fats: — for  convenience,  the  lactic  acid 
will  be  mentioned  as  the  principal  product,  and  indicative  of  the  entire  group  of 
acidic  compounds. 

"  The  theoretical  advantage  of  preparing  patients  for  surgical  operations,  especially 
those  upon  the  large  intestines,  by  the  induction  of  a  suitable  fermentiitive  flora  in  place 
of  a  putrefactive  flora  ife  suggested.  Of  course  this  applies  to  operations  which  are 
not  emergency  cases,  since  time  is  required  to  effect  this  change. 


694  ARTHUK  ISAAC  KEJ^DALL 

only  with  respoct  to  temperature  [that  of  the  body  being  37.5°  C,  and 
that  of  the  outside  world  varying  with  climate  and  season],  but  also 
in  association  with  those  purely  intestinal  factors  of  secretions,  includ- 
ing bile,  enzymes  and  products  of  enzyme  activity.  These  ancillary  fac- 
tors exercise  a  not  immaterial  influence  upon  prospective  intestinal  ten- 
ants. It  is  significant,  however,  that  notwithstanding  these  environmental 
differences,  the  intestinal  souring  of  milk  is  the  qualitative  equivalent 
of  the  spontaneous  souring  outside  of  the  human  body.  The  significant 
factor  is  the  continuous  availability  of  lactose  in  both  processes. 

Experimental  Evidence  of  the  Effects  of  Sugars  upon  the  Intestinal 
Flora. — ]VIany  studies  upon  experimental  animals  have  shown  the  effects 
of  utilizable  carbohydrates,  as  lactose,  glucose,  and  other  bioses,  and 
polysaccharids,  upon  the  establishment  of  an  intestinal  flora  in  adult 
animals  and  man.  When  such  substances  are  added  to  the  diet  in  suffi- 
cient amounts  to  permeate  the  entire  absorptive  length  of  the  alimentary 
canal,  the  flora  induced  is  the  chemical  replica  of  that  of  the  normal 
nursling.  When  the  carbohydrates  are  reduced  or  eliminated  from  the 
regimen^  proteolytic  bactei-ia  rapidly  gain  the  ascendency. 

Escherich  appears  to  have  been  the  first  obsei-ver  actually  to  per- 
form dietary  experiments  upon  animals.  Dogs  were  selected.  A  four 
weeks'  old  puppy  was  fed  first  upon  milk,  then  upon  meat.  The  changes 
in  the  character  of  the  excreta  and  of  the  bacteria  in  the  excreta  were 
observed  in  each  instance.  A  milk  diet  led  to  the  evacuation  of  bright 
yellowish  dejecta,  the  consistency  and  odor  of  which  were,  reminiscent 
of  those  characteristic  of  the  normal  nursling.  The  organisms  detectable 
were  very  similar  to  those  of  a  normal  nursling.^^  Gelatin-liquefying 
bacteria  were  few  in  numbers,  but  coccal  forms  became  more  numerous. 
The  substitution  of  meat  for  milk  induced  a  striking  change  in  the 
appearance  of  the  feces,  and  in  the  character  of  the  fecal  bacteria.  The 
former  lost  their  golden  yellow  color  and  became  dark  in  color,  smaller 
in  bulk,  and  possessed  of  a  fecal  odor,  suggesting  in  this  respect  that 
of  a  normal  adult.  Gelatin-liquefying  bacteria  increased  very  decidedly 
in  numbers  and  in  activity.  Coccal  forms  were  relatively  diminished. 
Spores  of  proteolytic  organisms,  presumably  of  the  mesentericus  gi'oup, 
became  prominent  in  stained  smears  from  the  meat-diet  feces,  and  the 
entire  picture,  bacterial  and  chemical,  so  far  as  determinations  were 
possible,  suggested  that  the  entire  intestinal  condition  induced  was  simi- 
lar to  that  of  noraial  adults. 

Following  this  monumental  work  of  Escherich,  v/hich  was  so  care- 
fully carried  out  but  unfortunately  limited  because  of  the  meager  fund 
of  bacterial  knowledge  and  the  lack  of  adequate  chemical  methods  avail- 

*'It  should  be  remembered  that  the  dominant  organism  of  the  typical  nursling's 
feces — Baci/lus  bifidus — was  not  known  in  Escherieh's  time.  It  was  isolated  nearly 
fifteen  years  later    (Tissier). 


BACTEKIAL  METABOLISM  WITHIN  THE  BODY      695' 

able  at  that  time  [1886],  a  series  of  investigations  appeared  whicli 
added  many  detached  facts  to  the  problem  of  intestinal  bacteriology. 

The  discovery  of  the  dysentery  bacillus  in  1898,  and  of  Bacillus 
bifidus  in  1000,  marks  the  close  of  the  older  period  of  the  study  of  in- 
testinal bacteria.  The  greatly  improved  cultural  methods,  both  aerobic 
and  anaerobic,  which  resulted  in  the  isolation  and  identification  of  closely 
related  types  of  organisms,  as  the  several  types  of  dysentery  bacilli, 
focused  attention  upon  the  value  of  carbohydrates,  or  derivatives  of 
carbohydrates,  for  diagnostic  purposes  in  bacteriology.  The  decade  be- 
tween 1895  and  1905  was  particularly  noteworthy  for  the  numbers  of 
new  types  and  kinds  of  bacteria,  both  aerobic  and  anaerobic,  which  were 
detected  by  this  procedure. 

The  problem  of  the  intestinal  bacteria  was  restudied,  by  the  author, 
with  the  great  advantage  of  reasonably  accurate  methods  of  bacterial  and 
chemical  procedures  in  1909.  The  relationship  between  diet  and  intestinal 
flora  was  observed,  and  the  general  phenomena  relating  to  the  alterna- 
tions in  dominance  of  fermentative  and  putrefactive  intestinal  floras  in 
response  to  carbohydrate  and  protein  regimens  were  elucidated  at  this 
time.  The  first  observations  were  made  upon  cats  and  monkeys.  It  was 
found  that  both  carnivorous  and  omnivorous  animals  responded  to  the 
same  dietary  changes  in  a  similar  manner. 

The  striking  features  were  the  dominance  of  an  acidogenic  intestinal 
flora,  similar  to  that  of  a  nursling,  u]x>n  a  caj'bohydrate  diet  [glucose 
added  to  milk],  and  the  dominance  of  proteolytic  bacteria  in  the  ali- 
mentary canal  upon  a  purely  protein,  diet.  The  urinary  changes  also 
were  significant.  Upon  a  carbohydrate  regimen  the  urinary  products  of 
putrefaction,  as  indican  and  phenols,  were  greatly  diminished,  or  absent. 
This  corresponded  to  the  chemical  activities  of  the  nursling  bacteria  cul- 
tivated outside  the  body.  Such  organisms  do  not  form  indol  or  phenol 
in  culture  media.  The  return  to  a  protein  diet  was  followed  very  soon 
by  the  appearance,  or  gieat  increase,  of  the  indolic  and  phenolic  sub- 
stances of  the  urine.  The  fecal  bacteria  from  such  diets  were  predomi- 
nantly-proteolytic  and  reproduced  in  culture  medias  under  proper  condi- 
tions the  antecedent  substances  from  which  indican  and  the  ethereal 
sulphates  are  derived. 

It  would  appear  from  these  observations  that  there  was  a  very  definite 
and  controllable  relationship  between  cei-tain  diets,  the  bacterial  types  of 
intestinal  flora,  and  the  presence  or  absence  of  urinary  putrefactive 
products.  These  experiments  were  re]>eated,  greatly  amplified,  and  con- 
firmed in  a  later  series  (Hei-ter  and  Kendall). 

The  following  observers,  Bahrdt  and  Beifeld,  Sittler,  Rettger  and 
Horton,  Torrey,  Hartje  and  Klotz,  have  since  corroborated  the  principle  of 
the  alternation  of  bacterial  types  in  the  alimentary  canal  in  response  to 
definite  dietary  stimuli,  and  have  extended  the  field  by  indicating  the 


696  AKTHUR  ISAAC  KENDALL 

selective  effects  of  various  carbohydrates  upon  the  types  of  lactic  acid  pro- 
ducing microbes  which  become  dominant  in  the  intestinal  tract  as  ane  or 
another  sugar  is  added  to  the  diet. 

A  more  recent  series  of  observations  by  Torrey  has  not  only  ampliiied 
this  particular  aspect  of  the  subject  and  confirmed  anew  the  principle 
of  the  bacterial  response  to  dietary  alternations,  it  has  also  shown  that 
fats  play  a  very  minor,  or  entirely  negligible,  part  in  this  process. 

In  general,  therefore,  it  may  be  stated  that  the  normal  nursling  in- 
testinal flora  is  essentially  fermentative  in  character.  It  represents  the 
natural  bacterial  response  to  a  definite  nutritive  condition  created  within 
the  alimentary  canal  by  the  continuous  passage  of  milk  sugar — lactose — 
throughout  the  absorptive  area.  Furthermore,  it  is  possible  to  reproduce 
essentially  the  same  chemical  activities  and  bacterial  types  in  the  in- 
testinal tracts  of  experimental  animals,  both  carnivora  and  omnivora,  by 
the  administration  of  the  diet  of  the  normal  nursling. 


2.    Adolescent  and  Adult  Intestinal  Bacteriology 

Adolescents  and  adults,  unlike  nurslings,  are  normally  omnivorous. 
The  proportions  of  proteins  and  carbohydrates  [principally  starches  and 
dextrins]  in  the  average  adolescent  and  adult  diet  are  more  nearly. equal 
than  is  the  case  with  nurslings  or  milk-fed  children.  The  large  intestine, 
from  the  cecum  to  the  rectum,  therefore,  becomes  more  and  more  a 
receptaculum  of  the  products  of  protein  digestion,  and  of  protein  deriva- 
tives altered  by  bacterial  digestion.  The  tendency  is  for  putrefactive 
processes  to  predominate,  due  to  the  more  or  less  periodic  intervals  of 
carbohydrate  disappearance.  These  periods  of  carbohydrate  presence  and 
absence  exercise  a  very  decided  influence  upon  the  types  of  bacteria 
which  can  thrive  under  these  intervals  of  carbohydrate  and  protein  offer- 
ings for  energy.  The  obligate  lactic  acid  flora,  either  Bacillus  bifidus 
or  Bacillus  acidophilus,  according  to  Moro,  Finkelstein,  and  the  author, 
dies  out  and  the  succeeding  bacteria  are  of  the  colon  type,  which,  as  has 
been  stated  before,  can  utilize  protein  for  energy  nearly  as  well  as 
carbohydrates. 

Organisms  of  the  Bacillus  coli  type,  in  fact,  are  the  dominant  bacteria 
of  the  intestinal  and  fecal  flora  in  normal  adolescents  and  adult  life, 
when  the  ordinary  mixed  diet  is  that  of  the  dweller  of  the  temperate 
zone.  Under  such  conditions  some  indol  is  foi-med  in  the  alimentary  tract 
and  in  many  individuals  at  least — more  frequently  those  who  are  heavy 
protein  eaters — it  will  be  foimd  as  indican  in  moderate  amounts  in  the 
urine. 

The  conditions  under  which  indol  is  formed  are  also  favorable  to 
the  formation  of  aromatic  amins,  as  histamin,  indol  ethylamin,  or  even 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      607  * 

tyramin.  The  bacteria  which  can  form  amins  by  the  decarboxylization 
of  the  aromatic  arains  are  not  thoroughly  studied.  Bertholot  and  Ber- 
trand  have  described  Bacillus  aminophiius,  a  member  of  the  Mucosus 
capiulatus  group,  but  according  to  Koessler  and  Hanke,  Ilarai,  Yoshimura, 
Guggenheim,  Einis,  and  Berthelot,  it  is  probable  that  a  number  of  in- 
testinal bacteria  can  decarboxylize  these  com]:X)unds. 

The  amounts  of  the  putrefactive  derivatives  of  the  aromatic  amino 
acids  found  in  the  urine  of  normal  adults  under  nonnal  dietary  conditions 
are  not  large  in  proportion  to  the  amount  of  protein  ingested.  The 
figures  for  indican  and  phenolic  bodies,  chiefly  phenol  and  paracresol, 
are  the  best  known  because  these  substances  give  color  reactions  which 
are  . quantitative,  or  approximately  so;  consequently,  fairly  accurate 
measurements  are  possible.  About  10  milligrams  of  indicao  and  about 
0.3  gram  phenolic  bodies  are  usually  found  (Folin  and  Denis).  The 
fecal  content  of  indol  and  phenols  under  these  conditions  is  unknown, 
although  a  variable  amount  of  each  must  escape  absorption. 

At  times,  particularly  in  purulent  infections  incited  by  Staphylococci, 
and  to  a  lesser  extent  by  Bacillus  coli  and  Bacillus  proteus,  some  indican 
may  properly  be  of  parenteral  origin,  it  being  well  known  that  these  or- 
ganisms form  indol  and  phenols  fj*om  the  degTadation  of  tissue  and  blood 
proteins.  This  is  not  the  usual  source  of  the  urinary  putrefaction  prod- 
ucts, however;  as  a  rule  they  are  derived  solely  from  bacterial  activity 
in  the  intestinal  tract. 

Obstruction  of  the  lower  levels  of  the  small  intestine,  intestinal  stasis, 
and,  in  general,  any  factor  which  leads  to  an  upward  extension  of  the 
habitat  of  Bacillus  coli  and  related  forms,  is  a  potent  factor  for  in- 
creased protein  putrefaction. 

It  should  be  noted  that  the  relative  desiccation  of  the  intestinal  con- 
tents at  the  lower  levels  of  the  large  intestine,  together  with  the  accumu- 
lation of  products  of  bacterial  proliferation  carried  downi  from  higher 
levels,  restricts  materially  the  intensity  of  gi'owth  and  activity  of  the 
intestinal  flora  from  the  transverse  colon  to  the  rectum.  On  the  other 
hand,  the  relative  emptiness  of  the  upper  small  intestine,  pai-ticularly  the 
duodenum,  in  interdigestive  periods,  has  beeji  emphasized  by  Eschericb, 
Tissier,  and  the  author  and  is  correlated  with  a  periodic  diminution  of  bac- 
teria, most  of  which  are  carried  do\^^lward  mechanically  with  the  food. 
The  net  result  is  a  large  fluctuation  in  the  numbers  of  bacteria  in  the 
duodenum,  corresponding  approximately  with  the  ebb  and  flow  of  the 
duodenal  content  of  food,  and  a  gradual  increase  in  numbers  and  decrease 
in  fluctuation,  as  the  ileum  is  reached,  where  an  intestinal  residuum  is 
almost   constantly   present. 

At  the  rectum,  the  number  of  living  microbes  is  vei-y  gi-eatly  reduced, 
although  the  corpses  of  bacteria  [which  appear  to  be  insoluble  in  the 
digestive  juices]  are  present  in  enormous  numbers.    It  has  been  estimated 


698  ARTHUR  ISAAC  KENDALL 

that  fully  eighty  per  cent  of  the  bacteria  seen  in  the  feces  are  dead  or 
so  weakened  in  vitality  that  they  can  no  longer  be  cultivated  in  artificial 
mediums.  In  other  words,  the  most  intense  bacterial  proliferation  is  in 
the  lower  ileum,  the  cecum,  and  the  ascending  colon. 

The  types  of  bacteria  vary  at  the  different  levels.  In  the  duodenum 
and  jejunum,  where  the  carbohydrates  are  ordinarily  abundant  during 
digestive  periods,  the  amylolytic  bacteria — those  which  thrive  best  ^vhere 
starches  are  present — are  found  in  dominating  numbers.-^  At  the  lower 
levels,  facultative  bacteria,  as  Bacillus  coli — ^which  can  grow  well  upon 
a  carbohydrate  or  upon  a  protein  diet — are  found  to  be  the  principal 
types.  The  carbohydrophilic  bacteria  are  carried  to  these  levels  with  the 
downward  passage  of  the  intestinal  contents,  but  gradually  decrease  in 
numbers  as  well  as  activity  with  the  diminution  of  the  sugar  content  of 
the  intestinal  medium. 

In  the  cecum  a  considerable  number  of  types  of  bacteria  are  found, 
chiefiy  those  which  thrive  upon  a  protein  regimen.  Starches  appear 
to  play  a  minor  paii;  in  determining  bacterial  types,  especially  in  the 
lower  levels  of  the  alimentary  canal;  the  products  of  hydrolysis  of  the 
ordinary  starches  are  glucose,  and  polymers  of  glucose.  These  are  not 
liberated  in  considerable  amounts  at  any  one  time,  and  the  soluble  products 
of  hydrolysis  are  usually  absorbed  relatively  rapidly.  Under  these  con- 
ditions the  effect  of  starches  upon  intestinal  bacterial  metabolism,  par- 
ticularly with  reference  to  their  sparing  action  for  protein,  is  not  gi'eat. 
The  observation  of  Torreyis  that  fats  do  not  apparently  play  a  prominent 
part  in  the  nutrition  of  intestinal  microbes. 

It  is  not  difficult  to  advance  an  explanation  of  the  sudden  rise  in 
indican  when  an  intestinal  obstruction  is  created.  In  such  cases,  car- 
bohydrate is  removed  more  rapidly  from  the  intestinal  contents  than  llie 
protein,  leaving  a  nitrogenous  pabulum  for  the  bacteria.  The  gradual 
filling  of  the  intestines  to  the  higher  levels  encourages  a  corresponding 
extension  upward  of  the  habitat  of  the  indol-forming  bacteria  of  the 
colon  type  and  the  periodic  emptying  of  the  duodenum  no  longer  is  a 
factor  in  sweeping  down  the  organisms  which  are  resident  there.  The 
net  result  is  an  upward  extension  of  the  putrefactive  €ora,  and  an  aug- 

*  Surgical  operations  involving  the  small  intestine  are  said  to  be  less  frequently 
complicated  by  bacterial  infection  than  those  of  the  large  intestine.  The  suggestion 
is  offered  that  the  microbes  of  the  upper  small  intestine  are  not  only  fewer  in  numbers 
but  are  also  lactic  acid  producing,  and  therefore  fermentative  rather  than  loxicogenic 
in  their  activities.  Whatever  of  carbohydrate  (starcli  or  siifar)  there  may  be  in 
the  food  is  absorbed  chiefly  from  tlie  intestines — not  from  tlie  Ktomach  (TTowell)  — 
and  therefore  the  upper  levels  are  periodically  or  even  constantly  bathed  in  this  group 
of  non-nitrogenous  substances.  In  the  interdigestive  periods  the  food  passes  downward, 
carrying  a  majority  of  the  bacteria  with  it.  This  appears  to  be  an  explanation  of  the 
prominence  of  acidogenic  bacteria  in  the  duodenum. 

At  the  lower  levels,  the  normal  adult  intestinal  flora  is  facultative  with  reference 
to  proteolysis;  such  organisms  are  more  commonly  found  to  be  incitants  of  infection 
than  the  more  strictly  or  obligately  acidogenic  forms. 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      690 

mentation  of  its  activity  beyond  normal.  Indol  an^  other  substances  are 
formed  in  increased  amounts  and,  for  a  time  at  least,  appear  to  b©  ab- 
sorbed from  the  intestinal  contents  [which  are  not  desiccated  at  these 
levels]  into  the  blood  stream.  Very  shortly  thereafter  the  noi-mal  capacity 
of  the  liver  to  oxidize  the  indol  to  indoxyl,  and  to  pair  the  latter  with 
sulphuric  acid  [or,  more  accurately,  with  the  monopotassium  salt  of  sul- 
phuric acid]  is  exceeded,  and  there  is  an  overflow  of  indol  into  the  general 
circulation. 

Normally,  the  indol  and  phenols,  and  other  products  arising  from  the 
bacterial  decomposition  of  aromatic  amino  acids,  are  oxidized  in  the  liver, 
as  indicated  in  a  preceding  article,  before  they  enter  the  general  circu- 
Uition.  They  are  excreted  from  the  circulation  chiefly  as  aromatic  sul- 
phates, but  whenever  the  available  sulphate  is  decreased  in  amount,  the 
body  produces  glycuronic  acid,  and  pairs  these  aromatic  nuclei  with  that 
substance  prior  to  elimination  through  the  kidneys  into  the  urine.  By 
this  process  the  body  is  rid  of  these  somewhat  toxic  putrefactive  sub- 
stances, their  toxicity  being  reduced  materially  by  the  dual  process  of 
oxidization  and  pairing  with  sulphuric  or  glycuronic  acid. 

The  phenomena  of  intoxication  ordinarily  ascribed  to  indol,  and 
probably  participated  in  by  other  aromatic  residues  of  amino  acids,  are 
frequently  associated  with  one  or  more  of  three  factors;  first,  the  con- 
tinued production  of  unusual  amounts  of  indol  formed  in  the  alimentary 
canal  as  the  result  of  an  unsuitable  amount  of  protein  in  the  diet,  or 
persistent  intestinal  stasis,  or  both.  This  may  lead  to  the  absorption  of 
amounts  of  the  aromatic  nucleus  beyond  the  normal  capacity  of  the  liver, 
and  the  excess  of  indol  then  may  appear  as  such  in  the  general  circulation. 
Secondly,  defective  oxidative  power  of  the  liver,  leading  again  to  the  sys- 
temic flooding  with  indol ;  or,  finally;  an  impaired  power  of  combining 
the  oxidized  indol  with  sulphuric  or  glycuronic  acid. 

Any  of  these  processes,  imperfectly  carried  out,  may  result  in  the 
slow,  cumulative  effects  which  eventually  are  recognized  clinically  by 
lassitude,  malaise,  headache,  and  dizziness,  and  other  symptoms  spoken 
of  as  "auto-intoxication." 

It  is  quite  as  possible  for  an  individual  to  suffer  from  an  excessive 
production  of  lactic  acid  of  intestinal  origin  as  it  is  to  be  injured  by  an 
overproduction  of  indol  or  other  bacterial  derivatives  of  the  aromatic 
amino  acids.  Such  conditions  have  been  described  by  Escherich,  Finkel- 
stein  and  Salge.  The  few  cases  on  record  occurred  in  young  children, 
once  in  almost  epidemic  proportions,  in  a  hospital  in  Gratz. 

The  causative  factor  appears  to  be  an  upward  extension  of  the  normal 
zone  of  growth  of  Bacillus  acidophilus,  or  a  closely  related  organism,  into 
the  small  intestine.  The  most  prominent  symptom  is  a  profuse,  watery 
diarrhea.  The  dejections  are  yellowish  and  have  a  very  sour  smell.  The 
acidity  in  the  few  cases  studied  was  found  to  be  four  to  eight  or  even 


700  AKTHUR  ISAAC  KENDALL 

ten  times  that  characteristic  of  the  normal  acidophilic  stool.  In  spite  of 
the  great  prostration,  there  was  little  evidence  of  a  toxemia  of  ali- 
mentary origin.  The  removal  of  all  carbohydrate  from  the  diet  appeared 
to  reduce  the  excessive  acidity  quite  promptly.  Excessive  lactic  acid  pro- 
duction in  the  digestive  tract  is  uncommon. 


3.    Sour  Milk  Therapy  and  Bacterial   Metabolism 

For  more  than  two  decades,  evidence  relating  to  possible  correlations 
between  products  of  protein  putrefaction  in  the  alimentary  canal  and  those 
somewhat  general  symptoms  designated  by  many  observers  "auto-intoxica- 
tion," has  been  collecting.  Metchnikoff,  following  a  suggestion  by  Herter, 
wove  the  various  observations  and  facts  upon  this  subject  into  a  coherent 
theory  covering  the  salient  features  and  advanced  his  sour  milk  therapy 
as  a  remedial  procedure  to  combat  these  conditions. 

Briefly,  the  Metchnikoff  hypothesis  is  as  follows:  In  advanced  adult 
life,  or  earlier,  the  intestines  become  populated  with  bacteria,  chiefly  an- 
aerobic, which  produce  indol  and  other  putrefactive  products  in  unusual 
or  intolerable  amounts.  The  antecedent  cause  is  a  protein-rich  dieto  The 
absorption  of  these  substances  for  variable  periods  of  time  leads  to  arterial 
hardening  and  that  series  of  structural  changes  which  is  frequently  spoken 
of  as  premature  senility.  The  site  of  trouble,  says  Metchnikoff,  is  chiefly 
the  large  intestine.  In  support  of  this  view,  two  or  three  instances  are 
cited  in  his  book  in  which  patients  suffering  from  so-called  intestinal 
toxemia  were  benefited  by  the  shortening  or  removal  of  the  large  intestine 
by  surgical  operation.  By  so  doing,  the  offending  bacteria  and  their  en- 
vironment were  simultaneously  eliminated. 

In  contrast  to  this  possibility,  that  longevity  and  the  normal  approach 
to  uncomplicated  old  age  are  interfered  with  to  a  degree  by  excessive 
bacterial  putrefaction  in  the  cecal  cesspool,  attention  was  directed  to  the 
unusual  span  of  life  enjoyed  by  some  of  the  Biblical  patriarchs  (Piffard). 
Metchnikoff  also  found  that  longevity  is,  or  was,  a  noteworthy  char- 
acteristic of  those  inhabitants  of  southeastern  Europe  who  drink  milk 
soured  by  lactic  acid  bacteria  as  a  principal  article  of  food.'^ 

The  suggested  relationships  between  soured  milk,-^  sour  milk  bacteria, 
longevity,  on  the  one  hand,  and  mixed  diets,  intestinal  putrefaction  and 
auto-intoxication,  with  premature  senility  on  the  other  hand,  have  led 
Metchnikoff  to  conceive  of  the  possibility  of  replacing  the  putrefactive 
intestinal  flora  by  the  lactic  acid  bacilli  of  Bulgaria.     Keplacing  malig- 

"  Souring  is  induced  by  addinjr  to  the  freshly  drawn  milk  lumps  of  coagulated 
casein  containing  impure  cultures  of  lactic  acid  bacilli,  known  variously  as  Kephir 
granules,  Lebenraib,  Maadzoun,  Yoghourt.  and  by  other  names. 

**The  souring  of  milk  is  the  only  method  of  preservation  in  warm  countries  where 
refrigeration  can.  not  be  practiced. 


BACTERIxVL  METABOLISM  WITHIX  THE  BODY      701 

nant  microbes  bj  beneficent  bacilli,  and  encouraging  the  latter  to  colonize 
in  the  large  intestines  as  a  safeguard  against  future  endogenous  poisoning 
is  the  essence  of  the  Metchnikoff  hypothesis. 

The  method  of  administration  of  the  Bulgarian  sour  milk  bacillus  was 
through  milk  which  first  was  to  be  sterilized,  then  inoculated  with  a 
pure  culture  of  the  organism,  and  set  aside  to  fei-ment  to  a  high  d^ree 
of  acidity.  Milk  thus  soured  and  populated  with  enormous  numbers  of 
Bulgarian  bacilli  was  to  be  drunk  in  laige  amounts  daily.  It  will  be  seen 
that  the  objective  to  be  attained  was  to  introduce  naturally  preserved  milk 
[soured  milk]  containing  preformed  lactic  acid,  into  the  alimentary  canal, 
in  the  expectation  that  it  would  not  undergo  putrefaction  there.  Also, 
that  the  Bulgai-ian  bacillus  would  become  resident,  and  supplant  the  na-* 
tive  putrefactive  microbes. 

The  results  have,  on  the  whole,  been  disappointing  from  the  clinical 
point  of  view,  although  sour  milk  has  unquestionably  become  a  popular 
beverage.  It  is  unfortunate  that  the  emphasis  was  laid  upon  the  accli- 
matization of  the  bacilli  of  Bulgarian  kephir  granules  in  the  alimentary 
tract  of  man.  Available  evidence  through  the  work  of  Herter  and  Ken- 
dall, and  Rahe,  indicates  they  do  not  grow  in  the  alimentary  tract  in  com- 
petition with  the  normal  intestinal  flora.  From  a  priori  considerations 
there  is  little  justification  for  the  belief  that  they  would  gi*ow  there.  Ob- 
servations upon  the  alimentary  flora  of  normal  or  milk-fed  nurslings  have 
never  revealed  the  presence  of  Bulgarian  bacilli.  It  might  confidently 
be  expected  that  lactic  acid  producing  bacteria,  parasitic  in  milk,  would 
grow  if  they  could  endure  the  intestinal  environment.  On  the  contrary, 
the  human  intestinal  lactic  acid  bacilli  which  thrive  on  a  milk  diet  are 
Bacillus  bifidus  in  the  normal  nursling,  and  Bacillus  acidophilus  in  arti- 
ficially fed  babies. 

One  of  the  important  details  of  the  Metchnikoff  sour  milk  therapy 
procedure  is  a  restriction  of  the  protein  in  the  diet  of  the  patient.  It  is 
quite  clear  that  rigorous  attention  to  this  factor  is  of  unqualified  benefit. 
To  make  up  the  requisite  caloric  [energy]  content  of  the  food,  some  soi-t 
of  carbohydrate  is  recommended.  It  was  surmised  that  the  carbohydrate 
might  also  help  establish  the  Bulgarian  bacillus  as  an  intestinal  inhabit- 
ant 

It  may  be  stated  that  the  chief  value  of  the  sour  milk  therapy  as  out- 
lined above  was  to  introduce  considerable  amounts  of  preformed  lactic 
acid.  There  appears  to  be  little  doubt  that  this  lactic  acid  of  exogenous 
origin  is  an  impoitaut  restriclor  of  certain  types  of  intestinal  fermenta- 
tion, especially  that  in  which  the  "gas  bacillus"  is  either  a  causative  factor 
or  at  least  an  indicator  through  its  unusual  kixuriance  of  growth  (Kendall 
and  Smith,  Hewes  and  Kendall,  and  Simonds). 

There  is  no  very  definite  proof  that  anaerobic  bacteria  are  important 
factors  in  intestinal  putrefaction.    Indeed,  the  evidence  points  to  Bacillus 


702  AKTHUFw  ISAAC  KEJSTDALL 

coli  and  related  forms  as  the  more  common  organisms  which  pi'ocluce 
indol  in  the  alimentary  canal. 

From  what  has  been  stated  above,  the  increase  in  carbohydrate  and 
a  restriction  of  the  protein  in  the  diet  tend  of  themselves  to  change  tlie  na- 
ture of  the  products  foi-med  by  colon  and  other  bacilli  from  the  iudolic  to 
the  lactic  type.  If  enough  carbohydrate  can  be  ingested  to  maintain  a  car- 
bohydrate content  throughout  that  |X)rtion  of  the  tract  where  bacterial  pro- 
teolysis is  dominant,  the  substitution  of  lactic  acid  for  products  of  protein 
putrefaction  through  the  shifting  of  the  metabolism  of  the  facultative 
bacteria,  as  Bacillus  coli,  naturally  follows.  The  success  of  the  dietary 
change  v/ill  depend  in  no  small  degree  upon  the  extent  to  which  carbo- 
hydrate may  be  kept  continuously  in  the  alimentary  canal.  In  general, 
therefore,  it  may  be  stated  that  the  chief  beneficial  results  observed 
in  cases  of  so-called  intestinal  auto-intoxication  which  have  been  dieted 
upon  Bulgarian  lactic  acid  milk  are  to  be  ascribed  largely  to  the  restriction 
of  the  protein,  and  to  an  increase  in  the  carbohydrate. 

This  leads  to  a  diminution  of  the  protein  residuum  in  the  intestine,  to 
the  shifting  of  the  metabolism  of  the  intestinal  putrefactive  bacteria,  and  to 
lactic  acid  production  in  place  of  indologenesis.  The  increase  of  peristal- 
sis, and  pai-tial  or  complete  relief  from  constipation,  which  not  infre- 
quently follows  the  change  from  a  basic  to  an  acidic  reaction  in  the  middle 
segment  of  the  alimentary  tract,  may  also  be  a  factor  in  the  beneficial 
process. 

Since  the  publication  of  Metchnikoff's  work,  many  attempts  have  been 
made  to  secure  cultures  of  lactic  acid  bacilli  for  purposes  of  lactic  acid 
implantation.  Xone  of  these  to  date  are  selected  with  a  view  to  their 
fitness  for  intestinal  acclimatization.  The  efforts  have  been  to  seek  for 
milk  parasites,  which  will  produce  a  smooth,  palatable  and  very  acid 
sour  milk  outside  the  human  body.  Some  cultures  have  even  been  dis- 
pensed as  tablets  or  lozenges.  The  bacteria  in  such  preparations  are 
dried,  much  like  commercial  yeast  cakes,  and  are  to  be  taken  in  this  form. 
Frequently,  the  directions  for  using  these  dried  cultures  of  bacteria  fail 
to  indicate  that  sugar  be  taken  with  the  bacterial  tablets.  It  must  be 
obvious  that  these  bacteria,  or  almost  smy  other  bacteria,  cannot  be  ex- 
pected to  produce  therapeutic  amounts  of  lactic  acid  unless  they  are  pro- 
vided with  a  source  of  energy  from  which  lactic  acid  may  be  formed. 

If,  therefore,  intestinal  implantation  of  normal  lactic  acid  bacilli  is 
to  be  practiced,  it  would  appear  logical  to  select  normal  intestinal  lactic 
acid  bacilli  for  inoculation  into  milk,  intended  for  therapeutic  purposes, 
or  for  ingestion  as  pure  cultures,  and  to  maintain  these  cultures  imder 
conditions  which  shall  guarantee  they  have  not  lost  their  intestinal  para- 
sitism in  favor  of  parasitism  upon  artificial  media  outside  the  lx>dy  (Eotch 
and  Kendall).  It  is  not  improbable  that  frequent  passage  of  sucli  cul- 
tures throu£>h  the  alimentary  canal  will  be  found  essential  to  maintain 


BACTERIAL  METABOLISM  WITHIX  THE  BODY       703 

their  intestinal   parasitism,   quite  as  frequent  passages  of  pneumococci 
through  experimental  animals  are  required  to  maintain  their  virulence. 

To  summarize :  there  appears  to  be  an  abnormal  state  or  condition 
more  common  in  adults  of  middle  age  or  older,  in  which  available  evidence 
points  to  putrefactive  products,  the  results  of  bacterial  decomposition  of 
protein  residues  in  the  alimentary  tract,  as  the  underlj-ing  cause.     This 
state  or  condition  is  referred  to  by  many  as  ^^auto-intoxication." 

If  such  be  the  case,  the  cure,  or  at  least  the  arrest,  of  the  morbid 
process,  naturally  would  be  a  restriction  or  prevention  of  the  putrefactive 
bacterial  processes  within  the  alimentary  canal.  The  bacteria  which  are 
known  to  produce  indol,  aromatic  amins,  and  other  similar  putrefaction 
products  associated  with  the  phenomena  of  auto-intoxication  are  for  the 
most  part  microbes  of  the  colon-proteus-raesentericus  gi-oups.  These  bac- 
teria produce  the  putrefaction  products  when  they  utilize  protein  or 
protein  derivatives  for  energy.  When  they  utilize  carbohydrate  for 
energy,  these  same  bacteria  produce  lactic  and  other  acids.  If  periods  of 
ebb  and  flow  of  carbohydrate  occur  in  the  alimentary  canal,  where  these 
organisms  are  abundant,  there  w^U  be  corresponding  alternate  periods  of 
putrefaction  and  fermentation. 

It  follows  that  a  continuous  supply  of  the  proper  kind  of  carbohydrate 
will  result  in  a  continuous  production  of  lactic  acid.  Implantation  with 
normal  intestinal  lactic  acid  bacilli,  as  Bacillus  acidophilus,  with  a  con- 
tinuous supply  of  carbohydrate,  will  tend  theoretically  at  least  to  dimin- 
ish the  numbers  of  colon-proteus-mesentericus  types,  and  restrict  their 
activities.  Such  a  procedure  probably  will  be  found  to  be  feasible  in 
a  pro}X)rtion  of  appropriate  cases.-"* 

Lactic  acid  or  sour  milk  therapy  has  not  yet  reached  its  final  develop- 
ment. The  brilliant  conception  of  its  possibilities  as  a  contribution  to 
gastro-intestinal  therapy  is  a  monument  to  Metchnikoff's  genius  and  con- 
structive imagination. 

The  discussion  of  intestinal  bacteriology  thus  far  has  revealed  two 
distinct  but  related  types  of  response  to  dietary  alternations:  First,  a 
change  in  the  type  of  bacteria,  as,  for  example,  the  dominance  of  Bacillus 
bifidus  in  the  normal  breast-fed  infant,  and,  secondly,  the  change  in 
metabolism  as  protein  or  carbohydrate  is  available  for  the  energy  require- 
ments of  the  bacteria.  The  dominance  of  types  is  usually  met  w^ith  when 
the  diet  is  monotonous,  and  with  a  prepondei-ance  of  one  or  another  type 
of  energ;)^-producing  substance.  In  the  case  of  milk  in  the  nonnal  nursling, 
the  seven  per  cent  of  lactose  is  the  determining  factor.  On  the  other 
hand,  when  the  energy  producing  substance  changes  from  time  to  time, 
as  for  example  in  the  lower  levels  of  the  small  intestine  of  adults,  where 
periods  of  carbohydrate  ebb  and  flow  are  superimposed  upon  a  protein 

**  Certain  ill  eflFecta  of  unrestricted  feeding  of  carbohydrate  are  discussed  under 
Endogenoii.s  Intestinal  Tiifectioiis,  ride  ivfrn. 


r04r  AKTHUR  ISAAC  KENDALL 

residuum,  bacteria  which  are  accommodative  to  alternations  in  metabolism 
are  confidently  to  be  looked  for.  Such  happens  in  the  adult  alimentary 
canal,  and  facultative  bacteria,  as  Bacillus  coli,  which  can  accommodate 
their  metabolism  to  protein  or  carbohydrate  energy,  become  the  dominant 
organisms. 

The  nature  and  extent  of  bacterial  acclimatization  in  the  intestinal 
tract  is  not  a  matter  of  indifference  to  the  host;  the  character  of  the 
normal  resident  flora  is  of  e<|ual  or  greater  importance. 

It  is  conservatively  estimated  that  a  normal,  healthy  adult,  enjoying 
an  average  mixed  diet,  excretes  daily  in  the  feces  from  one  hundred  to 
thirty  hundred  billion  of  bacteria  (Schmidt  and  Strasburger,  Mcl^eal, 
Latzer  and  Kerr,  and  Cammidge).  The  dried  weight  of  this  bacterial 
mass  would  exceed  five  grams,  and  the  nitrogen  in  it  alone  would  weigh 
nearly  seven-tenths  of  a  gram.  It  is  apparent  that  the  ingested  food 
does  not  contain  this  prodigious  number  of  bacteria,  and,  furthermore, 
the  kinds  of  organisms  isolatable  from  the  excreta  do  not  coincide  in 
type  or  proportion  with  those  of  the  regimen.  Indeed,  many  of  the  latter 
do  not  appear  to  endure  intestinal  conditions  and  the  bacterial  antagonisms 
therein.  It  must  be  conceded,  therefore,  that  the  alimentary  canal  is  a 
singularly  efficient  incubator  and  culture  medium  from  the  bacterial  point 
of  view;  an  environment  in  which  bacterial  growth  along  rather  definite 
lines  exceeds  in  intensity  and  selectiveness  that  of  any  known  natural 
process. 

The  range  of  reaction  and  the  composition  of  nutritive  substances 
at  different  levels  are  such  that  theoretically  a  great  variety  of  organisms, 
capable  of  gi'owing  at  body  temperature,  might  find  conditions  favorable 
for  their  development.  IsTotwithstanding  the  nutritive  possibilities 
throughout  the  alimentary  canal,  from,  starches  to  glucose  and  fermenta- 
tion acids,  from  practically  unaltered  protein  to  amino  acids  and  extrac- 
tives, and  from  fats  to  fatty  acids  and  glycerin,  the  number  of  types 
of  bacteria  which  occur  normally  and  in  significant  numbers  in  this  in- 
cubator-culture medium  is  surprisingly  small.  They  are  also  fairly  well 
known.^^  - 

The  underlying  principles  of  normal  intestinal  bacteriology,  in  the 
light  of  available  infonnation,  may  be  summarized  from  the  clinical  view- 
point as  follows: 

1.  The  constant  temperature,  variety  of  food,  and  range  of  reac- 
tion in  the  alimentary  canal  create  conditions  favorable  to  bacterial 
growi;h. 

2.  The  bacterial  response  to  these  conditions  is  enormous,  viewed 

*»A  distinction  is  made  between  the  resident  bacterial  types  which  persist  \inder 
normal  dietary  conditions  for  considerable  periods  of  time,  and  those  transient  forms 
which  siiccessfnllv  run  the  intestinal  gauntlet,  and  which  may  be  encountered  in  any 
massive  bacterial  process.  Exogenous  pathogenic  bacteria,  which  will  be  discussed 
below,  are  specifically  excluded  from  the  present  discussion. 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      705 

from  the  standpoint  of  numbers — a  normal  adult  eliminates  daily  several 
hundreds  of   billions  of  microorganisms  in  the  feces. 

3.  The  opportunities  for  bacteria  of  the  most  varied  kinds  to  enter 
the  mouth  and  to  pass  to  the  intestinal  tract  are  almost  unlimited.  At 
one  time  or  another  virtually  all  bacteria  from  the  outside  world  may 
thus  become  prospective  tenants.  Notwithstanding  this  possibility  of  a 
most  varied  immigi*ant  flora,  the  predominant  and,  presumably  therefore, 
the  normal  intestinal  flora  is  composed  of  strikingly  few  types.  The 
daily  proliferation  of  these  few  types  is  responsible  for  the  bulk  of  bacteria 
excreted  in  the  feces. 

4.  Starvation  reduces  the  number  of  bacteria  materially,  but  the 
types  found  in  the  intestinal  flora  under  such  a  condition  are  of  the 
normal  kinds. 

5.  A  monotonous  diet,  in  which  carbohydrate  continuously  permeates 
the  intestinal  tract,  leads  to  a  simplification  of  the  intestinal  flora.  In 
normal  nursling's,  obligately  acidogenic  bacteria  of  the  bifidus  type  be- 
come dominant.  In  dextrin-starch  mediums,  members  of  the  Bacillus  acid- 
ophilus type  predominate. 

6.  The  products  characteristic  of  the  acti\aty  of  the  obligate  fer- 
mentative flora  are  normally  innocuous  and  in  a  measure  protective,  in  that 
the  lactic  acid  generated  is  a  deten-ent  to  the  gi'owth  of  non-fermentative 
[putrefactive]  organisms.  A  similar  phenomenon  is  observed  in  milk 
soured  outside  the  body.     It  does  not  ordinarily  putrefy. 

7.  It  is  sometimes  observed  that  an  overgi'owth  of  acidogenic  bac- 
teria, as  Bacillus  acidophilus,  may  lead  to  intestinal  disturbances,  par- 
ticularly in  young  children.  An  overgrowth  of  the  gas  bacillus  [Bacillus 
welchii]  may  also  lead  to,  or  be  associated  with,  severe  intestinal  dis- 
turbances w^hich  may  become  serious. 

8.  Upon  a  diet  in  which  the  proportion  of  carbohydrate  to  protein  is 
nearly  equal,  leading  to  periods  of  ebb  and  flow  of  carbohydrate  in  the 
low^er  levels  of  the  intestinal  tract,  the  facultative  organisms,  members  of 
the  colon-proteus-mesentericus  groups,  become  the  principal  kinds  met 
with.  Such  a  flora  is  more  varied  because  a  gi-^ater  number  of  bacteria 
capable  of  deriving  their  energy  from  carbohydrate  or  protein  can  thrive 
in  the  intestinal  environment  than  appears  to  be  possible  with  the  more 
or  less  obligately  fermentative,  lactic  acid  types. 

9.  The  facultative  flora,  in  which  periods  of  carbohydrate  ebb  and 
flow  is  the  dietary  determinator,  partakes  of  the  acidogenic  and  amino- 
genic  types  respectively.  At  a  given  level  of  the  tract,  during  tliese  periods 
in  which  ample  carbohydrate  is  present,  the  acidogenic  activities  of  the 
flora  are  stimulated.  During  intervals  of  carbohydrate  deficiency,  the 
proteolytic  activities  are  resumed. 

10.  A  continuous,  relative  deficit  of  carbohydrate  in  proportion  to 
the  protein  in  the  diet  leads  to  the  establishment  of  a  proteolytic  flora, 


TOG  AETHUR  ISAAC  KE:^DALL 

in  which  protein-liquefying  organisms  of  the  mesentericus  and  proteus 
types,  together  with  smaller  numbers  of  other  similar  oj-ganisms,  are 
the  prominent  varieties  met  with. 

11.  The  putrefactive  pro<lucts  formed  by  the  facultative  and  purely 
proteolytic  types  of  intestinal  bacteria  comprise,  in  addition  to  unknown 
substances,  aromatic  amins,  fatty  acids,  and  aromatic  nuclei  of  amino 
acids.  Of  these,  histamin,  tyramin  and  indol  ethylam in  are  physio- 
logically active  even  in  minute  amounts.  Also,  indol,  phenol,  paracresols, 
and  skatol  are  formed  in  recognizable  amounts.  The  subsequent  fate 
of  these  substances  within  the  body  has  already  been  discussed. 


4.    Exoj^enous  Intestinal  Infections 

Bromatherapy. — Thus  far,  emphasis  has  been  placed  upon  the  prin- 
ciples imderlying  the  general  phenomena  of  bacterial  metabolism,  and 
applications  of  these  principles  to  the  elucidation  of  the  mutual  and  re- 
ciprocal relations  between  diet  and  microbic  response  in  the  normal,  or 
nearly  normal,  digestive  tract. 

An  obvious  extension  of  these  principles  to  the  therapeutics  of  ex- 
ogenous and  endogenous  infections  of  the  intestinal  tract  clearly  presents 
itself.  The  need  for  specific  therapy  in  intestinal  infections  is  very 
gi'eat.  The  treatment  of  typhoid,  cholera,  dysentery,  and  other  enteric 
diseases  is  expectant  and  supportive.  There  are  no  serums  or  antitoxins 
of  proven  value  available,  and  chemotherapy  is  thus  far  unsuccessful. 
There  is  clearly  an  important  place  in  clinical  medicine  for  pi-ocedures 
of  specific  intervention  which  are  in  favor  of  the  host,  and  antagonistic  to 
the  microbe,  once  infection  is  established.  The  prevention  of  infection 
does  not  of  course  enter  into  the  discussion  at  this  point. 

A  theoretical  basis  for  specific  intervention  in  intestinal  bacterial  in- 
fection resides  in  the  relation  of  carbohydrate  and  protein  soui'ces  of 
energy  to  the  production  of  beuig-n  or  noxious  products  of  metabolism  by 
pathogenic  and  parasitic  bacteria.  It  will  be  remembered  that  diphtheria, 
dysentery,  cholera,  typhoid,  paratyphoid,  colon,  proteus,  and  many  other 
organisms  form  benign  lactic  acid  from  utilizable  carbohydrate.  They 
are  potentially  buttei-milk  bacilli  so  far  as  the  chemical  products  of  their 
gi-owtlj  are  concerned,  upon  a  suitable  sugar  diet  The  removal  of  the 
carbohydrate,  however,  is  immediately  followed  by  the  formation  of 
nitrogenous,  noxious  products,  many  of  which  are  poisonous. 

Available  evidence  indicates  that  the  same  metabolic  phenomena  are 
involved  in  the  intestinal  culture  in  vivo  and  in  the  artificial  culture 
in  vitro.  The  underlying  principles  are  identical.  "Utilizable  carbo- 
hydrate protects  protein  from  bacterial  decomposition.^^ 

This  principle  of  the  protective  action  of  utilizable  carbohydrate  for 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      707 

protein  has  been  deliberately  applied  by  the  author  in  the  treatment  of 
bacillary  dysentery.  This  is  a  severe  infection  of  the  intestinal  mucosa 
incited  by  Bacillus  dysenteriae,  of  the  Shiga,  Flexner,  or  Elexner  variant 
types.  The  effects  are  particularly  severe  in  young  children.  The  in- 
fective agent  is  restricted  chiefly  to  the  large  intestine,  and  the  organisms 
do  not  usually  penetrate  tissues  deeper  than  the  mesenteric  lymph  nodes. 
The  essential  specific  feature  of  this  treatment  was  to  feed  the  patient 
lactose  solution  by  mouth ;  glucose  was  injected  subcutaneously  for  reasons 
to  be  detailed  later. 

Lactose  was  fed  to  permeate  the  entire  digestive  tract  of  the  patient. 
By  so  doing  the  metabolism  of  the  dysentery  bacilli,  and  of  the  resident 
intestinal  population  as  well,  was  shifted  from  protein  to  carbohydrate.** 
Two  distinctly  specific  but  related  beneficial  results  were  expected:  To 
reduce  the  foi*mation  of  toxins  by  the  dysentery  bacilli  and  to  prevent 
the  foi-mation  of  indol  and  other  putrefactive  products  by  Bacillus  coli 
and  other  intestinal  organisms.  The  other  beneficial  effect  hoped  for 
would  come  from  the  acidification  of  the  intestinal  tract,  due  to  the  com- 
bined lactic  acid  generation  of  the  entire  intestinal  flora,  both  pathogenic 
and  parasitic.  One  of  the  significant  results  of  lactose  feeding  was  a 
reappearance  of  the  normal  nursling  lactic  acid  bacilli ;  especially  Bacillus 
bifidus  and  Bacillus  acidophilus.  In  favorably  progi'essing  cases,  these  or- 
ganisms rather  rapidly  became  prominent.  Their  energetic  lactic  acid 
generating  powers  were  of  undoubted  significance  in  rendering  intestinal 
conditions  intolerable  for  the  acidophobic  dysentery  bacilli. -'''  ^^ 

In  addition  to  the  oral  feeding  of  lactose  solutions,  two  other  pro- 
cedures for  the  administration  of  carbohydrate  were  practiced.  One  of 
these  was  an  attempt  to  give  glucose-lactose  irrigations  per  i*ectum  in 
the  hope  that  some  of  the  sugar  would  pass  the  sigmoid  and  enter  the 
absorptive  areas  of  the  large  intestine.  This  was  soon  abandoned.  It 
proved  to  be  annoying  to  the  young  patients  without  a  proportionate  gain. 
The   ether   procedure   was   to   infuse  glucose   solutions   subcutaneously 

"The  generally  accepted  treatment  for  bacillary  dysentery  in  young  children  at 
this  time  was  starvation,  upon  the  assumption  apparently  that  the  dysentery  bacilli 
would  gradually  exhaust  themselves.  Water  alone  was  given.  It  was  obvious  that 
all  the  intestinal  microbes  of  necessity  became  proteolytic.  Tlie  dysentery  bacilli 
formed  toxin,  the  colon  bacilli  indol,  and  the  entire  burden  of  detoxicating  whatever 
of  these  nitrogenous  products  were  absorbed  from  the  intestinal  tract  fell  upon  the 
liver.  The  intestinal  secretions  and  tissues  furnished  the  requisite  protein  for  the 
formation  of  these  harmful  products. 

"The  antagonistic  effects  of  lactic  acid  production  upon  the  viability  of  dysentery 
bacilli  in  the  intestinal  tract  and  dejecta  have  recently  received  unexpected  substantia- 
tion in  the  Report  of  the  Medical  Research  Committee. 

"  It  is  probable  that  lactic  acid  produced  by  microbic  action  within  the  alimentary 
canal  and  immediately  in  the  presence  of  acidophobic  bacteria  is  more  effective  in  its 
action  than  an  equal  quantity  would  be  brought  from  a  distance.  The  neutralizing 
effect  of  salts  and  alkaline  secretions  would  certainly  change  considerable  amounts 
of  the  acid  to  the  lactate,  which  is  far  less  effective  in  its  inhibition  of  microbic 
activity. 


708  /        ARTHUR  ISAAC  KENDALL 

(Heilner',  Allen). ^^  It  was  found  that  young  children  could  not  retain 
even  water  by  mouth  when  the  dysenteric  infection  was  severe.  The  dehy- 
dration of  the  tissues  following  the  profuse  diarrhea  left  the  patients  in  a 
serious-condition.  The  addition  of  glucose  (Allen)  to  tlie  saline  infusion 
was  devised  to  provide  the  tissues  with  an  immediately  utilizable  source  of 
energy  as  well  as  restore  body  fluid.  It  was  also  hoped  that  some  of 
this  glucose  Avoukl  be  carried  to  the  mesenteric  lymph  nodes  or  other 
tissues  where  bacteria  might  be  growing  within  the  body,  and  thus  aid  in 
a  reformation  of  their  metabolic  products.  This  would  mean,  if  it  were 
realized,  that  the  dysentery  bacilli  within  the  tissues  would  produce  lactic 
acid  in  place  of  toxin  so  long  as  the  glucose  was  available.  In  other 
words,  these  dysentery  bacilli  would  become  potentially  lact  ic  acid  microbes. 

An  unexpected  beneficial  effect  of  lactose  feeding  was  noticed.  Chil- 
dren that  constantly  regurgitated  water  appeared  to*  retain  the  lactose 
solution  without  difficulty.  INTo  explanation  presented  itself  to  account 
for   this   peculiar  result. 

At  first  sight,  the  selection  of  lactose  as  the  carbohydrate  for  oral 
administration  might  be  criticized  on  the  ground  that  dysentery  bacilH 
do  not  ferment  this  sugar.  It  should  be  emphasized,  however,  that  lactose 
is  more  slowly  absorbed  from  the  digestive  tract  than  any  other  sugar. 
This  fact  alone  would  increase  raanyfold  the  chances  of  permeating  the 
entire  intestinal  canal  with  sugar.^^  Lactose  is  fermented  by  a  majority 
of  the  normal  intestinal  bacteria  and  it  will  be  remembered  that  one 
objective  of  the  specific  dietary  treatment  of  toxic  intestinal  infection 
is  to  reduce  intestinal  bacterial  proteolysis  and  augment  lactic  acid  pro- 
duction. Acidogenesis  should  extend  the  entire  length  of  the  tract  to  be 
effective.  - 

Lactose  is  apparently  hydrolyzed  in  the  intestinal  mucosa  by  the 
enzyme  lactase  (Morse  and  Talbot).  The  products  of  hydrolysis  are  the 
hexoses,  glucose  and  galactose,  both  of  which  are  readily  utilized  for  en- 
ergy by  dysentery  bacilli.  Inasmuch  as  the  dysentery  bacilli  are  gTow- 
ing  in  the  intestinal  mucosa,  the  advantages  of  liberating  fermentable 
sugars  there  are  obvious. 

There  is  of  course  the  possibility  that  the  intestinal  mucosa  and  im- 
mediately underlying  tissues  might  be  so  injured  by  the  poisons  of  the 
dysentery  bacilli  that  the  cleavage  of  lactose  might  be  interfered  with. 
It  is  not  possible  to  disprove  this  contingency,  but  it  may  be  stated  that 
repeated  examinations  of  urines  from  a  series  of  cases  treated  in  this 
manner  were  invariably  negative  with  reference  to  the  presence  of  re- 

"  These  infusions  were  sterilized  solutions  of  normal  saline  containing  2.5  per 
cent  of  Kahlbaum's  chemically  pure,  anhydrous  glucose.  From  two  to  four  ounces  were 
injected  very  slowly  each  day  by  the  subcutaneous  route  for  several  days. 

*•  Repeated,  relatively  small,  feedings  of  lactose  were  prescribed  rather  than  fewer, 
larger  amounts.  This  was  to  insure  the  continuous  presence  of  sugar  throughout  the 
intestinal  tract. 


^        BACTERIAL  METABOLISM  WITHIN  THE  BODY      709 

(lucifig  sugars.  This  would  suggest  that  unaltered  lactose  failed  to  enter 
the  tissues  and  blood  stream  in  significant  amounts. 

It  was  soon  realized  that  prolonged  feeding  of  carbohydrate  alone 
became  harmful.  This  might  confidently  have  been  expected.  Subse- 
quent feeding  with  lactose-protein  solutions  were  very  well  tolerated,  no 
evil  results  attributable  to  the  protein  being  observed  so  long  as  the  car- 
bohydrate was  fed  in  amounts  sufficient  to  insure  a  continuous  flow  to 
the  lowest  levels  of  the  alimentary  canal.  Protein  solutions  without  car- 
bohydrate were  found  to  be  distinctly  harmful. 

The  earlier  cases  of  bacillary  dysentery  treated  with  the  protein-lac- 
tose diet  as  indicated  showed  neither  signs  nor  symptoms  suggestive  of 
harm  arising  from  the  liberal  use  of  lactose.  Somewhat  later  in  the 
season,  however,  a  striking  instance  of  apparent  hann  attributable  to 
lactose  feeding  presented  itself.  Inasmuch  as  this  case  presents  details 
of  importance  in  connection  with  the  therapeutic  application  of  dietary 
procedures  to  bacterial  infections,  the  salient  features  will  be  briefly 
related. 

A  young  child  was  convalescent  from  a  severe  attack  of  bacillary 
dysentery.  It  had  passed  successfully  through  the  febrile  and  diarrheal 
stages  of  the  disease  upon  the  lactose-protein  diet,  and  was  apparently 
in  such  good  condition  that  a  more  liberal  regimen  ^vas  indicated.  Sud- 
denly, without  warning,  the  diarrhea  reappeared  together  with  the  san- 
guineous, mucopunilent  intestinal  discharges  previously  observed.  The 
clinical .  picture  at  first  sight  was  one  of  a  severe  relapse.  It  was  per- 
fectly clear  at  this  stage  of  the  case  that  the  lactose-protein  feedings  were 
distinctly  hannful.  They  aggravated  the  patient's  condition  beyond  rea- 
sonable doubt.  It  was  observed  that  there  was  a  slight  difference  in 
the  constitutional  symptomatology  of  this  new  attack.  The  patient  was 
weakened  very  greatly,  but  the  mental  signs  of  profound  toxemia  were 
disproportionately  slight  as  compared  with  those  of  the  initial  infection. 

Repeated  attempts  to  isolate  dysentery  bacilli  from  the  feces  and 
blood-stained  mucus  were  unsuccessful  at  this  time,  although  no  trouble 
had  been  exi>erienced  in  cultivating  the  organisms  during  the  earlier 
diarrheal  period.  Gas  bacilli  [Bacillus  aerogenes  capsulatus  or  Bacillus 
welchii],  however,  were  found  in  abundance.  This  had  not  been  en- 
countered in  the  dysenteric  period  of  this  case,  nor  had  they  been  de- 
tected in  other  dysentery  cases  previously  studied. 

It  is  well  known  that  gas  bacilli  are  intolerant  of  preformed  lactic 
acid,  and  with  this  in  view  well-soured  buttermilk  was  administered  in 
considerable  amounts  in  place  of  the  lactose-protein  solution. ^^  The  symx>- 
toms,  including  the  diarrhea,  promptly  abated,  and  the  patient  made  an 

**The  use  of  well  soured  milk  in  cases  of  overgrowth  of  gas  bacilli  in  the  intestinal 
tract  is  an  important  example  of  the  value  of  lactic  acid  milk  in  intestinal  therapy. 
(Kendall  and  Smith,  Hewes  and  Kendall.) 


/ 

710  ARTHUR  ISAAC  KENDALL 

uneventful  recovery.  Subsequent  examination  of  some  of  the  lactose 
itself  revealed  an  extensive  contamination  with  the  spores  of  the  gas 
bacillus.  Even  so  small  an  amount  as  ten  milligrams  sufficed  to  produce  . 
the  well-known  stormy  fermentation  of  milk,  and  the  development  of 
the  rancid  odor  characteristic  of  butyric  acid.  The  injection  of  some  of 
this  milk  into  rabbits  produced  the  characteristic  distention,  foamy  liver 
and  other  signs  of  the  Welch-Nuttall  test,  thus  affording  ample  con- 
firmation of  the  diagnosis. 

The  origin  of  the  second  attack  of  profuse  diarrhea  and  the  obvious 
relationship  between  the  lactose  and  the  aggravation  of  the  symptoms  in 
this  case  is  very  clear.  The  contaminated  lactose  was  responsible  for  a 
direct  implantation  of  spores  of  the  gas  bacilli  in  the  digestive  tract 
of  this  child. ^^  These  spores  vegetated,  and  the  gas  bacilli  multiplied 
rapidly.  Inasmuch  as  Bacillus  welchii  is  a  most  energetic  ferm  enter 
of  carbohydrates  (Simonds,  Blake),  producing  therefrom  considerable 
amounts  of  butyric  acid,  it  was  in  all  probability  the  irritant  effect  of 
this  acid  upon  the  intestinal  mucosa  which  caused  the  diarrhea.  The 
absence  of  symptoms  of  toxemia  is  probably  associated  with  the  fact 
that  butyric  acid  is  not  a  toxin. 

Two  other  patients,  out  of  a  number  of  dysentery  cases  undergoing 
the  lactose-protein  treatment,  also  developed  gas  bacillus  diarrhea  before 
the  condition  and  its  remedy  were  recognized.  The  administration  of 
buttermilk  was  as  effective  in  arresting  the  process  in  these  cases  as  it  was 
in  the  first  instance.  It  should  be  mentioned  in  passing  that  gas  bacillus 
diarrhea  was  so  prevalent  two  years  later  among  patients  coming  to  the 
same  hospital,^^  that  it  might  be  said  to  have  existed  in  epidemic  pro- 
portions (Kendall  and  Smith).  It  was  not  transmitted  through  lactose 
at  this  time,  however,  inasmuch  as  the  infection  existed  prior  to  their 
admission  to  the  clinic.  Buttermilk  proved  to  be  as  efficacious  in  the 
treatment  of  this  group  as  it  had  been  in  the  single  cases  just  men- 
tioned.^* 

To  summarize:  these  dysentery  cases  and  the  gas  bacillus  infections 
arising  from  them  are  of  iiiterest  from  two  viewpoints:  Eirst,  because 
underlying  principles  of  bacterial  metabolism  observed  in  culture  and  in 
the  normal  digestive  tract  have  a  direct  bearing  upon  the  specific  dietary 
treatment  of  intestinal  infections.  Indeed,  these  principles  are  applicable 
to  any  infection  where  the  anatomical  relations  to  the  host  are  such  that 
full  advantage  may  be  taken  of  procedures  w^hich  shall  alter  directly 
the  metabolism  of  the  microbe  in  favor  of  the  host.     These  conditions 

"All  lactose  solutions  were  subsequently  sterilized  in  the  autoclave,  and  all  trouble 
from  this  source  was  at  an  end. 

"  Fifty-three  out  of  a  total  of  one  hundred  and  thirty-five  cases  of  severe  diarrhea 
studied.     (Kendall.) 

** Similar  cases  have  been  seen  in  adults;  also  subacute  and  chronic  types  are 
occasionally  met  with.   They  are. usually  unrecognized,  however.    (Hewes  and  Kendall.) 


BACTERIAL  METABOLISM  WITHIX  THE  BODY      Tii 

usually  may  be  predicted.  Secondly,  apparent  exceptions  to  the  practical 
working  out  of  these  principles  may  he  caused  by  the  abrupt  development 
of  latent,  unr(X'ni»nized  organisms  whose  activities  are  favored  by  the 
regimen  which  controls  those  of  the  primary  infective  agent. 

Such  instances  are  not  indicative  of  a  faihirc  of  the  principle;  in 
fact,  they  are  su|>plementary  evidence  of  the  correctness  of  the  principle. 
They  do  suggest  tlie  necessity  of  a  complete  survey  of  the  residual  intestinal 
flora  as  a  basis  for  the  formulation  of  a  correct  dietotherapy.  The 
gradual,  or  rapid,  reestablishment  of  a  normal  lactic  acid  flora,  antago- 
nistic to  the  development  of  the  dysentery  bacilli  was  readily  determined 
by  direct  examination  of  the  fecal  flora,  by  cultural  methods,  and  by 
chemical  determinations  of  lactic  acid.  The  shifting  of  the  metabolism 
of  intestinal  organisms  of  the  colon  type  was  rendered  probable.  The 
shifting  of  the  metabolism  of  the  dysentery  bacilli  from  toxicogenic  to 
acidogenic  was  surmised.     It  could  not  be  definitely  proven. 

The  clinical  results  were,  generally  speaking,  fav^orable.  In  no  in- 
stance was  any  harm  to  the  patient  discernible.  If  it  were  possible  to 
determine  the  initial  damage  to  the  patient  by  the  dysenteric  infection 
before  specific  food  therapy  was  started,  much  more  accurate  statements 
could  be  made  with  reference  to  the  probable  beneficial  effects  of  dietary 
treatment  as  a  means  of  preventing  subsequent  poisoning.  It  may  be 
stated  without  reservation  that  whatever  was  accomplished  by  direct 
dietary  interference  with  the  antagonistic  activities  of  the  dysentery 
bacilli  was  entirely  in  the  interest  of  the  hosf. 

It  is  unfortunate  that  accurate  chemical  studies  of  the  metabolism  of 
at  least  a  few  of  the  cases  so  treated  could  not  liave  been  made.  It 
was  apparent  that  the  dysenteric  intoxication  produced  a  deep-seated  and 
unfavorable  effect  upon  the  metabolic  processes  of  these  patients. 

The  only  available  evidence  is  qualitative,  not  quantitative.  The  re- 
duction of  signs  and  symptoms  of  toxemia,  the  general  suggestion  of  an 
amelioration  of  the  severity  of  the  infection,  improvement  of  intestinal 
conditions  with  respect  to  digestion,  and  a  tendency  toward  a  relatively 
early  recovery  from  loss  of  weight  suggested  that  those  same  dietary 
factors  which  would  theoretically  restrict  the  pemicious  activities  of  the 
invading  microbe  were  favorable  to  the  return  of  the  host  to  a  normal 
state. 

Although  metabolic  studies  upon  dysentery  cases  fed  with  the  lactose- 
protein  diet  are  not  available,  the  effects  of  the  Shaffer-Coleman  high 
calorie  diet  in  typhoid  fever  offer  a  somewhat  parallel  condition.  It 
has  long  been  known  that  there  is  a  ^'toxic  destruction  of  body  protein" 
in  infectious  febrile  diseases,  as  typhoid,  which  is  probably  due  in  part 
to  "Simple  pyi*exia,  and  in  part  attributable  to  the  toxins  originating  with 
the  organisms  causing  the  morbid  condition.  The  loss  of  tissue  nitrogen 
and  of  body  weight  may  be  very  considerable  in  typhoid  fever,  particu- 


712  ARTHUR  ISAAC  KEISTDALL 

larly  if  the  partial  starvation  diet  principle  be  adhered  to.  Shaffer  and 
Coleman  sought  to  prevent  this  large  loss  of  body  nitrogen.  They  were 
led  to  prescribe  a  diet  moderately  rich  in  protein  and  fat,  and  extremely 
rich  in  carbohydrate,  through  a  consideration  of  the  well-established  physi- 
ological dictum  that  carbohydrate  spares  body  protein.  They  were  able 
to  keep  several  typhoid  patients  in  approximate  nitrogen  equilibrium, 
but  little  below  the  normal,  upon  such  a  high  calorie  diet,  and  this  form 
of  dietary  treatment  has  been  rather  generally  adopted  since  the  appear- 
ance of  their  studies. 

The  sparing  action  of  the  carbohydrate  for  body  protein  was  mani- 
fested by  the  relatively  slight  losses  in  weight  experienced  by  their  pa- 
tients. Another,  and  perhaps  unexpectedj  result  was  observed.  The 
toxic  appearance,  the  "typhoid  facies''  of  older  days  and  accompanying 
symptoms  of  toxemia  were  noticeably  reduced  in  those  patients  who  were 
obviously  benefited  by  the  carbohydrate-rich  diet.  Among  their  conclu- 
sions, they  state:  "The  ^toxic'  destruction  of  body  protein,  as  well  as 
the  destruction  due  to  simple  pyrexia  in  this  disease  [typhoid]  may  be 
either  prevented  or  compensated  for."  "If,  as  seems  probable  from  our 
results,  the-  *toxic*  destruction  of  body  protein  may  be  prevented  by  a 
large  carbohydrate  intake,  the  mechanism  of  this  ^toxic'  destruction  can- 
not be  a  direct  [poisonous]  injury  to  body  cells  and  protein." 

Bacteriologically,  typhoid  fever  exhibits  several  similarities  to  bacil- 
lary  dysentery.  Both  are  initially  intestinal  infections.  The  dysentery 
bacillus  rarely  penetrates  beyond  the  mesenteric  lymph  nodes,  but  typhoid 
bacilli  usually  invade  the  blood  stream  and  may  enter  all  the  tissues. 
From  the  viewpoint  of  bacterial  metabolism,  a  carbohydrate  rich  diet 
would  be  quite  as  much  indicated  to  induce  a  reestablishment  of  the 
intestinal  flora,  and  a  reformation  of  the  metabolism  of  the  typhoid 
bacillus  in  typhoid  fever  as  is  the  case  correspondingly  in  bacillary 
dysentery.  The  careful  study  of  Torrey  upon  the  intestinal  floi-a  of 
typhoid  patients  receiving  the  high  calorie  diet  indicates  that  there  is 
a  clearly  discernible  change  of  the  intestinal  bacteria  very  similar  to  that 
observed  in  bacillary  dysentery  cases  fed  upon  a  lactose- pi'otein  diet. 
Torrey  says,  "On  a  diet  consisting  of  a  daily  average  of  50-100  grm.  of 
protein,  75-100  grm.  of  fat,  and  250-300  gi-m.  of  carbohydrate,  including 
lactose,  the  intestinal  flora  tended  to  become  converted  into  a  fermenta- 
tive type  in  which  the  dominant  organism  was  Bacillus  acidophilus. 
Patients  exhibiting  an  initial  fermentative  flora  of  the  aciduric  type 
adapted  themselves  more  readily  to  the  high  calorie  diet  of  Coleman 
— in  such  patients  the  disease  showed  a  marked  tendency  to  run  a  mild 
course." 

In  addition  to  the  changes  noted  in  the  types  and  metabolism  of  the 
bacteria  of  the  intestinal  tract,  there  is  the  additional  possibility  that 
a  reformation  of  the  metabolism  of  typhoid  bacilli  in  the  blood  stream. 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      713 

and  possibly  even  in  the  tissues,  may  take  place.  Feeding  a  diet  rich 
in  carbohydrate  certainly  tends  to  keep  the  glycogen  reservoir  in  the 
liver,  muscles  and  elsewhere  at  a  high  level.  The  normal  blood  sugar, 
nearly  0.1  per  cent  in  man,  would  likewise  tend  to  be  kept  at  or  near  its 
maximal  level,  through  continuous  repletion  from  the  glycogen  deposits 
and  additions  from  the  intestinal  tract.  One-tenth  of  one  per  cent  of 
glucose  continuously  present  in  the  general  circulation  would  abundantly 
supply  the  minute  requirements  of  the  typhoid  bacilli  therein  present. 
Under  such  conditions  it  is  difficult  to  conceive  of  the  failure  of  the 
organisms  to  utilize  such  a  readily  assimilable  source  of  euergy.^^  The 
living  typhoid  bacilli  in  the  circulation  would  become  potentially  lactic 
acid  bacilli.  Furthermore,  inasmuch  as  glucose  appears  to  exist  in  simple 
solution  in  the  plasma,  it  would  diffuse  readily  into  the  tissues.  It  is 
possible,  even  probable,  that  the  outside  of  necrotic  foci  containing  the 
organisms  in  the  spleen,  liver  and  other  organs  would  receive  glucose. 
Whether  this  glucose  would  penetrate  to  the  depths  of  such  foci  cannot 
be  stated.  A  large  carbohydrate  intake  stands  in  some  very  direct  rela- 
tion to  the  favorable  progi'ess  of  the  disease.  Sugar  can  not  neutralize 
toxins,  however,  although  they  do  prevent  the  formation  of  toxins  in 
many  well  kno^vn  instances. 

The  diminution  in  signs  of  toxemia  and  the  ''prevention  of  or  com- 
pensation for  toxic  destruction  of  protein  and  body  cells,"  noticed  by 
Shaffer  and  Coleman,  has  significance  in  the  light  of  the  eifect  of  utiliz- 
able  carbohydrate  upon  the  metabolism  of  the  typhoid  bacillus.  It  must 
be  recognized  that  the  "toxic"  action  observed  in  typhoid  fever  rests 
ultimately  with  the  growth  of  the  organisms,  because  they  alone  incite 
the  disease,  typhoid  fever.  An  amelioration  of  the  signs  and  syniptoms 
of  toxemia  suggests  direct  interference  with  the  formation  of  the  toxic 
agent,  whatever  it  may  be.  Looking  at  this  reduction  of  toxic  phenomena 
from  the  viewpoint  of  the  shifting  of  the  metabolism  of  the  typhoid 
bacillus  from  proteolytic  [toxicogenic]  to  fermentative,  it  will  be  seen 
that  the  continuous  supply  of  glucose,  furnished  by  the  Shaffer-Coleman 
high  calorie  diet,  provides  exactly  the  chemical  basis  for  its  accomplish- 
ment. 

Attention  is  redirected  again  at  this  point  to  the  general  theoiy,  attested 
to  by  physiologists,  that  ''utilizable  carbohydrate  spares  body  protein"  and 
the  essential  agreement  of  the  physiological  and  bacteriological  response, 
under  parallel  conditions. 

"Metabolic  studies  of  typhoid  bacilli  in  sterile,  defibrinated  blood,  and  in  sterile 
blood  serum  (containing  the  normal  percentage  of  blood  sugar)  have  shown  that  the 
protein  constituents  are  left  practically  intact  until  the  glucose  is  fermented.  In  'this 
connection,  the  observations  of  McGuigan  and  von  Hess  that  glucose  may  be  obtained 
from  the  circulating  blood  in  animals  by  dialysis  through  collodion  membranes  is  of 
significance.  They  conclude:  "Dialysis  of  normal  circulating  blood  shows  the  blood 
sugar  to  be  entirely  free  and  to  exist  in  simple  solution  in  the-water  of  the  plasma." 
Sugar  in  this  state  is  available  for  energy  in  the  blood  stream  by  typhoid,  or  in  fact 
any  other,  bacteria  which  can  utilize  it. 


71  i  ARTHUR  ISAAC  KEXDALL 


Summary  and  Conclusions 

Other  infectious  diseases  of  the  digestive  tract  of  the  toxicogenic  type, 
as  paratyphoid  fever,  Asiatic  cholera,  coli  colitis,  and  invasion  hy  the 
meat  poisoning  bacteria,  are  equally  available  for  carbohydrate  therapy. 
The  general  principle  involved  is  the  same.  The  objectives  to  be  attained 
are: 

1.  The  establishment  of  a  lactic  acid   [fermentative]   intestinal 

flora  in  which  Bacillus  acidophilus  or  Bacillus  bifidus,  or 
both,  become  dominant.  - 

2.  The  shifting  of  the  metabolism  of  the  normal,  facultatively 

proteolytic  org-anisms  to  the  fermentative  side. 

3.  The  shifting  of  the  metabolism  of  the  invading  organism  from 

the  toxicogenic  [proteolytic]  to  the  fermentative  side. 

4.  To  be  certain  that  organisms  productive  of  abnormal  fermen- 

tative products,  as  gas  bacilli,  are  not  resident  in  the 
intestinal  tract  in  numbers  sufficient  to  become  offensive 
when  the  carbohydrate  regimen  is  established. 
6.  To  administer  carbohydrate  in  amounts  and  at  intervals  suf- 
ficient to  keep  the  entire  digestive  tract,  and  particularly 
the  lower  levels,  continuously  permeated  with  the  requisite 
amount  and  kind  of  sugar. 

Properly  carried  out,  this  bromatherapeutic  method  of  specifically 
influencing  infection  will  result  in  several  important  contributions  to  the 
welfare  of  the  patient. 

The  reestablishment  of  a  normal  acidogenic  flora  will  create  intestinal, 
conditions  unfavorable  to  the  development  of  those  invaders  which  are  in 
the  alimentary  canal. 

The  fermentative  shifting  of  the  metabolism  of  the  members  of  the 
facultative  group  will  prevent  the  fomiation  of  indol  and  other  bacterial 
decomposition  products  of  !he  amino  acids.  This  will  lessen  materially  the 
work  of  the  liver. 

The  fermentative  shifting  of  the  metabolism  of  the  invading  organism 
will  make  it  potentially  a  lactic  acid  bacillus  in  place  of  a  toxicogenic 
organism.  The  abundant  supply  of  carbohydrate  will  tend  to  reduce  the 
loss  of  body  protein  to  a  minimum,  thus  conserving  the  strength  of  the 
patient.  It  wall  be  seen  that  this  procedure  of  bromatherapy  is  equally 
indicated  from  the  physiological,  bacteriological,  and  biochemical  view- 
points. It  is  specifically  in  the  interest  of  the  host  and  equally  dij-ectly 
in  opposition  to  the  baneful  activities  of  the  parasite.  It  must  be  lealized 
that  bromatherapy,  as  outlined  above,  is  subject  to  the  same  general 
limitations  as  any  other  form  of  therapy.    Damage  already  accomplished 


BACTERIAL  METABOLISM  WITHIN  THE  BODY      715 

before  dietary  procedures  are  begun  can  not  be  rectified,  nor  can  the  Influ- 
ence of  this  damage  upon  the  subsequent  progi-ess  of  the  disease  be  deter- 
mined with  precision. 

Perforations,  liemorrhage,  or  other  complications,  can  not  be  influ- 
enced to  any  extent,  nor  can  they  be  prevented,  in  all  probability,  by  such 
measures.  Some  time  the  specific  poison  or  poisons  of  the  cholera-typhoid- 
dysentery  gToup,  as  well  as  those  of  other  intestinal  invaders,  may  be  dis- 
covered, and  more  specific  antidotes  discovered  for  them  than  are  now 
available.  In  the  meantime,  the  possibility  of  reforming,  but  not  of 
annihilating,  these  microbes  appears  to  be  the  most  direct  method  of  re- 
stricting their  activities.  The  dietary  route,  both  in  the  intei-est  of  the 
metabolism  of  the  patient  and  the  reformation  of  the  metabolism  of  the 
microbe,  is  the  procedure  which  thus  far  has  had  experimental  justification 
and  practical  application. 


SECTION  VII 


Actions  of  Drugs   and  Therapeutic 

Measures 


The  Effects  of   Certain   Dru^s   and   Poisons   upon    the 

Metabolism Henry  C  Barbour 

Water  and  Salts — Deficiency  of  Water — "Mineral  Waters'' — Salts — Saline 
Cathartics — Other  Cathartic  Drugs — Sodium  Chlorid — Potassium,  Lith- 
ium and  Other  Salts — Bromids — lodin  and  lodids — Salts  of  Organic 
Acids — The  Alkaline  Earths — Calcium  Deprivation — Calcium  in  Leprosy 
— Calcium  in  Tetany — Other  Effects  of  Calcium,  etc. — Aluminium — 
Acids  and  Alkalies — Neutrality  Regiilation — Acids — C.C.  of  CO  Bound 
by  100  C.C.  of  Plasma — Total  ]\Ietabolism— Purin  Metabolism — Boracic 
Acid  and  Borax — Oxygen  and  Asphyxiants — Oxygen  Deficiency — Carbon 
Dioxid— Carbon  Mouoxid — Other  Blood  Poisons — Cyanids — C.C.  CO  in 
100  C.C.  Blood — Phosphorus,  Arsenic,  Heavy  Metals,  etc. — Organic  Phos- 
phorus— Cod  Liver  Oil — Arsenic  and  Antimony — ^lercury — Chromates — 
Lead,  Platinum,  Copper,  Zinc — Radium— Narcotics — General  Anesthet- 
ics :  Chloroform  and  Ether — Hypnotics — Alcohol — Opiates — Antipyretics 
— Quinin  and  Its  Congeners — Ethjlhydrocuprein — Cinchoplicji  (Ato- 
phan ) — Ammonia,  Amins,  Alkaloids,  Purins,etc. — Ammonia — Hydrazin — 
Ethylenediamin- — Iso-amylamin,  Phenylethylamin,  and  Tryamhi — Beta- 
tetrahydronaphthylamin — The  Amino  Acids — Atropin  Pilocarpin,  etc. — 
Strychnin — Some  Other  Convulsants — Camphor — Santonin — Curare — 
Cocain — Purins — Endocrine  Drugs — Epinephrin— Thyroid  Gland  Sub- 
stance— Pituitary  Substance — Anterior  Pituitary  Lobe—Other  Gland 
Products — Thymus  Gland — Parathyroid  Gland — Spleen — Prostate  Gland 
—Testis— Pineal  Gland. 


The  Effects  of  Certain  Drugs  and 
Poisons  upon  the  Metabolism 

HENRY  G.  BARBOUR 

McGILL  UNIVERSITY,  MONTBEAI. 

I.     Water  and  Sails 

Water  taken  in  excess  of  demand  is  promptly  eliminated  from  the 
body,  but  its  removal  may  alter  the  mineral  balance  or  disturb  the  relative 
proportions  of  the  ions.  The  metabolic  changes  may  include  a  temporary 
increase  in  the  urinary  nitrogen,  due  apparently  not  only  to  "flushing," 
but  also  to  some  extra  protein  breakdown  (Hawk). 

The  effects  of  water  in  moderate  amounts  upon  the  total  metabolism 
were  first  investigated  by  Bidder  and  Schmidt  (1852),  who  reported  them 
negligible,  and  F.  G.  Benedict  employing  highly  perfected  technique  has 
recently  shown  that  normal  adults  may  ingest  5^y<)  e.c.  of  water  at  room 
temperature  without  altering  the  basal  metabolism.  Larger  amounts  may 
prove  stimulating,  but  200  c.c.  of  water  given  per  os  did  not  alter  the 
metabolism  of  Lusk^s  9.3  kilo  dog. 

Such  water  ingestion  in  health  does  not  affect  the  body  temperature. 

Large  amounts  of  water  taken  with  proteins  and  fats  do  not  influence 
the  absorption  of  the  latter  from  the  alimentary  canal  (Edsall). 

Deficiency  of  Water. — Water  deprivation  as  well  as  excess  results 
in  an  increased  protein  destruction;  the  excess  metabolites  do  not,  how- 
ever, appear  in  the  urine  until  its  checked  flow  has  been  restored  by  re- 
newed intake  of  fluid.  (Straub.) 

An  adequate  water  content  of  the  blood  is  so  essential  to  the  various 
processes  of  heat  elimination  that  any  considerable  dehydration  of  the 
body  (because  of  the  diminished  blood  volume)  j-esults  in  fever.  Salt 
fever  (see  below)  has  been  thus  explained  by  Balcar,  Sansum,  and  Wood- 
yatt,  w^ho  themselves  produced  extraordinary  temperature  elevations  in 
dogs  by  dextrose  dehydration  (in  one  case  125°  F.  was  observed!).  Con- 
versely water  often  seives  as  an  antipyretic  agent.  The  fever  of  the  new- 
born, formerly  accepted  as  physiological,  can  be  prevented  entirely  by  an 
occasional  spoonful  of  water. 

The  effects  of  water  deficiency  are  further  discussed  in  connection 
with  salt  action. 

717 


TIS  HENKY  G.  BAEBOUR 

"Mineral  Waters." — iN'atural  spring  waters  have  been  so  long  and 
extensively  exploited  that  the  tendency  to  ascribe  to  them  some  occult 
therapeutic  value  still  lingers.  iN'o  evidence  exists,  however,  that  their 
employment  (most  successful  at  their  source)  is  associated  with  effects 
beyond  those  attributable  to  the  individual  mineral  ingredients  (see  below) 
or  to  psychic,  climatic  and  hygienic  factors. 

Salts. — The  effects  of  salts  upon  the  metabolism  fall  into  two  categories, 
namely,  those  due  to  (1)  "salt  action"  (chiefly  osmotic  processes)  and 
(2)  the  action  of  individual  ions.  Pertaining  chiefly  to  the  first  group 
are  the  effects  of  the 

Saline  Cathartics. — ^Poorly  absorbable  salts,  of  which  the  sulphates 
of  sodium  and  of  magnesium  are  noted  examples,  act  as  dehydrating 
agents,  their  systemic  effects  being  therefore  essentially  those  of  water 
deficiency.  This  applies  as  well  to  parenteral  administration,  where 
diuretic  instead  of  cathartic  action  results. 

Body  Temperature. — In  connection  with  the  therapeutic  employment 
of  saline  cathartics  significant  temperature  changes  are  not  seen.  Hay 
was  unable  to  substantiate  the  reputed  "cooling  effect"  in  fevers.  On 
the  contrary,  where  the  dehydrating  effect  becomes  pronounced,  some 
increase  in  temperature  may  be  anticipated  (salt  fever). 

Total  MetahoUsm. — It  was  claimed  by  Loewy(??)  that  saline  cathartics 
augment  the  total  metabolism,  this  effect  being  attributed  to  increased 
peristalsis.  Others,  on  the  basis  of  Hay's  theory  considered  that  the  alleged 
increase  in  the  total  metabolism  was  due  to  the  work  involved  in  the  active 
"secretion"  of  water  into  the  intestine.  However,  after  Wallace  and 
Cushny  showed  that  osmotic  factors  alone  will  account  adequately  for  the 
passage  of  fluid  into  the  bowel,  it  was  not  surprising  that  Brodie,  Oullis 
and  Halliburton  should  find  that  hypertonic  magnesium  sulphate  causes 
no  increase  in  the  oxygen  consumption  of  the  intestine  itself.  Ultimately 
F.  G.  Benedict  demonstrated  that  oral  therapeutic  doses  of  the  saline 
cathartics  do  not  measurably  increase  the  total  metabolism  of  healthy 
individuals. 

An  instance  of  increased  oxygen  consumption  in  a  single  organ  is, 
however,  seen  in  the  results  of  Bainbridge  and  Evans,  who,  in  a  contribu- 
tion to  the  secretory  theory  of  diuretic  action,  describe  an  increase  in  iho 
gas  consumption  of  kidneys  subjected  to  the  action  of  sodium  sulphate. 

Protein  Metabolism. — The  protein  catabolism  may  be  increased  by 
saline  cathai-tics  when  exhibited  in  amounts  sufficient  to  deplenish  the 
body's  stock  of  v^^ater. 

Fat  MetahoUsm. — The  habitual  use  of  salines  is  frequently  efiicient  in 
reducing  the  weight  in  obesity.  Many  of  the  natural  mineral  watei's  have 
acquired  a  reputation  in  such  cases.  Their  action  appears  to  be  due  in 
part  to  their  hindering  the  absorption  of  proteins  and  fats  (Hay),  in  part 
to  a  depletion  of  the  body  fluids  by  the  salt  action.     Saline  cathartics  are 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        710 

said  to  increase  the  percentage  of  butter  fat  in  cow's  milk,  but  this  is 
not  a  dependable  result  (^IcCandlish). 

Carbohydrate  Metabolism. — Franck  attributed  '^salt  glycosuria"  (dis- 
cussed below)  to  polyuria,  but  other  explanations  are  better  supported 
by  the  evidence. 

Mineral  Metabolism. — Chiari  has  suggested  that  since  all  cathartic 
ions  are  antagonistic  to  calcium  the  action  of  the  saline  cathartics  may  be 
explained  by  assuming  that  the  calcium  normally  present  keeps  the  intes- 
tinal cells  in  a  state  of  low  permeability. 

The  specific  systemic  effects  of  neither  the  magnesium  ion  of  Epsom 
salts  nor  the  tartrate  ion  of  Rochelle  salts  are  seen  after  oral  administra- 
tion. For  a  discussion  of  these  see  under  "Alkaline  Earths"  and  "Salts 
of  Organic  Acids,"  respectively.  '  - 

Other  Cathartic  Drugs.— The  effects  upon  the  metabolism  of  those 
cathartic  drugs  which  act  primarily  by  stimulation  of  peristalsis  have  never 
been  adequately  investigated. 

Aloin. — This  drug  was  administered  to  mammals  and  birds  by  Berrar, 
who  observed  a  marked  increase  in  the  energy  exchange  accompanied  by 
a  rise  in  temperature.  The  nitrogen  excretion  (especially  urea  in  mammals 
and  uric  acid  in  birds)  was  also  augmented.  • 

Sodium  Chlorid. — Because  of  the  high  normal  sodium  chlorid  con- 
tent of  the  body  (150-300  gi-ams  according  to  Magnus-Levy)  and  the 
fairly  delicate  chlorid-regulating  mechanism,  a  considerable  salt  intake 
is  required  before  effects  upon  the  metabolism  are  noted.  In  general  the 
effects  of  sodium  chlorid  upon  the  metabolism  are  probably  due  rather  to 
osmosis  than  to  specific  ion  actions. 

Mineral  Metabolism. — The  skin  acts  as  the  chief  of  several  chlorid 
depots,  storing  or  releasing  salt  according  to  need. 

Rosemann(e)  found  the  entire  chlorid  content  increased  by  100  per 
cent  when  dogs  were  given  highly  salted  food.  The  chlorid  thi-eshold  of  the 
plasma  is  said  to  be  5.62  gi*ams  per  liter.  According  to  MacLean  if  the 
concentration  falls  below  this  level  no  chlorid  is  excreted;  if  it  exceeds 
it  the  excretion  varies  as  the  square  of  the  excess. 

Holt,  Courtney  and  Fales(c)  have  investigated  in  children  the  effects 
upon  the  mineral  metabolism  of  200  c.c.  injections,  by  hypoderraoclysis,  of 
physiological  saline.  Salt  and  water  are  retained  for  several  days.  The 
effects  are  most  marked  in  conditions  where  salt  and  water  deficiency  exist, 
as  in  acute  diarrhea,  marasmus  and  protracted  vomiting.  The  retention 
is  accompanied  by  much  symptomatic  improvement.  The  changes  in 
magnesium,  calcium,  phosphorus,  and  potassium  metabolism  were  also 
followed  by  Holt  and  his  collaborators,  but  no  uniformity  could  be  de- 
tected. A  ^'balanced"  salt  solution  (potassium  and  calcium  chlorids  being 
added)  gave  results  not  differing  from  those  of  the  sodium  chlorid  solu- 
tion alone. 


720  HENRY  G.  BARBOUR 

Water  Metabolism. — The  urine  is  increased  in  araoiint  bv  sodium 
chlorid,  as  by  other  solids  which  the  kidney  eliminates.  All  salts  readily 
absorbable  from  the  alimentary  tract  act  therefore  as  diuretics^  It  is 
well  known  that  salts,  especially  sodium  chloridj  play  an  important  role 
in  the  movement  of  fluids  everywhere  in  the  body,  as  in  secretions,  effusions 
and  edemas. 

Body  Temperature, — ^The  phenomenon  known  as  salt  fever  came  to 
light  through  observations  of  pediatricians,  notably  Finkelstein  and 
Schaps,  who  observed  a  rise  in  the  body  temperature  of  infants  sub- 
sequent to  oral  or  subcutaneous  administration  of  saline  solutions.  In 
adults  Bingel  obtained  less  constant  results  from  one  liter  injections  of 
0.9  per  cent  sodium  chlorid;  the  maximum  temperature  changes  varied 
all  the  way  from  — 0.3°  to  +2.5°  C,  the  fevers  greatly  predominating, 
however.  When  a  solution  containing  NaCl  1.8,  CaClg  0.24,  KCl  0.42  and 
XaHCOg  0.2  gm.  in  one  liter  was  given  the  temperature  increases  were 
also  frequent  and  pronounced. 

To  account  for  salt  fever  a  specific  sodium  ion  effect  has  been  claimed 
by  many ;  Burnett  and  Martin,  for  example,  were  able  to  prevent  its  ap- 
pearance by  antagonizing  the  sodium  with  proper  amounts  of  calcium. 
While  the  above-mentioned  results  of  Bingel  in  no  wise  disprove  the 
sodium  ion  theory,  some  observers,  as  Roily  and  Christjansen,  find  hyper- 
tonic (3  per  cent)  saline  more  effective  than  isotonic,  indicating  that  salt 
action  is  at  least  an  important  factor. 

Heubner(&)  studied  the  effects  of  intravenous  saline  injections  in  rab- 
bits and  states  that  while  0.1-0.3  milligram  were  pyretic,  doses  of  twenty 
times  this  magnitude  gave  a  prompt  temperature  decrease.  This  latter  ef- 
fect was  possibly  associated  with  protracted  dilution  of  the  blood.  Having 
obtained  negative  effects  with  his  Ringer  solution  injections  Heubner 
favors  the  sodium  ion  theory. 

Extensive  work  upon  salt  fever  has  been  reported  by  Freund,  who 
pointed  out  a  parallelism  between  sodium  chlorid  and  epinephrin  effects; 
under  similar  conditions  he  produced  both  fever  and  glycosuria  by  in- 
jecting either  of  the  two  agents  intravenously.  From  these  and  like 
results  he  concluded  that  "the  disposition  to  sodium  chlorid  fever'^  is 
equivalent  to  a  state  of  hyperirritability  of  the  sympathetic  nervous 
system.^ 

Ereund  also  obtained  sodium  chlorid  fever  by  oral  administration 
in  rabbits,  1.5-2  gi-ams  giving  the  best  results;  3  grams  frequently,  and  4 
grams  always,  reduced  the  temperature  (as  was  the  case  witli  lleubuer's 
larger  injections).  He  pointed  oat  that  the  oral  experiments  dispose 
eft'ectively  of  a  rather  widespread  contention  that  salt  fever  might  be 
attributed  entirely  to  the  "water  infection"  which  intravenous  injections 

*  Epinephrin,  salt  and  sugar  fevers  lend  themselves  to  a  single  i::terpret^<ioTi: 
loss  of  water  from  the  blood. 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        721 

of  stale  distilleil  water  sometimes  produce.  He  also  failed  to  obtain  salt 
fever  with  intravenous  Ringer  solution. 

In  the  hands  of  the  present  author  20  c.c.  per  kilo  of  dextrose-free 
Locke  solution  made  with  water  freshly  redistilled  from  glass  gave  the 
same  results  as  physiological  sodium  chlorid  solution, — a  temperature 
rise  of  over  1 "  C.  when  either  was  injectetl  into  the  ear  veins  of  nonnal 
rabbits.  (In  both  cases  a  fall  of  0.2"^  C.  during  the  first  twenty  minutes 
was  obtained.)  Furthermore  Barbour  and  Howard  with  8  c.c.  per  kilo 
of  a  similar  Locke's  solution  intravenously  injected  were  able  after  an 
intei-val  of  fifteen  minutes  to  superimpose  a  steep  salt  fever  rise  upon  the 
plateau  of  the  ''coli  fever"  curve  in  dogs. 

It  certainly  appears  probable  that  salt  fever  is  due  chiefly  to  a  loss  of 
water  from  the  blood,  whether  the  water  be  drawn  chiefly  to  the  kidneys, 
to  the  site  of  salt  administration  or,  on  account  of  disturbed  capillary 
permeability  (for  which  complex  ion  interchanges  might  be  responsible), 
to  other  tissues. 

Hashimoto  has  shown  that  salt  fever  is  less  readily  produced  during 
artificial  warming  of  the  ''heat  centers''  in  rabbits.  The  contention  that 
salt  fever  results  from  irritation  of  the  "heat  centers"  by  products  of  the 
interaction  of  sodium  with  (he  tissues  has  not,  however,  been  substantiated. 

The  salt  fever  riddle  has  important  bearings  upon  infectious  fevers,  in 
many  of  which  disturbances  of  the  water  and  chlorid  metabolism  are  well 
recognized. 

Total  Metabolism. — Sodium  chlorid  increases  oxidations  slightly 
whether  given  per  os  or  subcutaneously.  Freund  and  Grafe  found  that 
the  heat  production  w^as  augmented  8  per  cent  as  against  22  and  28 
per  cent  increases  after  Ringci*  and  dextrose  solutions,  respectively. 

Raeder  found  in  the  case  of  subcutaneously  injected  saline  solutions 
that  hypertonicity  favors  the  increase  in  oxidations.  This  may  be  merely 
the  result  of  a  higher  body  temperature  or  it  may  be  due  in  part  directly 
to  osmotic  action. 

Tangl  found  the  oxidations  increased  by  sodium  chlorid  given  per  os 
to  curarized  animals  without  kidneys.  This  would  tend  to  relegate  both 
central  nervous  and  diuretic  factors  to  a  position  of  secondary  importance 
in  salt  fever  questions.  Apparently  dehydration  into  the  stomach  would 
account  for  Tangl's  results. 

Nitrogen  Metabolism. — In  salt  fever  Freund  and  Grafe  found  20  to 
45  per  cent  increases  in  the  excietion  of  urinary  nitrogen (6).  (Compare 
the  effects  of  water  drinking  described  b}^  Hawk.)  Straub(&),  however, 
states  that  sodium  chlorid  in  non-dehydrating>concentrations  exerts  a  slight 
sparing  effect  upon  the  nitrogen  metabolism ;  similar  results  have  been  ob- 
tained with  the  nitrate,  acetate,  carbonate,  sulphate  or  phosphate  of  sodium 
(Loewi). 


722  HENRY  G.  BxVRBOUR 

Salt  Glycosuria. — This  phenomenon,  which  has  been  investigated 
chicrij  in  rabbits,  bears  an  undoubted  relation  to  salt  fever.  It  was  dis- 
covered in  1871  by  Bock  and  Hoffmann  as  the  result  of  injecting  into 
the  arterial  circulation  of  rabbits  large  amounts  of  1  per  cent  sodium 
chlorid.  Others  have  added  to  the  list  of  glycosuria-producing  salts  the 
acetate,  bicarbonate,  phosphate,  succinate,  valerianate  and  sulphate  of 
sodium.  Kleiner  and  Meltzer(&)  have  shown  that  the  last  mentioned  pro- 
duces no  hyperglycemia,  thus  differing  from  magnesium  sulphate  (see 
below). 

A  number  of  authors  have  considered  the  possibility  that  salt  acting 
through  the  central  nervous  system  may  exert  a  stimulating  influence  upon 
the  adrenal  glands.  This  woxild  accord  with  Freund's  parallelism  between, 
the  glycosurias  and  fevers  caused  respectively  by  salt,  sugar  and  epineph- 
rin.  Furthermore,  Waterman  and  Smit  found  an  increased  epinephrin 
content  in  the  blood  in  salt  glycosuria,  while  Stewart  and  Rogoff(a)  have 
recently  shown  that  concentrated  sodium  carbonate  solutions  increase  the' 
epinephrin  output  from  the  adrenals.  Mobilization  of  glycogen  by  salt 
through  the  agency  of  these  glands  would  thus  seem  to  be  strongly 
suggested. 

However,  MacGuigan's  demonstration  that  epinephrectomy  in  cats  is 
without  influence  upon  salt  glycosuria  (although  in  dogs  the  operation 
does  make  the  glycosuria  more  difficult  of  accomplishment)  seems  to 
exclude  the  adrenals  as  the  prime  causative  factor. 

Fischer  (a)  found  that  the  intravenous  injection  of  sodiimi  chlorid  (one- 
sixtji  molecular  or  stronger)  causes  glycosuria  in  rabbits  after  a  certain 
latent  period.  Weaker  solutions  exert  less  effect  or  none  at  all.  The 
addition  of  calcium  chlorid  prevents  or  puts  an  end  to  the  appearance  of 
sugar;  the  latter  reappears,  however,  after  returning  to  pure  sodiuin 
chlorid.  Fischer  was  inclined  to  exclude  osmosis  as  a  factor  because  urea, 
glycerin  and  alcohol  all  failed  to  produce  glycosuria.  Since  salt  injec- 
tions into  arteries  leading  directly  to  the  brain  caused  quicker  and  more 
profound  results  the  theory  of  a  central  action  was  favored. 

The  blood  sugar  in  salt  glycosuria  was  investigated  by  Underbill  and 
Closson,  who  found  it  diminished.  Underbill  and  Kleincr(&)  were  able  to 
inhibit  the  hypoglycemia  and  glycosuria  as  well  as  the  accompanying 
polyuria  by  calcium  chlorid  whence  they  concluded  that  the  latter  restores 
the  retaining  power  of  the  kidney  for  glucose  which  sodium  chlorid  appar- 
ently impairs.  The  calcium  injection  even  made  the  kidneys  unusually 
impermeable  to  injected  glucose  which  affords  a  counterpart  to  Pavy 
and  Godden's  experiment  in  which  sodium  chlorid  was  shown  to  reduce 
the  tolerance  of  rabbits  towards  injected  sugar.  Salt  glycosuria  was  there- 
fore attributed  by  Underbill  and  his  co-workers  to  increased  leiial  j>erme- 
ability;  dyspnea  was  invoked  as  an  additional  factor,  for  in  the  case  of 
arterial  injections  hyperglycemia  and  glycosuria  without  polyuria  were 


EFFECTS  OF  CERTAIN  DRUGS  XNB  POTSOjNTS        723 

noted.    Recently  ^IcDauell  and  Underliill  have  accomplished  further  work, 
showing  that V  sodium  chlorid  produces  glycosuria  with  neither 

relative  nor  absolute  hyperglycemia. 

Hypeiglycemia  has  also  been  found  by  others,  but  only  when  concen- 
trated saline  solutions  were  injected.  According  to  Wilenko  intravenous 
injection  of  20  |)er  cent  saline  produces  by  stimulation  of  the  central 
nervous  system  a  hyperglycemia  in  which  the  muscles  and  probably  the 
liver  lose  glycogen.  He  concluded  that  the  nervous  stimulation  is  a  sodium 
ion  effect  and  that  owing  to  osmotic  factors  the  permeability  of  the  kidney 
is  first  increased  and  then  decreased.  Ilirsch  also  obtained  hyperglycemia 
from  concentrated  (10  per  cent)  sodium  chlorid;  2.5  per  cent  or  more 
dilute  solutions  did  not  increase  the  blood  sugar  nor  did  sodium  car- 
bonate, sodium  acetate  or  calcium  chlorid.  He  favored  the  central  nei-v- 
ous  system  theory,  which,  however,  fails  to  account  for  the  non-appearance 
of  hyperglycemia  with  the  dilute  injections. 

Burnett  has  demonstrated  the  inhibiting  effect  of  potassium  salts  upon 
the  glycosuria  produced  by  sodium  salts,  thus  adding  weight  to  the  im- 
portance of  the  ions  wherever  the  action  may  be  exerted. 

That  the  point  of  action  of  the  ion  antagonism  in  salt  glycosuria  is 
renal  seems  difficult  to  doubt  in  the  light  of  the  recent  experiments  of 
Hamburger,  Brinkmann  and  their  co-workers  (a)  (/;).  These  invest igatoi-s 
have  studied  the  permeability  of  the  glomerular  membrane  in  the  frog  (the 
tubules  being  anatomically  separated  therefrom  in  this  animal).  They 
have  demonstrated  clearly  the  power  of  the  glomeruli  to  retain  free 
dextrose,  but  have  also  shown  that  this  power  depends  upon  the  main- 
tenance of  a  very  delicate  ion  balance  in  the  perfusion  fluid.  While  Ham- 
burger's attention  was  confined  more  to  the  calcium-potassium  relations 
and  the  bicarbonate  requirement,  it  is  obvious  that  conditions  which  alter 
the  sodium-ion  concentration  are  likely  to  disturb  seriously  the  entire  ion 
balance.  This  applies  to  ion  physiology  in  general,  as  shown  by  Loeb,  and 
to  the  instance  of  salt  glycosuria  in  particular,  as  shown  by  the  calcium 
antagonism  of  Eischer  and  of  Underhill  and  the  potassium  antagonism 
of  Burnett. 

An  interesting  practical  deduction  which  Hamburger  makes  is  that 
the  oatmeal  treatment  in  diabetes  mellitus  may  owe  its  value  to  bolstering 
up  the  retaining  power  of  a  glucose-surfeited  glomerular  membrane  by 
the  excess  of  potassium  ions  contained  in  that  food.  Hamburger's (6)  work 
should  lead  to  a  new  understanding  of  the  various  types  of  renal  glycosuria, 
of  which  sodium  chlorid  glycosuria  appears  to  be  a  notable  example. 

Salt  Starvntion, — A  deficient  salt  intake  leads  to  emaciation,  the  oc- 
currence of  acetone  in  urine  and  breath  and  other  untoward  s%inptoms.  A 
generally  lowered  mineral  excretion  results.  The  nitrogen  balance  ap- 
pears to  be  but  little  affected  (Rosemann(6)). 


T24  HENRY  G.  BAEBOIJR 

Potassium,  Lithium  and  Other  Salts. — Outside  of  the  importance  ol 
tho  potassium  iou  in  preserving  the  retaining  power  of  tlie  glomeruli  for 
dextrose  practically  no  metabolic  effects  peculiar  to  potassium  salts  have 
been  demonstrated.  They  are,  however,  said  to  antagonize  the  beneficial" 
effects  of  calcium  in  parathyroid  tetany  (MacCallum  and  Voegtlin). 
These  ion  relations  in  tetany  appear,  however,  to  concejn  rather  the 
irritability  of  muscle  than  the  metabolism  (Zybell,  cited  by  Gamble). 

Salts  of  lithium,  rubidium,  cesium,  etc.,  are  more  toxic  than  the  corre- 
sponding sodium  or  potassium  salts.  Specific  njetabolic  effects  have  not 
been  shown.  Lithium  does  not  form  soluble  urates  in  the  presence  of 
sodium  or  potassium^  which  fact  disposes  of  its  formerly  alleged  value 
in  gout. 

Bromids. — Chlorids  and  bromids  mutually  increase  the  elimination 
of  one  another.  The  theory  of  Wyss,  however,  that  the  therapeutic  action 
of  bromids  is  due  to  chlorid-deprivation  is  not  sound,  for  simple  dechlora- 
tion  exerts  no  antispasmodic  eft'ect.'  Furthermore,  Janusche  has  shown 
that  bromid  depression  can  be  neither  efficiently  antagonized  by  sodium 
chlorid  administration  nor  reenforced  by  chlorid-poor  food. 

Bromids  appear  to  reduce  the  edema  of  uranium  poisoning,  stimu- 
lating the  retarded  water  and  chlorid  excretion  (Laeva). 

Boenniger  claimed  that  bromid  administration  may  save  animals 
from  chlorid  stan'ation  and  replace  completely  the  chlorid  of  the  serum, 
but  Bernoulli  finds  that  the  replacement  by  bromid  of  more  than  40  per 
cent  of  the  blood  chlorid  is  generally  fatal. 

The  protein  metabolism  remains  uninfluenced  even  by  large  doses  of 
bromids;  for  example,  Chittenden  and  Culbert  found  it  unchanged  dur- 
ing ten  days  in  which  46  gTams  of  potassium  bromid  were  given.  In 
experiments  upon  himself  Schultze  observed  an  average  reduction  of  19 
per  cent  iii  the  phosphate  excretion  following  10  gram  doses  of  potassium 
bromid;  the  excretion  of  nitrogen  and  sulphur,  however,  remained  un- 
affected. Japelli(a)  in  more  recent  investigations  found  little  or  no  effect 
upon  the  total  nitrogen  or  phosphorus  excretion,  but  observed  a  diminution, 
in  the  uric  acid  accompanied  by  an  increase  in  the  purin  bases, 

Schabelitz  has  studied  chronic  bromism,  which  leads  to  emaciation. 
The  administration  of  chlorid,  in  addition  to  stopping  the  drug,  was 
found  to  hasten  the  disappearance  of  the  symptoms. 

lodin  and  lodids. — ^In  very  exact  experiments  ]\Iag'nus-Levy  was 
unable  to  detect  any  influence  of  potassium  iodid  or  of  iodin  upon  the 
total  metabolism  of  either  healthy  or  obese  persons;  3-10  grams  of  potas- 
sium iodid  or  4-10  drops  of  tincture  of  iodin  were  given  daily  over  a 
period  of  weeks.  Magnus-Levy  further  found  iodin  inactive  in  a  case  of 
myxedema  in  which  the  metabolism  had  been  notably  stimulated  by 
iodothyrin.  The  only  case  in  which  he  observed  any  increase  in  the  total 
oxidations  under  iodids  was  that  of  an  emphysematous  patient  in  whom 


EFFECTS  OF  CERTAm  DRUGS  AX  J)  POISONS        T25 

the  drn^  aroused  a  febrile  reaction  towards  the  clo^e  of  each  day.    Magnus- 
Levy's  negative  results  have  been  confirmed. 

According  to  Christoni  iodids  may  increase  the  excretion  of  urea, 
total  nitrogen,  uric  acid,  purin  bases  and  chlorids. 

Hunt  and  Seidell  have  shown  that  thyroid  preparations  are  efficient 
in  treatment  in  proportion  to  their  iodin  content. 

Recent  investigations  upon  the  catabolic  effect  of  various  th^Toid  prep- 
arations appear  to  indicate  that  the  increase  in  nitrogen  elimination  is 
proportional  to  their  iodin  content  (Courvoisier,  Peillon,  Lanz). 

Swingle  maintains  that  iodin  is  the  specific  agent  by  which  amphibian 
metamorphosis  is  accelerated  when  thyi-oid  substance  is  fed. 

Treatment  and  Preventimi  of  Goiter. — Iodin  becomes  rapidly  fixed 
in  the  thyroid;  Marine  and  Rogoff(6)  ascertained  that  the  fixation  end- 
point  is  reached  ^yq  minutes  after  the  intravenous  injection  into  dogs  of 
50  milligrams  of  potassium  iodid. 

The  careful  administration  of  iodids  causes  a  regression  of  active 
thyroid  hyperplasia  into  the  relatively  harmless  colloid  type  of  goiter. 
For  this  purpose  Marine  (a)  advocates  syrup  of  ferrous  iodid  in  doses  grad- 
ually increasing  from  0.3  to  1.2  c.c.  per  day. 

The  prevention  of  goiter  by  iodid  has  been  definitely  achieved  by 
Kimball  and  Marine.  They  fed  2-4  grams  sodium  iodid  (in  ten  equal 
doses)  to  school  girls  in  Akron,  Ohio,  none  of  whom  became  goiterous. 
Twenty-six  per  cent  of  the  control  series  of  girls  (according  to  expecta- 
tion in  that  locality)  show^ed  definitely  enlarged  thyroid  glands.  Hun- 
ziker  suggests  the  use  of  iodin-rich  manures  in  regions  where  goiter  is 
endemic  and  vegetation  lacks  the  standard  proportion  of  iodin.  He 
further  suggests  the  admixture  of  iodin  with  table  salt. 

Toxic  effects  are  often  seen  in  goiterous  (especially  Basedow)  patients 
if  the  large  doses  of  iodids  commonly  employed  in  other  diseases  are  ad- 
ministered. The  symptoms,  which  include  emaciation  and  fever,  are 
detailed  by  Oswald ( & ) .  Acute  untoward  effects  of  intravenous  or  subcutan- 
eous injections  of  iodids  include  pulmonary  exudation  and  edema  besides 
pericardial  effusion.  According  to  Chiari  and  Janusche  these  may  be  pre- 
vented by  calcium  injections. 

The  desti-uctive  effect  of  iodids  upon  pathological  growths,  particu- 
larly gummata,  has  never  been  completely  explained.  Jobling  and  Peter- 
son believe  that  they  restrain  the  antitryptic  activity  of  serum  and  tissues^ 
thus  permitting  autolytic  digestion  to  proceed.  Full  doses  of  iodid  in 
man  greatly  lower  the  anti-ferment  index  of  the  serum. 

SaJts  of  Organic  Acids — Oxalates. — Salts  of  oxalic  acid  possess  no 
known  therapeutic  value,  ^lany  of  their  effects  are  doubtless  due  \o 
calcium  deprivation.  Sarvonat  and  Roubier  found  that  sodium  oxalate 
diminishes  the  calcium  content  of  the  soft  tissues  before  affecting  the 
bones. 


726  HENKY  G.  BAKBOUK 

Corley  maintains  that  the  total  metabolism  is  much  deprcsscfl  in 
oxalate  poisoning  and  that  there  is  a  lowering  of  the  respiratory  quotient. 
Wiehern  has  described  anuria  followed  by  polyuria.  Asphyxia,  pyrexia 
and  glycosuiia  may  also  occur. 

Tartrates. — Intravenous  injection  of  tartrates  (Rochello  salts),  in 
rabbits  inhibits  markedly  the  excretion  of  urea,  but  chlorid  excretion 
remains  unaltered.  Underbill,  Wells  and  Goldschmidt  showed  that  this 
is  due  to  a  specific  effect  upon  the  renal  tubules. 

To  be  similarly  accounted  for  is  the  fact  that  tartrates  diminish  the 
intensity  of  various  glycosurias,  e.  g.,  phlorhizin  (Baer  and  Blum), 
epinephrin  and  dextrose  glycosurias  (Starkenstein). 

Benzoates. — These  are  of  importance  in  view  of  their  use  for  the 
preservation  of  food.  Chittenden,  Long  and  Herter  in  an  exhaustive 
study  could  demonstrate  no  effects  upon  healthy  individuals  if  the  in- 
gestion of  one-half  gram  per  day  was  continued  for  weeks.  Even  four- 
gram  doses  w^ere  rarely  injurious.  The  body  weight  did  not  diminish, 
the  digestion  and  utilization  of  fat  and  protein  as  well  as  the  nitrogen- 
balance  and  partition  and  the  quantitative  composition  of  the  urine  all 
remained  normal. 

In  man  benzoic  acid  ingested  in  doses  up  to  ten  gi-ams  per  day  is 
excreted  almost  quantitatively  as  hippuric  acid  (Dakin). 

Large  doses  of  benzoates  (eight  grams  per  day  in  man)  increase  the 
urinary  urates  at  the  expense  of  the  blood  (Denis(<^)  )c  During  the  period 
of  maximum  hippurate  excretion,  however,  Lewis  and  Carr  observed  a 
marked  decrease  in  uric  acid  excretion.  This  was  seen  after  seven  to 
eight  grams  of  benzoate,  but  could  not  be  produced  by  the  direct  adminis- 
tration of  hippuric  acid. 

Creatinin  metabolism  is  not  affected  by  benzoates. 

Acetates  and  Citrates. — Acetates  and  citrates  are  converted  into 
bicarbonates  in  the  tissues,  then  acting  as  alkaline  diuretics.  (See  Chap- 
ter III) 

IL    The  Alkaline  Earths 

Calcium,  Magnesium,  etc. 

Mineral  Metaholism, — That  calcium  administration  in  man  may  in-  -. 
crease  the  calcium  store  of  the  tissues  and  blood  was  shown  by  Voor- 
hoeve(c).    Heubner  and  Bona  state  that  intravenous  injections  of  calcium 
salts  in  cats  will  double  or  triple  the  calcium  content  of  the  blood  ;  this,  how- 
ever, returns  to  normal  within  two  hours. 

Givens((i)  (h)  has  shown  that  calcium  lactate  in  man  increases  the 
calcium  excretion  in  the  urine,  but  not  to  the  same  extent  as  milk  does.  On 
the  other  hand,  magnesium  citrate  does  not  increase  the  magnesium  excre- 
tion. 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        Y27 

The  calcium  content  of  the  serum  in  tuberculosis  was  investigated  by 
lEalverson,  who  found  that  it  is  not  increased  by  a  milk  diet. 

Magnesium,  as  shown  by  ^Malcolm,  lessens  lime  deposition  in  young 
animals.  In  accord  with  this  fact  Mendel  and  Benedict  found  that  it  in- 
creases the  urinary  calcium.  The  presence  of  phosphates,  however,  in- 
hibits the  increase  by  magnesium  of  calcium  excretion  in  the  urine  (Steea- 
bock  and  Hart). 

Strontiuni  administration  to  young  animals  disturbs  bone  formation. 
Lehnerdt  showed  that  the  osteogenetic  tissue  is  stimulated,  but  the  bones 
become  imperfectly  calcified,  the  calcium  being  deficient  and  the  strontium 
incompletely  deposited. 

In  the  magnesium  narcosis  of  Meltzer  and  Auer  (which  can  be  an- 
tagonized by  calcium  chlorid  injections)  Stronsky  has  studied  the  plasma 
and  has  shown  an  increase  in  the  magnesium  content  while  the  calcium 
content  is  diminished. 

C.  Mayer  maintains  that  the  chlorids  of  the  alkaline  earths  tend  to 
increase  urinaiy  acidity.  This  is  contradictory  to  the  usual  holding  since 
part  of  the  phosphate  is  deflected  by  calcium,  for  example,  to  the  intestines. 

Calcium  Deprivation. — In  young  animals  fed  on  a  calcium-poor  diet 
the  bones  may  contain  a  normal  percentage  of  calcium,  but  what  little  new 
bone  is  formed  is  thin,  pliable,  deformed  and  fragile  (E.  Voit).  It  con- 
tains more  water,  sodium  and  potassium,  while  the  magnesium  is  not 
materially  increased.  The  percentages  vary  in  different  parts  of  the 
skeleton.  Weiser  describes  the  animals  as  undersized,  with  poor  appetite 
and  defective  nutrition.  Luithlen  has  increased  or  decreased  the  calcium 
content  of  the  bones  in  rabbits  by  feeding,  respectively,  a  green  or  an  oat 
diet.     (See  also  Oxalates.) 

In  studies  of  multiple  exostosis  Underbill,  Honeij,  and  Bogert  found 
evidence  suggesting  that  a  restriction  of  the  calcium  and  magnesium  in- 
take during  the  stage  of  proliferative  cartilage  changes  would  be  bene- 
ficial. 

Calcium  in  Diseases  of  Bone  Deficiency. — Rickets,  being  due  not  to 
deficient  calcium  income,  but  to  derangement  of  the  processes  of  assimila- 
tion, the  therapeutic  inefficiency  of  calcium  in  this  disease  has  been  gen- 
erally upheld  (Klotz(&)).  This  does  not  mean,  however,  that  none  of  the 
administered  calcium  is  retained.  Schloss(&)j  for  example,  reports  in  a 
series  of  eighty  experiments  upon  rachitic  children  the  following  results: 

Retention  of  CaO 
gram  per  day. 

Fore  period 0.032 

With  calcium  administration 0.297 

With  cod  liver  oil .  0.167 

With  cod  liver  oil  and  calcium. 0.354 


728 


HENKY  G.  BARBGUB 


In  respect  to  enliancement  of  the  cod  liver  oil  effect  calcium  appeared 
superior  to  phosphorus,  which,  when  given  with  the  oil,  did  not  exhibit 
any  influence  upon  the  calcium  retention. 

Triacalcium  phosphate  Schloss  found  slightly  better  than  calcium 
acetate  and  equal  in  retention  v.alue  to  some  other  organic  calciujn  prep- 
arations. 

In  the  florid  stages  of  rickets  a  high  magnesium  retention  was  noted. 
This  fell  rapidly  as  the  calcium  retention  increased,  presumably  ownng  to 
medication. 

Gamble  cites  the  following  figaires  relative  to  calcium  retention  in 
osteogenesis  imperfecta: 


Author    Age  of  patient     Medication 


Bamburg  & 
Huldschinsky 

Bookman 

Orgler 


Schabad 


3  months 

3  months 
3  months 


!none 
cod  liver  oil  +  phosphorus 
none 
calcium  lactate  with  food 
none 
'^none 

cod  liver  oil  +  phosphorus 
cod  liver  oil  +  phosphorus 

+  calcium  lactate 
cod  liver  oil  +  phosphorus 


Eetention  of  CaO 

gram  per  day 

0.042 

0.0S9 

0.054 

0.402 

0.130-0.210 
0.176 
0.340 


0.338 


<-10  years 


Herbst 


+  calcium  lactate 
thyroid  substance 

Fowler's  solution 
Fowler's  solution 


(neg.  balance) 
(low  or  nega- 
tive) 
0.403 
0.382 
0.418 


Schabad (c)  prefers  arsenic  to  other  medication  in  this  condition,  but 
his  results  and  those  of  others  suggest  that  wide  variations  in  calcium  reten- 
tion occur  independently  of  medication. 

The  conditions  which  govern  calcium  retention  and  assimilation  in 
pathological  states  are  practically  unknown. 

Calcium  in  Leprosy. — Kecent  investigations  of  Underbill,  Honeij  and 
Bogert  suggest  that  in  leprosy  administration  of  calcium  may  be  of  benefit 
in  retarding  or  arresting  the  progress  of  the  characteristic  bone  chang-es. 

Calcium  in  Tetany. — Parathyroidectomy  is  followed  by  clonic  con- 
vulsions with  fever.  MacCallum  during  such  an  attack  in  a  dog  obsei'ved 
the  temperature  increase  from  39°  to  43,2'^  C.  The  administration  of 
calcium  acetate  stopped  the  convulsions  in  a  few  minutes  and  within  one- 
half  hour  the  temperature  fell  to  38.9°.     MacCallum  and  Voegtlin  also 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISOISrS       729 

reported  success  with  calcium  injections  in  a  number  of  cases  of  human 
tetany. 

The  precise  relationship  of  the  calcium  metabolism  to  parathyroid 
tetany  has,  however,  not  yet  been  demonstrated.  Wilson,  Stearns,  Tluir- 
low  and  Janney  as  well  as  ^AFcCann  and  others  liave  shown  that  removal 
of  the  parathyroid  is  followed  by  a  condition  of  all'alosts.  This  is  neu- 
tralized by  the  acid  production  incident  to  tetany,  or  the  tetany  may  be 

prevented  by  ~-  HCl  intravenously  injected.    Now  calcium  salts  have  been 

found  to  lower  the  oxygen-combining  power  of  the  hemoglobin  as  well  as 
the  alveolar  carbon  dioxid  tension,  both  of  which  effects  may  also  be 
induced  by  acids.  Calcium  is,  therefore,  in  some  respects  adapted  to 
reduce  a  condition  of  alkalosis. 

Howland  and  Marriott (6)  have  contributed  to  the  question  of  the  cal- 
cium metabolism  in  infantile  tetany  by  demonstrating  that  in  this  condition 
the  calcium  content  of  the  blood  is  approximately  halved.  Their  average 
figure  for  eighteen  cases  was  5.0  milligrams  in  100  c.c,  the  lowest  being 
3.5  milligrams.  The  corresponding  noi-mal  figure  was  found  to  be  10-11 
milligTams.  They  do  not  wholly  accept  the  alkalosis  theory.  Calcium 
chlorid  per  os  was  found  effective  in  increasing  the  serum  calcium  coin- 
cidently  with  cessation  of  the  symptoms,  although  in  most  cases  the  normal 
calcium  content  was  not  attained. 

Brown,  MacLachlan  and  Simpson  have  recently  found  that  intravenous 
injections  of  1.25  grams  calcium  lactate  may  keep  the  signs  of  tetany 
in  abeyance  for  from  seven  to  ten  hours.  They  state,  however,  that  no 
permanent  effects  are  obtained  unless  the  treatment  includes  cod  liver  oil 
and  phosphorus.  The  value  of  these  last  as  regards  rapid  reduction  of 
the  symptoms  is  enhanced  by  the  addition  of  the  calcium.  Cod  liver  oil 
and  phosphorus  produce  within  about  two  weeks  an  increase  in  the  calcium 
content  of  the  blood. 

Uhlenhuth(a)  has  succeeded  in  suppressing  with  the  lactate  of  calcium 
or  magnesium  as  well  as  with  a  weak  milk  solution  the  tetany  exhibited 
by  thymus-fed  salamander  larvae.  The  development  of  permanent 
paralyses  and  contractures  is  not,  however,  prevented.  This  form  of 
tetany  (which  Uhlenhuth  believes  to  be  a  true  parathyreoprival  tetany) 
is  therefore  shown  to  be  due  to  a  specific  toxic  substance  not  perfectly 
antagonized  by  calcium,  magnesium  or  milk. 

Marine (&)  has  shown  that  parathyroid  hyperplasia  of  the  fowl  (which 
is  produced  by  feeding  maize  or  wheat)  can  be  retarded  by  feeding  calcium. 

When  the  prevention  or  treatment  of  the  dysparathyroidisms  shall 
have  been  perfected,  one  feels  justified  in  believing  that  a  prominent  role 
therein  will  be  played  by  calcium. 


730  HENEY  G.  BARBOUK 

OTHER  EFFECTS  OF  CALCIUM,  ETC. 

Water  Metabolism. — The  effects  of  the  ealclimi  ion  upon  water 
exchanges  in  the  organism  are  very  imperfectly  understood. 

Many  of  them  may  be  ascribed  to  diminished  penneability  of  the 
kidneys.  Diminution  in  urine  flow,  for  example,  was  described  by  Forges 
and  Pribram.  Davis  has  observed  antagonism  of  sodium  chlorid 
diuresis  by  calcium  in  dogs.  Besides  this  the  elimination  of  injected  saline 
fluids  has,  by  Fleisher,  Iloyt  and  Leo  Loeb,  been  decreased  by  the  intra- 
venous injection  of  calcium  chlorid. 

The  last  named  authors  And,  however,  that  calcium  injection  increases 
the  tendency  to  peritoneal  and  pulmonary  transudation.  Augmented 
rather  than  reduced  permeability  would  be  indicated  in  such  a  case,  unless 
one  assumes  that  the  calcium  acts  rather  by  hindering  some  normal  re- 
absorptive  process  than  by  facilitating  the  escape  of  fluid  into  the  afl^ected 
cavities.     - 

On  the  other  hand,  prevention  of  various  experimental  inflammatory 
edemas  was  accomplished  by  calcium  injections  in  the  hands  of  Chiari 
and  Janusche. 

In  view  of  the  present  state  of  our  knowledge  it  is  not  surprising  that 
clinical  applications  of  calcium  in  the  treatment  of  effusions,  coryza,  etc., 
have  been  rather  disappointing.  The  success  attained  b}^  Choksy  and 
others  with  magnesium  sulphate  in  the  reduction  of  the  swellings  of 
erysipelas  and  other  inflammations  is  probably  due  largely  to  salt  action. 

Excess  of  calcium  did  not  retard  recovery  from  saline  hydremia  in 
the  rabbits  of  Bogert,  Mendel  and  Underbill,  although  a  positive  result 
might  have  been  anticipated. 

Body  Temperature. — The  effects  oi  calcium  upon  the  heat  regulation 
have  not  been  sufficiently  investigated. 

MacCallum,  as  mentioned  above,  describes  an  antipyretic  efl'ect  from 
calcium  in  tetany  and  Hill  has  obtained  a  similar  result  in  normal  rabbits 
when  small  doses  were  administered  intravenously.  Five  to  eight  c.c. 
of  a  ^ye  per  cent  solution  of  calcium  lactate  thus  given  cause  an  initial 
temperature  fall  of  from  0.4°  to  0.6°  C.  The  higher  of  these  doses  pro- 
duces toxic  symptoms  accompanying  this  temperature  fall ;  a  rise  of  from 
1.5°  to  2.5°  C.  then  ensues,  with  disappearance  of  the  other  symptoms 
of  poisoning. 

Gum  arabic  (consisting  largely  of  the  calcium  and  magnesium  salts 
of  arabinic  acid)  when  given  in  7  to  20  per  cent  solution  acts,  temporarily 
at  least,  as  an  antipyretic  agent  in  fevered  rabbits  and  dogs,  but  not  in 
healthy  animals.  In  normal  dogs,  moreover,  a  considerable  rise  of  tem- 
perature results.     (Barbour  and  Baretz.) 

Magnesium  salts  are  stated  by  Schuetz(&)  to  reduce  the  body  tempera- 
ture even  if  the  narcosis  is  prevented  by  calcium   (as  accomplished  by 


EFF^ECTS  OF  CERTAi:^  DRUGS  AND  POISONS        Y31 

jMeltzer  and  Aiier).     The  latter  fact  might  tend  to  exclude  a  centrally 
induced  antipyretic  action. 

The  pi'cvention  of  sodiuni  chlorid  fever  by  proper  concentrations  of 
calcium  salts  (balanced  solutions)  has  already  been  discussed. 

In  infants,  Bosvvorth  and  Bowditch  maintain  that  an  excess  of  ingested 
calcium  causes  an  accumulation  of  insoluble  derivatives  in  the  tissues. 
High  temperature  with  toxic  symptoms  results  and  calcium  lactate  appears 
in  the  urine.  The  untoward  effects  are  preventable  by  the  administration 
of  sufficient  chlorid  or  phosphate  to  keep  the  calcium  in  soluble  form. 

Carholnjdrate  Metabolism^ — The  inhibitory  effect  of  calcium  upon 
sodium  chlorid  glycosuria  has  been  discussed. 

The  effects  of  calcium  upon  blcod  and  urine  sugar  in  rabbits  have  been 
extensively  investigated  by  Underbill  (/?-).  He  maintains  that  calcium  salts 
play  a  noteworthy  role  in  the  regulation  of  the  blood  sugar  content;  al- 
though lacking  marked  effect  in  normal  animals  they  distinctly  alter  the 
character  of  the  curve  of  epinephrin  hyperglycemia,  often  augmenting 
the  glycosuria.  Furthermore,  withdrawal  of  calcium  (by  administration 
of  sodium  phosphate  or  oxalate)  produces  7i.?//?oglycemia,  curtailing  the 
hyperglycemia  and  often  the  glycosuria  produced  by  epinephrin.  Under- 
bill and  Blatherwick  showed  that  while  thyreoparathyroidectomy  results 
in  hypoglycemia  as  well  as  in  tetany,  calcium  lactate  will  temporarily  re- 
store the  blood  sugar  to  its  nonnal  level.  These  facts  accord  with  the 
conception  of  tetany  as  an  alkalosis. 

After  sulx?utaneous  injections  of  magnesium  sulphate  Underbill (;)  ob- 
served hyperglycemia  and  slight  glycosuria  when  general  anesthesia  de- 
veloped. With  subanesthetic  doses  only  a  slight  hyperglycemia,  without 
glycosuria,  was  seen.  Calcium  antagonizes  not  only  the  magnesium 
anesthesia,  but  also  the  hyperglycemia.  This  would  appear  to  classify 
the  latter  as  of  asphyxial  origin,  but  Kleiner  and  Meltzer(Z»)  have  shown 
that  it  occurs  under  adequate  artificial  respiration. 

Diabetics,  according  to  Kahn  and  Kahn,  exhibit  a  negative  calcium 
balance.  Following  cautious  injections  of  one-eighth  molecular  calcium 
chlorid  into  a  vein  these  authors  observed  decreases  in  glycosuria,  glyccmia 
and  polyuria.  Relief  of  symptoms  and  prevention  of  acidosis  were  also 
attributed  to  the  procedure.  The  renal  factor  appears  to  be  largely  re- 
sponsible here  and  calcium  therapy  is  unlikely  to  offer  permanent  relief, 
for  with  its  employment  no  improvement  in  the  capacity  of  the  organism 
to  oxidize  dextrose  has  been  demonstrated. 

Brinkniann(&)  has  shown  in  frogs  that  an  optimum  calcium  concentra- 
tion is  necessary  to  prevent  the  escape  of  glucose  through  the  glomenili. 
Jacoby  and  Rosenfeld's  demonstration  of  the  inhibitoiy  effects  of  calcium 
upon  phlorhizin  diabetes-  also  indicates  the  significance  of  the  renal 
factor. 

'Retention  of  nitrogen  and  of  acetone  were  also  noted. 


732  HENRY  G.  BARBOUR 

According  to  Salant  and  Wise  calcium  does  not  protect  against  zinc 
glycosuria  in  rabbits. 

Upon  the  permeability  of  the  kidneys  for  sugar,  there  appears  to  be  no 
question  of  the  inhibitory  influence  of  the  alkaline  cailbs,  but  their 
excessive  occurrence  occasionally  favors  glycosuria,  probably  asphyxial  in 
nature. 

Purin  Metabolism. — Abl  maintains  that  calcium  prevents  cinchophen 
(atophan)  from  increasing  the  excretion  of  uric  acid.  But  Gudzent, 
Maase  and  Zondek  state  that  calcium^  like  cinchophen,  increases  the  uric 
acid  of  the  urine  at  the  expense  of  the  blood. 

Pohl  found  that  two  grams  of  calcium  chlorid  per  os  decreased  allan- 
toin  excretion  from  0.397  to  0.104  gram.  It  did  not  alter  the  effect 
of  epinephrin  which  was  to  increase  both  allantoin  and  uric  acid  excre- 
tion. 

Strontium  is  stated  by  Lehnerdt  to  increase  uric  acid  excretion. 

Growth  and  Reproduction, — Emmerich  and  Loew  found  that  the 
administration  of  calcium  salts  to  female  mice,  guinea  pigs  and  rabbits 
was  followed  by  an  increase  in  the  number  of  pregnancies  and  of  offspring. 
Pearl (ct)  has  observed  that  such  salts  accelerate  growth  in  female  (but  not 
in  male)  chicks  and  that  this  effect  can  be  inhibited  by  corpus  luteum 
extract.  According  to  Cramer  the  growth  in  vitro  of  cells  of  mouse 
carcinoma  is  inhibited,  with  loss  of  water,  by  calcium  chlorid.  Sodium 
ions  antagonize  this  effect. 

Aluminium. — Schmidt  and  Hoagland  maintain  that  aluminium,  like 
calcium  and  magnesium,  deflects  phosphates  from  the  intermediary  metab- 
olism in  man.  In  special  cases  a  low  phosphate  intake  may  be  excreted 
entirely  in  the  feces,  in  combination  with  aluminium. 


III.     Acids  and  Alkalies 

Neutrality  Regulation. — The  mechanism  which  regulates  the  con- 
centration of  free  hydrogen  ions  in  the  blood  and  tissues  is  very  delicate. 
in  sixty  miscellaneous  medical  cases  Levy,  Rowntree  and  ]\[arriott  found 
the  reaction  of  the  serum  normal  (Ph=^  7.6-7.8) ;  the  whole  blood  was 
also  nearly  unchanged  (Ph=  7.1-7.3),  Even  when  symptoms  of  acidosis 
are  present  the  alkalinity  is  but  little  decreased  (serum  Ph  =  7.2-7.5)  ; 
alkali  therapy  combats  this  decrease.  In  diabetic  coma  Masel  found 
Ph  =  7.11  just  l>efore  death. 

The  addition  of  hydrochloric  acid  to  acidosis  blood  was  found  by  Van 
Slyke  to  raise  its  H-ion  concentration  relatively  more  than  when  added 
to  normal  blood ;  thus  the  essential  change  in  acidosis  is  loss  of  reserve 
alkali.  VanSlyke  defines  acidosis  as  "a  condition  in  which  the  concen- 
tration of  bicarbonate  in  the  blood  is  reduced  below  the  normal  level." 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        733 

If  the  normal  ^tt^ttt^t"  ^^^^^    (=A)  remains  undisturbed  the  condi- 
JN  aliCUa 

tion  is  one  of  compensated  acidosis,  hut  should  the  respirator^'  center  fail 

to  remove  the  relatively  excessive  carbon  dioxid  present  when  bicarbonate 

has  been  lost  the  acidosis  is  said  to  be  uncompensated. 

Since  excess  of  carbon  dioxid  gas  in  the  blood  may  occasionally  in- 
crease the  numerator  of  the  ratio  without  disturbing  the  denominator  a 
true  acidosis  without  change  in  the  bicarbonate  level  is  possible. 

Next  to  carbonic  acid  and  sodium  bicarbonate  the  acid  and  alkaline 
phosphates  of  the  corpuscles  and  tissues  assist  in  maintaining  the  neutrality 

of  the  blood.    The  normal  r- — ^     /^  ratio  in  the  blood  plasma  is  given  as 

^   by  Michaelis  and  Garmendia. 

Besides  these  defenses  and  the  ammonia  regulation  (see  "Acids"),  a 
factor  of  possible  significance  in  maintaining  the  neutrality 'is  lactic  acid. 
MacLeod  and  Knapp  observed  that  this  acid  may  appear  in  the  urine, 
after  alkali  injections  in  animals,  in  amounts  sufficient  to  account  for 
five  or  six  per  cent  of  the  alkali  given. 

Acids. — Walter  in  1877  appears  first  to  have  shown  that  acids  dimin- 
ish the  carbon  dioxid  content  of  the  blood  by  displacing  the  "weaker" 
acid,  H^COg.  Kraus  and  many  others  showed  later  that  acids  diminish 
the  total  or  titratable  alkalinity.  Walter  pointed  out  the  differences  be- 
tween herbivora  and  carnivora  with  respect  to  their  manner  of  regulating 
against  acids.  While  the  former  to  accomplish  this  must  surrender  their 
fixed  alkali  from  the  tissues,^  the  carnivora  are  able  to  deflect  ammonia 
from  the  protein  metabolism  (at  the  expense  of  urea  formation)  for  pur- 
poses of  neutralization.  Recently  Loeffler  has  shown  that  acids  inhibit 
somewhat  the  formation  of  urea  by  the  pei-f usion  of  the  liver  m  vitro  with 
ammonium  salts. 

Thus  an  augmented         ^  ratio  in  the  urine  has  become  a  significant 

guide  to  acidosis. 

The  term  "acidosis"  may  be  understood  in  its  broadest  sense  to  in- 
clude all  those  disturbances  of  the  acid-base  equilibrium  in  which  there 

occurs  either  an  actual  increase  in  the  Pj,  (i.  e.  in  the        xT/^r\     ^^^tio)  of 

JNaHCUs 

the  blood,  or,  as  is  far  more  frequent,  a  decrease  in  the  alkali  reserve,  or 
both.  The  appearance  of  the  acetone  bodies,  as  in  diabetes,  merely  indi- 
cates one  form  of  acidosis,  sometimes  designated  as  "ketosis." 

L.  J.  Henderson  and  Palmer (&),  as  well  as  Hanzlik  and  Collins,  have 
shown  that  acid  sodium  phosphate  increases  the  urine  acidity,  although 

•  But  Hart  and  Nelson  have  found  a  certain  degree  of  ammonia  regulation  in  cattle. 


734  HENRY  G.  BARBOUR 

scarcely  to  an  abnormal  extent.     The  highest  acidity  figures  in  the  two 
investigations  were,  respectively,  Ph    —  5.3  and  4.85. 

^farriott  and  ITowIand(fe)  have  found  an  interesting  difference  in  the 
reaction  of  dogs  to  hydrochloric  acid  on  the  one  hand  and  acid  phospliate 
on  the  other.  While  the  former  increased  the  urinary  ammonia  parallel 
to  the  acidity,  corresponding  amounts  of  the  latter  gave,  in  spite  of  a 
great  acidity  increase,  no  change  in  the  ammonia  excretion.  Tlie  authors 
attribute  this  to  a  difference  in  "strength'^  of  the  respective  acids,  ^Sveak" 
acid  being  apparently  unable  to  arouse  the  ammonia  metabolism. 

Alkalies.  Treatment  of  Acidosis. — Walter  established  the  efficiency 
of  sodium  carbonate  injections  in  combating  the  acidosis  produced  b^^ 
giving  hydrochloric  acid  by  mouth,  even  in  the  last  stages.  Using  the 
alkali  as  a  preventive  a  triple  fatal  dose  of  the  acid  could  be  withstood 
without  increase  in  the  ammonia  excretion  or  the  appearance  of  other 
symptoms. 

In  acid  poisoning  Salkowski  and  Munk  and  others  have  reduced  the 
ammonia  excretion  to  normal  by  giving  fixed  alkali. 

In  diabetes  Stadelman(a)  founded  the  theory  of  acid  poisoning  as  the 
cause  of  coma  and  increased  ammonia  excretion,  and  instituted  the  alka- 
line treatment.  Subsequently  ]\f  aginis-Levy  developed  the  use  of  alkalies  by 
injection  and  per  os,  both  in  preventing  and  meeting  the  diabetic  acidosis. 
The  bicarbonate  is  now  generally  employed,  its  potential  alkalinity  being 
high  in  proportion  to  its  actual  (locally  irritating)  alkalinity.  Even  the 
subcutaneous  injection,  which  may  result  in  serious  sloughing,  may  be 
accomplished  with  but  slight  irritation  if  the  solution  be  first  freed  from 
all  traces  of  the  carbonate  (]N'a2C03)  by  saturating  with  carbon  dioxid 
( Magnus-Levy  ) . 

The  bicarbonate  treatment  should  be  instituted  with  the  appearance 
of  acetone  substances  in  the  urine;  after  the  onset  of  coma  it  may  be  too 
late.  The  initial  dose  by  mouth  may  be  30  to  40  grams  in  divided  doses, 
freely  diluted,  given  between  meals.  In  coma  oral  administration  may 
be  supplemented  by  drop  enemata  (4  per  cent),  or,  for  a  more  prompt 
result,  1,000  c.c.  of  4-6  per  cent  solution  by  vein. 

In  the  acidosis  of  anesthesia  Palmer  and  VanSlyke  demonstrated 
depletion  of  the  alkali  reserve  of  the  blood  and  suggested  prophylactic  in- 
jections of  bicarbonate.  Morriss  employed  this  measure  in  gynecological 
cases  (under  chloroform  or  ether)  and  summarizes  his  results  as  follows: 

C.C.  OF  CO2  BOUND  BY  100  C.C.  OF  PLASM.\ 

Before  After  Differ-  No.  of 

anesthesia  anesthesia  ence  cases 

Without  bicarbonate             50.7  41.7             9.0  10 

With  bicarbonate                   54.7  49.0             5.7  10 


EFFECTS  OF  CERTAIJST  DRUGS  AND  POISONS        735 

In  studies  of  anesthesia  Killian  found  the  acidosis,  increased  diastatic 
activity  and  sugar  content  of  the  blood  all  controllable  by  alkali  (e.  g.,  20- 
30  grams  of  bicarbonate  per  os).  The  blood  acetone  bodies  in  operative 
anesthesia  Eeimann  and  Bloorn  found  increased  sufficiently  to  account 
for  from  20  to  100  per  cent  of  the  bicarbonate  depletion.  They  endorse 
the  recommendation  that  in  cases  where  the  carlx)n  dioxid  capacity  is 
less  than  58  c.c.  the  bicarbonate  be  used  prophyhictically. 

The  alkali  depletion  resulting  from  the  oven-entilation  usually  ac(?om- 
panying  light  ether  anesthesia  can,  as  Henderson  and  Haggard  have  shown, 
be  prevented  by  administration  of  a  suitable  carbon  dioxid  mixture  with 
the  anesthetic.  Reimann  and  llartman  prefer  the  bicarbonate  to  the  gas, 
believing  it  advisable  to  introduce  more  alkali  into  the  body  to  combat  the 
production  of  acid  metabolites. 

Uranium  nephritis  is  associated,  as  MacNider(«)  (6)  has  shown,  with 
ketosis  and  depletion  of  the  plasma  bicarb<mate.  He  finds  that  alkali  injec- 
tions protect  agijinst  the  toxic  effects  of  uranium  as  well  as  against  the  un- 
favorable action  which  anesthetics  exert  upon  the  kidneys  whether  uranium- 
poisoned  or  ^'naturally  ncphi'opathic."  Furthermore,  the  action  of 
diuretics  in  these  conditions  is  enhanced  by  soilium  carbonate. 

In  the  acute  experimental  nephritides  of  eantharadin,  arsenic,  diph- 
theria toxin  and  chromate  poisoning  Goto(a)  {h)  has  i*educed  the  acidosis 
with  oral  bicarbonate  injections. 

In- the  "retention  acidosis"  of  nephritis  Denis  and  Minot(&)  find  that 
small  intermittent  oral  doses  of  bicarbonate  keep  the  urine  free  of 
ammonia. 

In  infants  a  type  of  acidosis  occurs  during  attacks  of  severe  diarrhea; 
dyspnea  is  present  but  no  cyanosis,  and  Czerny  states  that  mineral  acid 
poisoning  in  rabbits  is  simulated.  Howland  and  Marriott (f)  were  the  first 
to  attempt  the  rescue  of  such  children  by  the  alkaline  treatment.  The 
blood  was  found  free  of  acetone  bodies  in  this  condition.  In  one  of  their 
cases  treated  with  bicarbonate  the  alveolar  carbon  dioxid  tension  (in 
millimeters)  was  on  five  successive  days:  21,  42  ,54,  55,  41.  The  normal 
tension  for  infants  is  3G-15  millimeters.  On  the  third  day  therefore  the 
treatment  was  stopped. 

Blood  studies  of  such  children  have  shown  not  only  a  depleted  alkali 
reserve,  but  also  a  reduction  from  1\  —7.4  to  P^  —7.2.  Anuria  is  fre- 
quent and  the  acidosis  is  attributable  to  a  retention  of  acid  phosphate  in 
the  organism. 

Schloss  and  Stetson  have  in  similar  cases  reported,  besides  the  de- 
creased carbcn  dioxid  in  alveolar  air  and  blood,  a  high  ammonia  co- 
efficient and  an  increased  ''bicarbonate  tolerance."  1.25-3.25  grams  of 
sodium  bicarbonate  rendered  the  urine  alkaline  in  nonnal  infants,  while 
5.5-7.0  grams  was  required  to  accomplish  tliis  in  cases  of  acidosis.     Such 


736  HE^iKY  G.  EAEBOUR 

doses  increased  the  carbon  dioxid  of  the  blood  from  19.0-26  to  40-52 
volumes  per  cent. 

Water  MetaJbolism. — Either  acids  or  alkalies  may  act  efficiently  as 
diuretics.  However,  if  the  blood  volume  of  rabbits  has  already  been 
doubled  by  the  intravenous  injection  of  saline  the  addition  of  0.4  per  cent 
sodium  carbonate  does  not  hasten  its  return  to  normal.  (Bogert,  j^lendel 
and  Underbill.) 

Alkalies  enjoy  considerable  repute  as  obesity  cures,  Stadclman(/>)  and 
others  having  noted  a  marked  reduction  in  weight  during  their  prolonged. 
use.  Much  of  this  may  be  attributed  to  water  loss.  (Digestive  disturb- 
ances may,  however,  play  a  role.) 

Bicarbonate  edema  sometimes  occurs  during  the  treatment  of  diabetes 
and  other  conditions  with  this  alkali.  Fitz  associates  it  with  a  retention 
of  sodium  chlorid. 

Body  Temperature. — The  relations  existing  between  the  acid-base 
equilibrium  and  the  regulation  of  body  temperature  are  not  yet  understood. 

Mineral  Metabolism, — A  retention  of  intravenously  injected  chlorids 
(as  well  as  of  lactose)  was  observed  by  Ilerz  and  Goldberg  after  the  ad- 
ministration of  alkali.  This  was  ascribed  to  renal  action,  and  is  con- 
firmed by  the  observations  of  Fitz  (a).  On  the  other  hand,  Bunge  and 
others  have  consistently  observed  an  increased  chlorid  excretion  after  alka- 
lies. 

That  acid  administration  per  os  increases  the  urinary  calcium  has 
been  noted  by  Secchi  as  well  as  Givens(a)  (?;),  in  animals  on  a  calcium- 
rich  diet.  Givens,  however,  found  the  calcium  balance  unaffected,  and 
noted  no  appreciable  increase  in  the  magnesium  excretion,  in  which  two 
respects  Secchi's  work  lacks  confirmation.  The  latter  found  the  sodium 
and  potassium  output  after  hydrochloric  acid  augmented  for  but  a  brief 
time,  in  contrast  to  the  persistent  ammonia  excretion. 

Stehle(a)  found  an  increased  calcium  and  magnesium  excretion  in  dogs 
given  hydrochloric  acid  by  mouth.  Sodium  and  potassium  excretion  were 
augmented  to  a  lesser  extent.  He  suggests  a  connection  between  calcium 
loss  and  diabetic  acidosis. 

Sawyer,  Baumann  and  Stevens  studied  the  mineral  loss  in  children 
during  acidt)sis  and  found  both  calcium  and  phosphates  largely  excreted. 
The  loss  of  these  ions  varied  with  the  severity  of  the  acidosis. 

Fitz,  Alsberg  and  Henderson  found  that  the  administration  of  acids 
first  increases  the  excretion  of  phosphates,  but  later  this  becomes  dimin- 
ished owing  to  exhaustion  of  the  supply. 

In  experimental  acute  nephritis  Goto(6)  succeeded  in  diminishing  the 
chlorid  retention  by  oral  administration  of  bicarbonat(s 

Total  Metabolism. — While  the  effects  of  acid  or  alkali  npon  the  total 
oxidations  are  not  marked,  there  is  some  evidence  that  the  former  tends 
to  diminish  and  the  latter  to  augment  the  respiratory  exchange.    Chvostek 


EFFECTS  OF  CERTAIN  DRUGS  AXD  POISONS        737 

gave  rabbits  orally  0.1)  gTam  (per  kilo)  doses  of  hydrochloric  acid  in  0.2 
to  0.3  per  cent  sohition.  In  four  experiments  both  carbon  dioxid  out- 
put and  oxygen  absorption  were  reduced  by  about  one-fourtli,  although 
decreased  muscular  activity  was  not  noted.  Lehmami  obtained  similar 
results  under  artificial  respiration,  noting  also  an  increase  in  oxidations 
when  alkali  was  administered. 

Lactic  acid  causes  a  slight  increase  in  the  basal  metabolism,  as  shown 
by  Atkinson  and  Lusk. 

Carbohydrate  Metabolism. — The  first  evidence  of  a  relation  of  the 
acid-base  equilibrium  to  the  carbohydrate  metabolism  was  furnished  by 
Pavy's  discovery  that  phosphoric  acid,  orally  or  intravenously  given,  pro- 
duces glycosuria  in  dogs. 

Elias  found  that  hyperglycemia  accompanies  acid  glycosuria  in  dogs 
and  rabbits.  He  and  Kolb  also  showed  that  in  the  ^'hunger  diabetes"  of 
young  dogs  there  is  a  diminution  of  the  carbon  dioxid  of  alveolar  air 
and  blood. 

The  inhibitory  influence  of  alkali  upon  the  glycosuria  of  ether  and 
chlorofomi  was  discovered  by  Pavy  and  Godden,  w^ho  abolished  the  sugar 
by  the  intravenous  injection  of  sodium  carbonate.  In  like  manner  Elias 
and  Kolb  inhibited  ^'hunger  diabetes." 

Murlin  and  Kramer  showed  further  that  sodium  carbonate  intro- 
duced into  the  blood  stream  of  a  depancreatized  dog  lessens  the  sugar 
excretion.  Bicarbonate  was  later  found  less  effective.  Xo  compensatory 
increase  of  sugar  w^as  found  in  the  blood  and  no  evidence  that  the  retained 
sugar  is  deposited  as  glycogen.  The  inference  that  alkali  increases  the 
combustion  of  sugar  was  only  partially  substantiated  in  such  cases  for, 
while  in  partially  depancreatized  dogs  both  mono-  and  disodium  carbonate 
increased  the  respiratory  quotient,  the  latter  was  found  ineffective  in  cases 
where  the  entire  pancreas  had  been  removed. 

Attempts  were  made  by  IMurlin  and  Graver  to  treat  human  diabetes 
by  the  administration  of  alkalies  through  a  duodenal  tube.  Sodium  car- 
bonate thus  given  reduced  the  glycosuria,  but  the  bicarbonate  curiously 
gave  opposite  results. 

Underbill  (t*)  showed  that  intravenous  sodium  carbonate  usually  induces 
a  marked  though  transient  fall  in  the  blood  suaar  content  of  rabbits.  He 
first  suggested  that  the  acid-base  equilibrium  is  a  factor  in  blood  sugar 
regTilation  and  showed  further  that  both  the  hyperglycemia  and  glycosuria 
provoked  by  epinephrin  can  be  prevented  partially  by  sodium  carbonate. 
He  further  pointed  out  the  association  between  hypoglycemia  and  alka- 
losis in  tetany  and  in  hydrazin  poisoning. 

Applying  the  acid-base  theory  to  therapeutics  Underbill  was  able  to 
maintain  a  diabetic  individual  in  a  state  of  comparatively  good  health 
and  vigor  over  a  period  of  years  by  giving  large  doses  of  sodium  bicar* 
bonate:  as  much  as  120  grams  was  once  given  in  a  single  day.    The  carbo- 


738 


HEXKY  G.  BARBOUR 


hydrate  tolerance  in  this  case  could  he  varied  at  will  hy  appropriate 
changes  in  the  dosage.  (See  figure  1.)  On  the  other  hand.  Beard  has 
been  unable  to  control  the  sugar  tolerance  in  this  fashion.  .Fitz  warns, 
in  this  connection,  that  the  possibility  of  bicarbonate  edenui  should  be 
kept  in  mind. 

The  hyperglycemia   resulting  from   etherization   and   operative  pro- 
cedure in  sugar-fed  dogs  was  reduced  by  ^lacLeod  and  Fulk  by  injecting 


t50 


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Fig.  1.  Influence  of  sodium  carbonate  ingestion  on  the  glycosuria  of  a  diabetic: 
solid  line,  sugar;  broken  line,  intake  of  sodium  bicarbonate.  (F.  P.  Underbill,  J. 
Am.  M.  Assn.,  1917,  LXVIII.) 


intravenously  enough  sodium  carbonate  to  lower  the  P^  of  the  blood. 
(Compare  Killian's  results,  mentioned  above.)  These  investigators  lay 
emphasis  upon  increased  storage  of  glycogen  in  liver  and  muscles,  under 
the  influence  of  alkali. 

The  influence  of  alkali  upon  renal  permeability  for  sugar  was  shown 
by  the  researches  of  Hamburger (&)  upon  the  frog  glomeruli.  When  the 
perfusion  fluid  contained  NaCl,  O.G  per  cent;  CaCL,  0.00V5  per  cent; 
KCl,  0.01  per  cent;  NaHCOy,  0.02  per  cent  and  0.1  per  cent  of  glucose 
a  "urine"  containing  0.07  per  cent  of  the  latter  was  excreted,  indicating 
a  retention  of  0.03  per  cent.  When,  how^ever,  the  bicarbonate  content  of 
the  perfusion  fluid  was  increased  to  0.285  per  cent,  the  ecpiivalent  of  the 
normal  frog  serum  content,  a  sugar-free  "^irine"  was  obtained. 


EFFECTS  OF  CERTAI]^  DRUGS  AND  POISOlv'^S        739 

While  the  exact  effects  upon  either  the  comhiistion  or  the  storage  of 
glucose  are  not  as  clear  as  the  influence  of  alkali  upon  renal  permeability 
it  may  safely  he  affirmed  that  acids  and  alkalies  tend,  within  certain  limits, 
to  increase  and  decrease^  respectively,  the  excretion  of  sugar. 

Protein  Metabolism. — The  augmented  excretion  of  various  protein 
metabolites,  following  administration  of  dilute  mineral  acids,  described 
by  some  observers,  is  probably  chiefly  a  diuretic  effect.  Alkalies  have  not 
been  shown  to  affect  appreciably  the  protein  catabolism.  Jawein  found 
that  20-40  grams  of  sodium  carbonate  or  citrate  produced  in  man  either 
inconstant  changes  or  none  at  all.  The  neutral  sulphur  of  the  urine,  liow- 
ever,  appeared  to  be  increased  at  the  expense  of  the  acid  sulphates. 

The  retention  both  of  non-protein  and  of  urea  nitrogen  in  the  acute 
nephritis  of  metal  poisoning,  etc.,  was  overcome  in  Goto's  experiments 
by  alkali  administration. 

The  excretion  of  creatin  in  rabbits  ma}^  be  initiated  or  augmented  by 
acids  or  diminished  or  abolished  by  alkalies,  as  shown  by  Underbill (/.•). 
Denis(Z)  and  Minot((Z)  failed  to  establish  such  a  relationship  in  a  few 
human  cases. 

Purin  Metabolism. — The  alkalies  have  been  extensively  used  in  gout, 
partly  on  the  theory  that  the  supposed  combustion  increase  would  destioy 
more  uric  acid  and  partly  in  an  attempt,  by  neutralizing  this  acid,  to  pro- 
mote its  excretion.  We  have  seen,  however,  that  increased  oxidation  has 
not  been  established  and  Ritter  has  showji  that  no  direct  solvent  action  of 
alkalies  upon  urate  tophi  can  occur  in  tlie  body.  MacLeod  and  Ilaskins 
maintain  that  citrates  by  their  alkalinity  increase  the  elimination  of 
endogenous  uric  acid  and  purins,  but  this  may  be  due  to  intestinal 
derangement. 

The  ^^alkaline  cures"  for  gout  probably  owe  their  beneficial  effects 
merely  to  the  considerable  quantitj^  of  iluid  ingested.  In  spite  of  the 
greater  solubility  of  urates  in  alkaline  form,  alkalies  do  not  remove  gouty 
calculi  from  kidney  or  bladder;  furthermore,  alkalinity  of  the  urine  is 
likely  to  promote  the  deposition  of  phosphates. 

Tetany. — Wilson  and  his  associates  found  intravenous  injections  of 
hydrochloric  acid  effective  in  ]3reventing  the  tetany  which  follows  thyreo- 
parathyroidcctomy.  They  describe  tetany  as  a  condition  of  alkalosis. 
McCann  found  a  lowered  carbon  dioxid  capacity  of  the  plasma  in  this 
condition  and  states  that  tetany  may  sometimes  depend  upon  derange- 
ments in  the  acid-base  relations  of  the  alimentary  secretions. 

Harrop(a)  has  described  a  case  of  tetany  i-esulting  from  the  intravenous 
infusion  (d'  sodium  carbonate  in  an  adult  suffering  from  mercuric  bi- 
chlorid  poisoning  and  totally  anuric.  He  emphasizes  the  danger  of 
the  use  of  bicarbonate  in  cases  of  marked  renal  impaiiment.  Tetany  has 
occasionally  been  observed  in  young  children  given  sodium  bicarbonate  for 
acidosis. 


740  HENKY  G.  BAKBOUK 

Boracic  Acid  and  Borax. — Boracic  acid  and  borax  are  respectively 
weakly  acid  and  alkaline  in  reaction.  Moderate  doses  of  either  do  not 
effect  the  metabolism,  but  Chittenden  and  Gies(6)  found  that  large  quanti- 
ties (5  to  10  grams  per  day  for  dogs)  increase  the  urinary  nitrogen;  a 
dose  of  4  to  8  grams  in  man  retards  the  absorption  of  proteins  and  fats. 

Under  borax  the  body  weight  often  falls,  which  has  been  attributed 
to  augmented  fat  destruction  by  Kost  and  by  Rubner(i),  who  found  a  cor- 
responding increase  in  the  carbon  dioxid  elimination.  Boracic  acid  is  said 
to  be  the  least  harmful  of  the  food  preservatives. 


IV.    Oxygen  and  Asphyxiants 

Breathing  undiluted  oxygen  produces  no  very  significant  effects,  but 
when  the  supply  of  oxygen  has  been  deficient  asphyxial  symptoms  are 
promptly  removed  by  inhalation.  Lavoisier  and  Seguin  in  1789  estab- 
lished the  fact  that  pure  oxygen  und.er  ordinary  conditions  does  not  affect 
the  metabolism.  Long  continued  exposure  to  atmospheres  rich  in  oxygen 
produces  pneumonia.     (Karsner.) 

Oxygen  Deficiency. — Haldane  has  described  the  acute  effects  of 
atmospheres  low  in  oxygen.  Chronic  oxygen-lack  as  seen  in  anemias,  etc., 
causes  considerable  tissue  destruction  (Frankel),  fatty  degeneration  and 
acidosis,  often  with  increased  ammonia  excretion.  A.  Loewy  found  amino- 
acids  in  the  urine.  Mansfeld  attributes  the  increased  protein  metabolism 
to  thyroid  influence,  for  it  fails  to  occur  in  the  partial  asphyxia  of  thyroi- 
dectomized  dogs.  In  anemias  with  the  hemoglobin  as  low  as  20  per  cent, 
Dubois  has  obsei-ved  a  marked  augmentation  cff  the  total  metabolism. 

Exposure  to  rarified  air,  as  first  shown  by  Viault,  increases  the  hemo- 
globin content.  This  is  preceded  by  a  relative  heraoglobinemia  (Dallwig, 
Kolls  and  Loevenhart).  This  blood  concentration  probably  induces  the 
fever  of  "mountain  sickness"  in  which  the  temperature,  according  to 
Caspari  and  Loewy,  sometimes  attains  42°  C.  Such  a  temperature  favors 
the  free  dissociation  of  oxygen,  tiding  over  the  period  of  preparation  of 
better  ox^'gen-transporting  facilities.  Douglas,  Haldane,  Henderson  and 
Schneider  at  an  elevation  of  4,290  meters,  found  the  hemoglobin  some- 
times increased  to  150  per  cent.  Some  evidence  of  "secretion''  of  oxygen 
into  the  pulmonary  capillaries  was  found. 

The  total  metabolism,  in  similar  investigations  by  TVendt  and  by 
Durig  and  Ziinz  was  found  increased,  while  there  were  evidences  of  a 
diminished  protein  catabolism. 

Asphyxial  Glycosuria. — Araki(<f)  and  others  have  shown  that  simple 
asphyxia  and  other  conditions  associated  with  oxygen-lack  cause  an  excre- 
tion in  the  urine  of  both  glucose  and  lactic  acid,  the  latter  being  regarded 
as  a  result  of  imperfect  combustion.     The  glycosuria,  like  those  produced 


EFFECTS  OF  CERTAIN  DEUGS  AND  POISONS        741 

by  piqiire  and  the  emotions,  appears  to  be  of  central  origin.  It  cannot 
occur  when  the  liver  glycogen  is  exhausted.  MacLeod  has  shown  that, 
although  it  can  still  be  produced  with  the  liver  denervated,  it  is  prevent- 
able by  double  splanchnotomy,  or  excision  of  both  adrenals.  The  effect 
is  apparently  due  to  increased  hydrogen  ion  concentration  of  the  blood 
(compare  the  acid  glycosuria  of  Pavy)  acting  through  the  nervous  centers, 
but  involving  often  the  cooperation  of  the  adrenals. 

Kellaway(a.)  (b)  produced  asphyxia  by  causing  animals  to  breathe  gas 
mixtures  low  in  oxygen  or  high  in  carbon  dioxid.  Accelerated  secretion  of 
epinephiin  and  hyperglycemia  were  obseiTed,  both  being  due  mainly  to 
lack  of  oxygen,  rather  than  to  carb(m  dioxid  excess.  The  hyperglycemia 
was  only  in  part  caused  by  acceleration  of  the  epinephrin  output.  In 
anoxemia  the  ordinary  mechanism  of  action  is  central,  the  splanchnics  pro- 
viding the  path  of  the  impulses. 

F.  M.  Allen  enumerates  a  list  of  poisons  to  which  the  production  of 
asphyxial  glycosuria  has  been  attributed.    !Many  of  them  w411  be  discussed. 

Blood  Alhalinity. — Galleotti  found  in  himself  and  several  others  as 
a  result  of  several  days'  residence  upon  ]\ronte  Rosa  (4,560  meters)  a  re- 
duction of  40  per  cent  in  the  blood  alkalinity. 

Lactic  Acid. — Araki's(a)  finding  of  increased  lactic  acid  excretion  in 
conditions  of  oxygen-lack  has  been  amply  confirmed  and  so  much  stress 
was  at  one  time  laid  upon  this  feature  that,  as  Lusk  points  out.  it  was 
wrongly  taken  as  pathognomonic  of  an  asphyxial  condition. 

Terray  found  that  when  the  oxygen  percentage  in  the  inspired  air 
was  reduced  to  10.5  an  increased  respiratory  activity  commenced.  With 
half  of  this  concentration  there  w^as  ever>'  indication  of  oxygen-lack,  and 
the  elimination  of  lactic  acid  became  pronounced.  The  lactic  acid  elimi- 
nated as  a  result  of  breathing  3  per  cent  oxygen  varied  in  eight  observa- 
tions from  1.206  to  3.686  grams  in  twenty-four  hours. 

Carbon  Dioxid. — Carbon  dioxid  acts  as  a  weak  acid,  seizing  as  the 
respiratory  regulating  hoimone.  The  central  nervous  system,  especially 
the  medulla,  is  so  sensitive  to  its  stimulating  effect  that  it  may  become 
an  important  factor  in  the  asphyxial  phenomena  just  described.  In  high 
concentrations,  however,  the  gas  evokes  the  symptoms  of  ox;^'gen-lack  in  tlie 
same  way  as  when  an  indifferent  gas  such  as  hydrogen  or  nitrogen  is  in- 
haled ;  Loevenhart  therefore  refers  its  effects  to  interference  with  oxygena- 
tion. Westenryk  showed  that  carbon  dioxid  inhalation  reduces  the  tem- 
perature, ^Magyary-Tvossa  finding  this  effect  more  marked  in  fever  than 
in  health,  and  associated  wit!)  reduced  oxidations.  To  produce  glycosuria. 
10  to  15  per  cent  of  carlx)n  dioxid  (enough  to  narcotize)  is  required 
(Edie,  ^loore  and  Roaf). 

Acajnua. — Excess  of  carbon  dioxid  is  rapidly  blown  off  by  the  respira- 
tory mechanism  and  overcompensation  often  occurs,  resulting  in  a  low^ered 
carbon  dioxid  content  of  the  blood  (Y.  Henderson).     Since  this  carbon 


742  HEXEY  G.  BARBOUR 

dioxid  content  nms  essentially  parallel  to  carbon  dioxid  capacity  (i.  e., 
varies  with  the  alkali  reserve  of  the  blood),  acapnia  is  a  variety  of  acidosis. 

Y.  Henderson  and  Underbill  showed  that  a  lowered  carbon  dioxid 
content  of  the  blood  was  associated  after  piqure,  pancreatectomy,  light 
etherization,  excessive  artificial  respiration  and  in  other  conditions  with 
hyperglycemia  and  glycosuria. 

Carbon  Monoxid. — Clearly  an  asphyxial  poison,  carbon  monoxid 
forms  a  fii-m  combination  with  hemoglobin  for  which  it  has  two  hundred 
times  the  affinity  of  oxygen.  When  an  atmosphere  containing  0.05  per 
cent  carbon  monoxid  is  inhaled  oxygen  transportation  is  seriously  ham- 
pered ;  0.2  per  cent  is  generally  fatal,  the  hemoglobin  then  being  about 
60  per  cent  saturated  with  the  poison  (Haldane(6)).  Carbon  monoxid 
acts  only  by  displacing  oxygen,  for  when  oxygen  is  breathed  under  two 
atmospheres  pressure  (which  renders  an  animal  independent  of  its  hemo- 
globin) the  addition  of  carbon  monoxid  in  any  amount  produces  no 
symptoms.  Furthermore,  in  gas  poisoning  cases,  oxygen  if  administered 
soon  enough,  which  is  rarely  feasible,  rapidly  dispels  the  symptoms. 
Hemoglobin-free  animals,  for  example,  insects,  exhibit  no  deleterious 
effects  in  the  presence  of  carbon  monoxid. 

Blood  Gases. — Saiki  and  Wakayama  in  carbon  monoxid  poisoning 
in  rabbits  found  the  carbon  dioxid  of  the  blood  reduced  from  30  to  6.21 
volumes  per  cent;  in  dogs  from  30-40  to  3.22  volumes  per  cent  The 
blood  oxygen  in  the  two  species  was  reduced  respectively  from  12.64  to 
7.62  per  cent  and  from  20  to  2.01  per  cent. 

The  low  carbon  dioxid  content  is  not  due  to  lessened  carbon  dioxid 
production,  for,  as  Hans  Meyer  has  shown,  the  latter  must  be  very  mark- 
edly reduced  to  produce  even  a  slight  diminution  of  the  blood  carbon 
dioxid  content;  it  indicates  rather  a  reduced  alkalinity  of  the  blood. 
Araki  confirmed  this  by  tritration  and  Saito  and  Katsuyama  showed 
further  an  increase  in  the  blood  lactic  acid  in  hens  from  0.02G9  to  0.1227 
per  cent.  The  fact  that  in  dogs  the  blood  carbon  dioxid  content  is  dimin- 
ished so  much  more  profoundly  after  carbon  monoxid  than  after  acid 
administration  does  not  militate  against  acid  production  being  the  cause 
of  this  acapnia,  for  Loewy  reminds  us  that  acid  feeding  by  mouth  is  one 
thing  and  acid  formation  in  the  tissues  another;  in  the  latter  case,  as,  for 
example,  in  carbon  monoxid  poisoning,  the  fijced  alkali  becomes  attacked 
before  the  ammonia  regulation  comes  into  play.  Spiro,  in  fact,  has  demon- 
strated a  marked  acapnia  as  a  result  of  the  injection  of  acids  intraven- 
ously (the  ammonia  regulation  being  thus  more  or  less  evaded).  The 
occurrence  of  acidos-is  may  satisfactorily  bejattributed  to  oxygen  deficiency. 

Total  MefahoUstii. — Bock  found  in  a  dog  subjected  to  an  atmosphere 
of  0.2  per  cent  carbon  monoxid  (leaving  less  than  half  the  hemoglobin 
saturated  w^th  oxygen)  that  the  oxygen  intake  remained  practically  un- 
changed, while  there  was  a  considerable  rise  in  the  carbon  dioxid  excre- 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS       743 

tion.  This  result  is  often  seen  in  oxygen-lack.  Profound  carhon  monoxid 
poisoning  leads,  of  course,  to  a  diminished  oxygen  intake  (Desplats),  but 
in  the  grade  induced  by  Bock  it  appears  that  the  total  metabolism  re- 
mains unaltered.  The  high  carbon  dioxid  output  is  attributable  to  dis- 
placement of  the  gas  from  the  blood,  first  by  the  carbon  monoxid  itself; 
secondly  by  the  decreased  alkalinity  as  the  condition  progresses,  and 
thirdly,   probably  temporarily  by   deeper  ventilation. 

Protein  Metabolism. — An  increase  in  the  protein  catabolism  in  man 
occurs,  persisting  for  two  or  three  days.  Miinzer  and  Palma  found  an  in- 
crease in  the  phosphate  excretion  parallel  to  the  nitrogen  increase.  In 
fasted  dogs  the  nitrogen  excretion  is  greater.  Jeannert  found  4.6  grams 
urea  excreted  in  the  6 14  hours  following  carbon  monoxid  poisoning  as 
against  2.5  to  2.9  grams  on  control  days.  The  increased  catabolism  is 
attributable  to  oxygen-lack. 

The  nitrogen  partition,  as  has  been  observed,  Jieed  not  be  altered  in 
this  type  of  acidosis;  Miinzer  and  Palma  in  man  and  Araki  in  animals 
noted  only  slight  increases  in  ammonia  excretion.  Occasionally  a  very 
high  uric  acid  excretion  has  been  noted  on  the  first  day  (Noel  Paton). 
Friinkel  failed  to  find  amino-acids  in  the  urine.  Katsuyaraa  and  others 
find  the  synthesis  of  hippurates  and  of  etliercal  sulphates  inhibited  in 
carbon  monoxid  poisoning. 

Mineral  Metabolism. — Phosphate  and  sulphate  excretion  are  prob- 
ably increased,  as  in  oxygen-lack.  Kast  found  in  carbon  monoxid  poison- 
ing a  decreased  chlorid  output  in  animals  whose  tissues  were  well  sup- 
plied with  this  ion.  In  chlorid-poor  animals,  however,  the  output  was 
increased.  This  apparent  paradox  is  explainable  upon  the  supposition 
that  in  the  latter  case  an  inherent  tendency  to  lose  cblorids  is  enhanced 
by  the  condition  of  oxygen-lack.  The  alkali-depleting  mechanism  is  doubt- 
less involved. 

Lactic  Acid, — Urinary  lactic  acid  was  found  in  carbon  monoxid 
poisoning  by  Miinzer  and  Palma  and  by  Araki,  blood  lactic  acid  (in  hens) 
by  Saito  and  Katsuyama.  Heffter  found  the  acidity  of  the  muscles  of 
carbon  nionoxid-poisoned  cats  decreased.  That  the  lactic  acid  appearance 
is  due  in  part  at  least  to  reduced  combustion  accords  with  Araki's  finding 
that  subcutaneously  injected  lactic  acid  passes  unchanged  into  the  urine. 
If  overproduction  of  lactic  acid  occurs  in  conditions  of  oxygen-lack,  the 
experiments  of  Lusk  and  Mandel  and  others  make  it  appear  that  this  is 
derived  from  glucose,  the  glycogen  of  the  liver  being  especially  drawm 
upon. 

Carbohydrate  Metaholism. — Claude  Bernard  and  Richardson  gave  the 
earliest  accounts  of  carbon  monoxid  glycosuria.  Araki  showed  that  it  is 
asphyxial.  Straub(a)  made  the  surprising  obsei-vation  that  it  is  best  ob- 
tained w4th  meat  feeding ;  after  pure  carbohydrate  feeding  carbon  monoxid 
produces  no  glycosuria.      The  sugar  is  derived   as  in  other  asphyxial 


744  HENRY  G.  BARBOTJE 

glycosurias  from  the  liver,  and  in  the  absence  of  liver  glycogen  none  is 
excreted.  Starkenstein  has  demonstrated  the  central  mechanism  of  car- 
bon monoxid  glycosuria  and  claims  by  histological  and  chemical  tests  to 
have  found  the  adrenal  glands  exhausted  after  carbon  monoxid  poisoning. 
In  view  of  the  work  of  Kellaway  on  asphyxial  glycosuria,  it  seems  prob- 
able that  the  central  action  is  exerted  through  the  neiTCS  of  the  liver 
as  well  as  of  the  adrenals. 

Other  Blood  Poisons. — Methemoglobinemia. — A  number  of  poisons 
besides  carbon  monoxid  reduce  the  oxygen-transporting  capacity  of  the 
blood.  Among  the  poisons  which  do  this  by  causing  methemoglobinemia 
are  the  nitrates,  chlorids,  bile  acids,  pyrogallic  acid,  arsin,  piperidin, 
toluylenediamin,  hydroxylamin  and  others.  Antipyretics,  phosphorus  and 
some  hea\'y  metals  produce  similar  effects,  but  these  constitute  a  minor 
part  of  their  action. 

When  in  its  alkaline  form,  methemoglobin  is  much  more  readily  con- 
verted back  into  oxygen.  In  accord  with  this,  herbivorous  animals  appear 
less  susceptible  to  its  formation  than  the  carnivorous.  Alkali  injec- 
tions have  therefore  been  suggested  in  the  treatment  of  methemoglobi- 
nemia. 

Acid-Base  Equilibrium. — Diminished  alkalinity  of  the  blood  was 
sho^vn  by  Hans  ^leyer,  Kraus,  Kose  and  others  to  be  commonly  asso- 
ciated with  the  blood  poisons. 

Protein  Metabolism. — Nitrogen  excretion  is  increased  by  relatively 
small  doses  of  chlorates  (Mering(a)).  Pyrogallol  increases  the  excretion 
of  nitrogen  (Noel  Paton),  of  uric  acid  (Kiinau)  and  of  neutral  sulphur 
(Bonanni(a)).  Pyrodin  (Frankel(Z))),  toluylenediamin,  and  bile  acids 
(Noel  Paton),  and  large  quantities  of  anilin,  quinolin,  salicylic  acid,  etc., 
also  stimulate  protein  catabolism.  Lawrence  has  shown  that  nitrites  may 
increase  the  nitrogen  and  solids  of  the  urine  in  man. 

Benzol  is  a  blood  poison  causing  especially  destructive  changes  in  the 
hematopoietic  organs,  and  diminution  of  the  leukocytes  and  blood  plate- 
lets. Increased  excretion  of  neutral  sulphur  and  of  ammonia  (Sohn)  and 
a  rise  in  body  temperature  also  occur. 

Carbohydrate  Metabolism. — Hoffman  observed  glycosuria  from  amyl 
nitrite  inhalation.  This  was  associated  by  Konikoff  with  the  disappear- 
ance of  glycogen  from  the  liver.  Araki  found  the  phenomenon  associated 
with  lactic  acid  secretion  in  both  fed  and  fasted  animals. 

Hydrogen  sulphid  is  one  of  the  blood  poisons  that  cause  glycosuria 
(Cahn),  but  since  sulphhemoglobin  is  found  only  in  traces  during  life, 
E.  Meyer  believes  the  sulphid  is  dii*ectly  toxic  to  the  central  nervous  sys- 
tem. Other  blood  poisons  causing  glycosuria  are  the  chlorates  (Stokvis(a) 
and  others)  anilin  (Brat),  nitrobenzol  (jMagnus-Levy)  and  orthoni- 
trophenol-propionic  acid  (Hoppe-Seyler). 

Bukowski  noted  in  phenol  poisoning  a  rapid  disappearance  of  liver 


EFFECTS  OF  CERTAm  DKUGS  A^B  POISOISrS        745 

glycogen  and  Borchardt  (cited  by  Allen)  found  glycosuria  in  rabbits  after 
0.5  c.c.  subcutaneous  injections. 

Piperidin  glycosuria  was  shown  by  Underbill  to  be  accompanied  by 
hyperglycemia  and  asphyxial  in  origin,  disappearing  under  oxygen  ad- 
ministration. Biihl  and  others  produced  glycosuria  by  inhalation  of 
acetone,  also  an  asphyxial  poison. 

Chlorid  Excretion. — Kast  found,  as  in  carbon  monoxid  poisoning,  an 
increased  chlorid  excretion  after  pyiT)gallol  and  toluylenediamin  in 
chlorid-poor  aninuils. 

Syntheses. — iVmyl  nitrite  inhibits  ethereal  sulphate  synthesis  (Katsu- 
yania)  and  certain  aromatic  diamins  which  are  also  blood  poisons  were 
found  by  Pohl(a)  to  inhibit  the  synthesis  of  hippuric  acid,  but  not  of 
glycuronic  or  of  ethyl-sulphuric  acid. 

Cyanids. — A  type  of  asphyxial  poisoning  occurs  in  which  neither 
the  external  respiratory  mechanism  nor  the  oxygen-transporting  capacity 
of  the  blood  is  disturbed. 

Claude  Bernard  pointed  out  that  the  venous  blood  in  cyanid  poison- 
ing is  red,  although  the  other  changes  are  those  of  asphyxia.  He  deter- 
mined that  the  action  of  cyanid  upon  the  blood  is  not  the  same  as  that  of 
carbon  monoxid  since  blood  when  mixed  with  cyanid  will  not  turn  red 
in  the  absence  of  air.  In  other  words,  the  red  color  of  the  venous  blood 
was  ascribed  simply  to  oxyhemoglobin.  This  was  conclusively  proven 
when  Zeynek  showed  that  at  body  temperature  hemoglobin  will  not  unite 
with  cyanid,  and  oxyhemoglobin  unites  with  it  only  after  heating  for 
several  hours. 

That  the  blood  returns  from  the  tissues  still  laden  with  oxygen  was' 
shown  by  Geppei't(&),  who  obtained  the  following  oxygen  determinations 
in  cyanid-poisoned  rabbits : 

VOLUMES  PER  CENT  OXYGEN 


Arterial  blood 

Venoiis  hhod 

Difference 

12.2 

10.9 

1.3 

13.0 

12.4 

0.6 

In  various  ways  this  investigator  showed  that  the  power  of  the  blood 
to  attach  or  to  release  oxygen  is  in  no  wise  interfered  with  during  cyanid 
poisoning. 

Geppert  showed  further  that  the  first  effect  of  moderate  doses  of  pnis- 
sic  acid  upon  the  oxygen  consumption  of  rabbits,  cats,  and  dogs  is  one  of 
augmentation,  which  is  soon  followed  by  a  marked  diminution.  The 
return  to  normal  in  non-lethal  poisoning  is  preceded  by  another  wave  of 
somewhat  high  oxygen  intake.  These  stages  are  illustrated  in  the  follow- 
ing table : 


Y46 


HE.VEY  G.  BARBOUR 


C.C.  OXYGEN  CONSUMPTION  PEIi  MINUTE 

Poisoned  Return 

Animal  Normal  1st  period  2d  period  to  normal       Normal 

rabbit  .       22.7  .  . .  .'  15.8-17.4  .......  23.8 

rabbit  20.7  ....  5.0-9.4  ....... 

cat  35.4  40.2  21.2-19.8-24.8  30.9 

cat  30.9  60.4  24.0-28.9                 44.8             

cat      .  28.8  •  46.4  16.6-20.0  30.5-30.8  33.7 

dog  39.7  80-52  26.1  60.6-53.2  39.3 

dog  35.7  65-46  21.7  36.6-52.0  42.1 

The  "second  period''  presents  the  picture  which  is  so  characteristic 
of  the  toxic  action  of  the  cvanids.  Now  Geppert  showed  that  this  marked 
fall  in  the  oxygen  intake  took  place  at  a  period  when  the  ventilation  was 
not  reduced,  but  was  enonmously  increased,  i.  e.,  the  asphyxial  demand 
for  oxygen  was  present.  Furthermore,  the  oxygen  consumption  was  low 
not  only  during  rest  but  during  all  stages  of  muscular  restlessness  up  to 
actual  spasms.  During  the  convulsions,  which  often  occurred,  dogs  occa- 
sionally (not  always)  exhibited  an  abnoi-mally  high  oxygen  consumption. 
In  other  species  the  oxygen  intake  was  always  subnormal  even  during  the 
spasms.  Similarly  during  the  tetanizing  respectively  of  normal  and  of 
poisoned  animals  Geppert  found  the  oxygen  consumption  lower  by  two- 
thirds  to  four-fifths  in  the  cyanid  animals  than  in  the  controls. 

The  oxygen  consumption  was  thus  found  reduced  under  circumstances 
in  which  an  opposite  effect  would  logically  be  expected. 

The  following  arc  Geppert's  figures  for  the  carbon  dioxid  content  of 
arterial  and  of  venous  blood : 


C.C.CO.  IX  100  C.C.  BLOOD 


Normal  Poisoned 


No. 

Arterial  Venous 

Art  eric 

34 

41.1         

22.0 

35 

43.7 

18.0 

36 

40.3         

23.6 

33 

50.3 

17.7 

41.4 


23.9 


48.2 


30.2 


Dog,  ai-t.  at  1st  spasm, 
venous    during    paraly- 
sis 
Dog,  moderate  spasm 

J  Rabbit,  6  rain,  after  in- 

[  jection 

Rabbit,  after  spasm 
Rabbit,  ven.  at  end  of 
spasm,  arterial  during 
paralysis 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS       747 

Noiifnal  Poisoned 

No.  Arterial  Venous    Arterial   Venous 


Rabbit,  ven.  at  begin- 
ning of  poisoning,  art,  4 
minutes  after  spasm, 
ven.  (2)  30  min.  after 
spasm 
38  3G.0         4G.2         11.0         33.1         Dog,  severe  paralysis 


29  ....         35.3 

7.7         17.0 


39 


44  8  .         27  6         ....     J  ^^a^bit.     beginning    of 

*  *  *  *     1    spasms 


It  will  be  seen  that  the  carbon  dioxid  in  the  arterial  blood  was  very 
low,  often  sinking  rapidly  (cf.  No.  36)  ;  that  of  the  poisoned  venous  blood 
was  usually  lower  even  than  the  carbon  dioxid  of  normal  arterial  blood. 
A  considerable  degi*ee  of  acidosis  was  therefore  indicated. 

This  acidosis  or  acapnia,  together  with  the  increased  ventilation  (fre- 
quently the  minute  volume  was  more  than  doubled),  was  taken  to  account 
for  the  high  respiratory  quotients  which  occasionally  exceeded  130,  Gep- 
pert  concluding  that  the  actual  production  of  carbon  dioxid  ran  essentially 
parallel  to  the  oxygen  intake. 

Since  the  return  to  the  lungs  of  oxygen-laden  blood  was  thus  found 
associated  with  a  profound  depression  of  the  oxidations  Geppei*t 
depicted  cyanid  poisoning  as  "an  internal  asphyxia  of  the  organs  in  the 
presence  of  superabundant  ox;v'gen." 

This  interference  by  cyanids  with  oxidation  has  been  demonstrated 
under  widely  varying  conditions  throughout  the  realm  of  biolog)'^,  e.  g.,  in 
"salted"  frogs  (Oertmann),  in  excised  kidneys  (Vernon),  and  in  many 
lower  animals  and  plants.  IJpnan  has  shown  a  reversible  decrease  fol- 
lowing a  temporary  increase  (cf.  Geppert's  first  period)  of  oxidations  in 
sponges  and  presents  an  able  review  of  certain  theoretical  aspects  of 
cyanid  poisoning.  Child  has  shown  that  previous  exposure  to  cyanids 
renders  sponges  more  susceptible  to  oxygen-lack. 

In  hyperthyroidism  it  docs  not  appear  feasible  to  reduce  the  high  total 
metabolism  by  cyanid  treatment.     (Snell,  Eord  and  Rowntree.) 

Ferments. — The  (reversible)  effects  upon  oxidative,  hydrolytic  (e.  g., 
alcoholic  fermentation  of  sugar)  and  other  fermentative  reactions  are 
inhibitory  (barring  certain  interesting  exceptions).  In  Surge's  experi- 
ments cyanid  poisoning  was  found  associated  with  a  decreased  blood 
catalase,  but  according  to  Duncker  and  lodbauer  the  inhibitory  concentra- 
tion for  catalase  is  not  reached  in  acute  cyanid  poisoning. 

Whatever  may  ultimately  prove  to  be  the  exact  nature  of  the  cyanid- 
enzyme  reaction  in  the  tissues,  Geppert's  theory  of  "internal  asphyxia" 
appears  firmly  established. 


748  HEKRY  G.  Bx\RBOUR 

Body  Temperature. — Increased  heat  elimination  by  blood  dilution 
probably  plays  a  to\q  in  the  cyanid  temperature  fall  of  mammals  (dis- 
covered by  Hoppe-Seyler). 

Carholiydrate  MctahoUsm. — Zil lessen  describes  an  increased  lactic 
acid  excretion,  but  contrary  to  the  results  of  some  authors  obtained  no 
glycosuria. 

Protein  Metabolism. — Loewy  finds  that  the  total  nitrogen  excretion 
is  notably  increased  (mainly  as  urea),  and  that  amino-acid  excretion 
occurs. 

V.    Phosphorus,  Arsenic,  Heavy  Metals,  Etc, 

Phosphorus. — The  'effects  of  phosphorus  upon  the  metabolism  are 
associated  with  two  distinct  conditions,  one  largely  of  a  catabolic  nature, 
the  other  anabolic.  To  the  first,  the  toxic  syndrome,  much  attention  has 
been  devoted. 

Phosphorus  poisoning  is  characterized  by  profound  liver  injury,  in- 
cluding fatty  changes,  in  which  respect  the  heart  also  is  involved.  The 
liver  glycogen  is  soon  exhausted.  There  are  a  wasteful  excretion  of  nitro- 
gen, a  somewhat  high  total  metabolism  and  an  acidosis  associated  espe- 
cially with  a  high  blood  and  urine  content  in  lactic  acid. 

While  phosphorus  was  formerly  assigned  by  many  to  the  category 
of  asphyxial  poisons,  Oswald  and  others  have  maintained  that  it  acts 
chiefly  by  impairing  the  anti-autolytic  agents  of  the  body.  The  present- 
day  theory  of  Lusk  hinges  largely  upon  the  lactic  acid  accumulation. 

Total  Metaholism. — Phosphorus  poisoning  is  not,  as  once  believed,  as- 
sociated with  a  low  level  of  bodily  oxidations.  Lusk  has  found  that  the 
oxygen  consumption  in  this  condition  is  augmented,  which  observation 
has  been  confirmed  by  Ilirz.  The  former  attributes  the  increase  both  to 
fever  and  to  augmented  protein  destruction. 

Fat  Metaholism. — In  spite  of  the  obvious  shifting  of  the  bodilj^  fat, 
its  total  combustion  was  found  unaltered  by  Lusk.  Loewi  has  com- 
piled the  figures  of  a  number  of  observers  with  regard  to  fat  and  water 
content  of  the  liver.  The  noi-mal  ether  extract  varied  from  2.8  to  3.6 
per  cent  of  moist  liver.  The  ether  extract  in  phosphorus  poisoning  varied 
from  19.5  to  37.7  per  cent  of  moist  liver.  The  water  content  of  the  liver 
is  slightly  reduced  w^hen  the  fatty  changes  are  marked. 

With  regard  to  the  origin  of  the  liver  fat,  Lebedeff  showed  that  fat 
from  other  species  injected  subcutaneously  in  phosiDliorus-poisoned  animals 
can  later  be  identified  in  the  liver.  Furthennore,  in  such  animals  fat 
does  not  appear  in  the  liver  unless  there  is  an  ample  store  elsewhere  in 
the  body.  The  older  hypothesis  of  true  fatty  degeneration  (the  fat  being 
derived  from  the  impaired  cells  of  the  affected  organ)  therefore  became 
displaced  by  the  theoiy  of  fatty  infiltration.    In  support  of  this  Ta3'lor(a.) 


EFFECTS  OF  CERTAi:^  DRUGS  AND  POISOISrS        749 

has  shown  in  frogs  that  there  is  an  actual. loss  of  total  body  fat,  that  of 
the  phosphorus-poisoned  animals  when  killed  being  22  per  cent  less  than 
that  of  the  controls.  There  was  some  increase  in  the  gross  weight  of  the 
poisoned  frogs  which  Taylor  ascribed  to  edema. 

Shibata  confinned  in  mammals  the  diminution  of  total  body  fat  after 
phosphorus. 

Rosenfeld(a)  (b)  confirmed  Lebedeff's  results  and  found  the  blood  con- 
tent in  fat  increased  under  phosphorus,  thus  detecting  the  material  in  the 
stage  of  transportation  to  the  liver.  Leathes(&)  showed  that  the  liver  alters 
the  depot  fats  in  certain  respects,  regarding  this  as  a  necessary  preliminary 
to  the  utilization  of  the  fats  in  metabolism.  Fatty  infiltration  of  the  liver 
would  represent  an  excessive  attempt  at  such  a  conversion ;  it  is  found  in 
all  conditions  in  which  there  is  a  high  need  for  fat  (starvation,  etc.}.  If 
such  animals  are  freely  fed,  the  fatty  infiltration  of  the  liver  may  disap- 
pear within  a  day  (Mottram(6)).  Rettig  has  shown  that  a  carbohydrate- 
rich  diet  tends  to  prevent  the  fatty  infiltration. 

Carbohydrate  Metabolism. — The  finding  by  numerous  of  the  earlier 
observers  that  glycogen  soon  disappears  from  the  liver  in  phosphorus  in- 
toxication was  confirmed  by  Welsch.  IsTotwithstanding  this,  glycosuria  is 
a  comparatively  rare  feature;  for  example,  Walko  detected  sugar  in  the 
urine  of  only  6  out  of  141  patients.  In  these  cases  it  was  not  associated 
with»any  special  degree  of  severity  or  other  definite  feature.  The  blood 
sugar  as  IS^eubauer,  as  well  as  Frank  and  Isaak,  found  is,  if  anything, 
somewhat  decreased.  Thus  phosphorus  poisoning  is  differentiated  from 
typical  asphyxial  conditions  where  glycogen  disappearance  is  regularly 
associated  with  hyperglycemia  and  glycosuria. 

Frank  and  Isaak  regarded  interference  with  the  synthesis  of 
glycogen  as  the  primary  action  of  phosphorus.  They  attributed  the  in- 
creased protein  destruction  to  the  need  of  compensation  for  a  low  energy 
production  from  carbohydrates. 

The  lactic  acid  which  accumulates  in  phosphorus  poisoning  arises  from 
glucose,  as  shown  by  Lusk  and  Mandel.  For  lactic  acid  disappears  from 
the  nrine  as  soon  as  the  phosphorus-poisoned  dog  is  treated  with  phlor- 
hizin;  the  glucose  is  hurried  away  before  the  lactic  acid  can  be  split  off 
from  it.  In  accord  with  this  Fuertli  has  show^n  that  the  quantity  of  lactic 
acid  elimination  in  phosphorus  poisoning  may  be  increased  by  feeding 
an  excess  of  sugar. 

Increased  autolysis,  especially  iu  the  liver,  is  regarded  as  the  funda- 
mental disturbance  in  phosphorus  poisoning  by  Jacoby,  as  well  as  Forges 
and  Pribram.  The  latter  authors  attribute  this  to  oxygen  deprivation. 
In  this  connection,  Duncker  and  lodbauer,  as  well  as  Burge,  maintain 
that  catalytic  activity  is  somewhat  decreased. 

Ishikawa  produced  alimentary  glycosuria  early  in  phosphorus-poisoned 
rabbits  but  obtained  no  hyperglycemia,  which  fact  he  attributed  to  dam- 


750  HEISTRY  G.  BARBOUR 

aged  kidneys.     He  states  that. the  glycolytic  power  of  muscles  and  liver 
was  low,  that  of  the  serum  high. 

Marshall  and  Rowntree  demonstrated  a  decreased  tolerance  for  galac- 
tose and  levulose  in  phosphorus-poisoned  dogs. 

Protein  Metabolism. — Storch  first  observed  profoundly  increased  nitro- 
gen excretion  in  phosphorus  poisoning,  finding  a  surplus  of  200  per 
cent  at  times.  Badt  and  others  substantiated  the  increased  catabolism. 
In  fasting  dogs  poisoned  by  phosphorus,  Lusk,  Ray  and  IMacDermott  found 
the  protein  metabolism  increased  by  from  83  to  183  per  cent.  They  con- 
trasted this  gain  with  that  obtained  under  phlorhizin  which  varied  from 
210  to  440  per  cent.  In  the  latter  case,  if  phosphorus  was  given  subse- 
quently there  was  no  further  essential  increase  in  protein  metabolism.  This 
was  interpreted  to  mean  that  phlorhizin  glycosuria  is  the  predominating 
factor  in  such  an  experiment  and  that  the  anti-autolytic  enzymes  are  in- 
hibited rather  by  lactic  acid  than  by  the  direct  influence  of  phosphorus. 

Lusk  believes  that  "phosphorus  may  affect  the  conditions  which  lead 
to  the  oxidation  of  the  lactic  acid  derived  from  glucose,  and  the  accumu- 
lation of  this  acid  may  prevent  the  action  of  some  of  the  deaminating 
enzymes;  and  further  its  non-combustion  may  necessitate  an  increase  of 
protein  metabolism." 

Rettig  has  shown  that  a  diet  rich  in  carbohydrates  prevents  the  in- 
creased protein  catabolism.  Simonds(?))  advocates  the  use  of  a  sugar  diet 
in  the  treatment  of  phosphorus  poisoning,  not  only  as  a  source  of  energy, 
but  also  to  inhibit  abnormal  enzyme  action. 

The  anomalies  of  the  protein  metabolism  in  phosphorus  poisoning  in- 
clude the  appearance  in  the  urine  of  amino-acids,  especially  leucin,  tyrosin, 
cystin,  and  sometimes  peptone-like  substances.  Gottlieb  and  Bondzynski, 
who  first  demonstrated  that  oxyproteic  acid  is  a  normal  urinary  con- 
stituent, found  it  increased  in  phosphorus  poisoning.  Mendel  and  Schnei- 
der found  cynurenic  acid  increased.  Wakeman  has  noted  changes  in  the 
relative  amounts  in  the  liver  of  the  basic  amino-acids,  histidin,  arginin 
and  lysin. 

Lusk  found  the  uric  acid  and  creatinin  excretion  unchanged. 

In  Marshall  and  Rowntree's  studies  of  the  blood  of  phosphorus- 
poisoned  dogs,  non-protein  nitrogen,  iirea,  and  amino-acids  were  all  found 
increased.     They  noted  a  terminal  acidosis, 

Hauser  showed  that  phosphoiiis  inhibits  the  synthesis  of  hippurates. 

Acid-Base  MetahoUsm. — Hans  Meyer  and  others  have  found  the  car- 
bon dioxid  content  of  the  blood  and  the  titration  alkalinity  markedly 
diminished.  Besides  the  lactic  acid,  Meyer  inculpates  the  sulphuric  and 
phosphoric  acids  derived  from  protein. 

Mineral  MetahoUsm. — Welsch  found  the  excretion  of  phosphates  and 
sulphates   increased,   but  that   of  chlorids  diminished.      Kast,   however, 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        751 

observed  subsequent  to  the  chlorid  retention,  an  unusually  high  excre- 
tion of  this  ion. 

Schloss(6)  obtained  negative  result.s  with  phosphorus  upon  the  calcium 
metabolism  in  rickets,  but  Brown,  l^^acLach]an  and  Simpson  find  that 
phosphorus,  especially  in  conjunction  with  cod  liver  oil,  produces  an  in- 
crease in  the  blood  calcium  in  tetany. 

Phosphorus  Deficiency. — Phosphorus  deficiency  leads  to  disturbances 


Fig.  2.     Leg  bones  in  osteogenesis  imperfecta.     Seven-year-old  bov  iintreatcil. 
Phemister,  J.  Am.  M.  As.sn.,  1918,  LXX.) 


(D.  B. 


in  growth  and  nutrition,  the  bones  becoming  soft  and  flexible  when  their 
content  in  the  element  has  fallen  by  about  one-sixth  (Ileubner). 

Effects  upon  the  Skeleton. — Wegner  in  1872  first  demonstrated  the 
favorable  effects  of  phosphorus  upon  the  formation  of  bone,  thus  bringing 
to  light  the  anabolic  aspect  of  phosphorus  action.  Small  doses  given  to 
growing  animals  were  found  to  result  in  a  production  of  compact  instead 
of  spongy  bone  from  the  epiphyses.  In  adults  the  canals  became  filled 
with  dense  bone,  having  a  normal  structure  and  chemical  constitution. 
Kassowitz  found  that  larger  doses  increased  the  vascularization  of  the 
bone.    He  described  favorable  results  from  phosphorus  in  rickets,  osteo- 


752 


HENRY  G.  BAEBOUR 


malacia  and  delayed  healing  of  fractures,  establishing  the  therapeutic  dose 
at  1  milligram  daily  with  meals.  Cod  liver  oil  (10  milligrams  phos- 
phorus in  too  c.c.)  is  often  used  as  a  vehicle. 

Jaw  necrosis  has  been  noted  even  with  therapeutic  doses.  By  laying 
bare  the  periosteum  of  the  jaw  and  otlier  bones  in  rabbits  which  were  then 
exposed  to  phosphorus  vapor  Wegiier  showed  that  the  necrosis  is  due  to 
the  direct  action  of  the  poison. 


^^^^m^^BBKS^m^''^ 

HHHE ' 

^^B^^^^^^^^^^^^^^^HH|^A  \  .*^ ' 

^^^^^^^^^^^^^^^^^^^j^^^UUSgl^' 

hH^^^^^^I^' 

'.^^^^^ 

M*^^^^"^^^^ 

mjk      'W 

^^^AVi^^K^^, 

,  *i^irlfe/"                    • 

^ 

Fig.  3.     Same  case  as  Fig.  2  after  two  years  of  treatment  with   1/150  grain  phos- 
pi.orus  twice  daily.     (D.  B.  Phcmister,  J.  Am.  M.  Assn.,  U>18,  LXX.) 


Definite  effects  of  phosphorus  upon  the  growth  of  nonnal  and  dis- 
eased bones  in  children  have  been  shown  by  Phemister,  employing  the 
X-rays.  Figiires  2  and  3  illustrate  the  effects  in  the  leg  bones  of  a  seven- 
year-old  boy  with  osteogenesis  imperfecta.  Phemister  administers  1/200 
grain  pills  on  an  average  of  three  times  a  day;  the  deposit  of  compact 
bone  continues  after  the  cessation  of  treatment. 

Organic  Phosphorus. — The  alleged  superiority  of  organic  phosphorus 
compounds  has  not  been  substantiated ;  for  example,  Plimmer  has  shown 
not  only  that  the  body  can  synthesize  its  organic  phosphorus  from  the 


EFFECTS  OF  CERTAm  DRUGS  AND  POISONS        753 

inorganic  forms,  but  that  the  organic  preparations  themselves  must  under- 
go hydrolysis  in  the  intestine  whence  they  are  assimilated  as  inorganic 
phosphates.  .On  this  subject  reference  should  be  made  to  the  review  by 
E.  K.  ]\rarshall. 

Lecithin  was  shown  by  Danilewski  to  hasten  the  growth  of  frogs'  eggs 
and  to  augment  assimilative  pi-ocesses  in  mammals.  Cronheim  and  Mliller 
produced  with  this  phosphorus-containing  lipoid  a  stimulating  effect  upon 
the  protein  anabolism. 

Cod  Liver  Oil. — Cod  liver  oil  was  selected  as  a  vehicle  for  phosphorus 
because  for  many  years  some  unknown  specific  property  as  a  nutritional 
stimulant  had  been  ascribed  to  it,  but  more  critical  authors  were  inclined 
to  regard  it  merely  as  a  well  assimilated  food.  Osborne  and  Mendel (/), 
however,  have  demonstrated  a  specific  influence  of  cod  liver  oil  upon  the 
growth  of  white  rats.  Fats  like  lard,  almond  oil  etc.,  do  not  possess  this 
property  which  appears  to  be  due  to  the  fat-soluble  vitamin.  Schloss  has 
apparently  demonstrated  for  it  a  calcium-retaining  power  in  rickets  (see 
Calcium),  in  which  disease  Mellanby(6')  finds  it  superior  to  all  other  fats. 

Howland  and  Park  recently  have  demonstrated  the  deposition  of  cal- 
cium in  bone  as  a  result  of  cod  liver  oil  administration ;  in  human  beings 
this  is  demonstrable  after  three  weeks.  ]\rarked  increase  in  the  blood 
phosphorus  was  also  observed. 

It  seems  probable,  therefore,  that  cod  liver  oil  promotes  in  some  way 
the  mobilization  of  phosphorus  in  the  blood  which  in  turn  stimulates  the 
calcium  metabolism,  perhaps  through  its  peculiar  tendency  to  augment  the 
lactic  acid  content  of  the  blood. 

He3s(c)  finds  cod  liver  oil  inferior  to  orange  juice  in  the  scurvy  of 
guinea  pigs. 

Arsenic  and  Antimony. — With  respect  to  its  effect  upon  the  metabol- 
ism, arsenic  appears  to  occupy  a  position  midway  between  phosphorus 
and  the  heavy  metals.  The  stimulating  effect  upon  bone  formation,  the 
fatty  infiltration,  the  lactic  acid  excess,  the  loss  of  the  capacity  to  store 
or  to  retain  glycogen  although  glycosuria  is  rare,  all  bring  it  into  close 
relationship  with  phosphorus.  The  fatt^'  degenerative  changes  after  arsenic 
are,  however,  less  marked  and  the  fat  balance  is  positive.  On  the  other 
hand,  it  appears  to  be  a  capillary  poison,  which  fact  is  held  to  account  for 
those  profound  intestinal  disturbances  which  suggest  the  behavior  of 
heavy  metals. 

The  metabolic  eff'ects  of  antimony  resemble  those  of  arsenic. 

T.  Gies  and  others  observed  that  repeated  administration  of  small 
doses  of  arsenic  to  animals  resulted  in  the  production  of  a  positive  fat 
balance  and  new  bone  formiitioii  in  which  the  long  bones  became  thickened 
and  the  Haversion  canals  filled.  That  the  therapeutic  administration  of 
arsenic  improves  the  nutiition  in  a  more  subtle  fashion  than  by  merely 
stimulating  the  appetite  or  improving  digestion  is  shown  by  the  investiga- 


754  HExVRY  G.  BAKBOUR 

I 
tions,  among  others,  of  Henius(a).  This  author  fed  arsenic  to  dogs  on  a 
constant  diet,  observing  increase  in  weight,  a  positive  fat  l)alance  and 
stimulation  of  bone  growth.    The  red  blood  cells  and  hemoglobin  were  also 
found  increased  under  these  conditions. 

Total  Metabolism, — The  contribution  of  Henius  includes  perhaps  the 
only  investigation  relating  to  the  effects  of  therapeutic  doses  of  arsenic 
upon  the  gaseous  exchange  in  man.  A  chlorosis  patient  who  was  gaining 
weight  under  atoxyl  was  found  to  exhibit  no  difference  in  the  basal  metab- 
olism as  a  result  of  the  drug  administration,  but  the  experiments  were 
not  long  extended. 

.  Chittenden  and  Cummins  gave  rabbits  35  milligrams  of  arsenic  daily 
and  observed  with  these  toxic  doses  some  apparent  diminution  in  the 
oxidations.     Large  doses  of  antimony  gave  similar  results. 

Nitrogen  Metabolism.— \^\\eii  affected  at  all,  the  nitrogen  excretion 
has  usually  been  found  increased  by  either  arsenic  or  antimony. 

After  arsenic  Boeck  found  no  effect  upon  the  nitrogen  excretion  in 
man,  while  Chittenden,  Henius  and  others  found  an  increase.  With  anti- 
mony Gaethgens(a)(&)  found  a  30  per  cent  increase  in  a  fasted  dog's  ni- 
trogen exci*etion.  Chittenden  and  Blake,  however,  found  the  protein  bal- 
ance unaltered  when  1-1.5  grams  antimony  oxid  w^ere  given  to  a  well-fed 
flog. 

Arsphenamin  induces  metabolic  effects  similar  to  those  produced  by 
the  inorganic  arsenicals,  according  to  Postojeff.  Capelli  found  in  syphi- 
litic patients  a  high  nitrogen  loss  on  the  first  day  after  arsphenamin  treat- 
ment, the  only  effect  noted  upon  the  metabolism.  Sodium  arsenate  pro- 
duced a  nitrogen  retention  in  two  patients  studied  by  Boyd.  This  may 
have  been  due  to  renal  injury. 

Uric  Acid  Excretion. — Abl  found  that  arsenic  and  antimony  in  com- 
mon with  other  intestinal  irritants  increase  uric  acid  excretion. 

Carbohydrate  Metabolism. — Rosenbaum  and  others  are  agreed  that 
arsenic  induces  a  prompt  disappearance  of  glycogen  from  the  liver.  The 
blood  sugar  content  was  not  found  increased,  but  work  with  newer  methods 
appears  called  for.  As  with  phosphorus,  glycosuria  at  all  events  is  rare. 
Saikowsky  noticed  that  the  arsenic  or  antimony  liver  becomes  free  of 
glycogen  before  the  beginning  of  fatty  infiltration  can  be  detected.  lie 
was  unable  to  produce  glycosuria  either  by  piqure  or  by  curare  injections 
in  arsenic-treated  animals. 

Konikoff  showed  that  excess  feeding  of  sugar  did  not  restore  the 
glycogen  in  arsenic  poisoned  animals.  Luchsinger  found  that  arsenic 
favors  the  production  of  alimentary  glycosuria.  Araki(a.)  found  lactic 
acid,  but  rarely  sugar  in  the  urine  in  arsenic  as  well  as  in  phosphorus  poi- 
soning. 

Acid-Base  Equilibrium'. — Hans  Meyer  correspondingly  observed  a  re- 
duction in  the  alkalinity  of  the  blood  after  toxic  doses  of  arsenic.    Mori- 


EFFECTS  OF  CEETAITs^  DRUG^  AND  POISONS        755 

shima,  investigating  the  source  of  the  hictic  acid,  noted  that  in  autolysis 
of  fresh  livers  the  disappearance  of  glycogen  is  ch>sely  paralleled  by  the 
gains  in  lactic  acid  content. 

Water  Metabolism. — Arsenic,  according  to  ^Fagnus,  exerts  a  specific 
toxic  effect  upon  the  endothelial  cells  of  the  capillaries  throughout  the 
body.  To  this  the  cholera-like  diarrhea  of  arsenic  has  been  ascribed.  The 
dehydration  is  sufficient  to  cause  marked  thirst  and  to  account  for 
much  of  the  hemoglobin  increase.  To  this  capillary  effect  Magnus  also 
attributes  the  edema  which  sodium  chlorid  injections  are  capable  of  pro- 
ducing in  arsenic-poisoned  animals. 

Karsner  and  Denis  described  in  the  glomeruli  of  the  kidneys  certain 
effects  of  arsenic  which  they  associated  with  anuria.  In  their  experiments 
nitrogen  retention  was  rather  slight,  but  caffein  diuresis  was  frequent. 

Body  Temperature. — The  well-known  febrile  reaction  frequently  fol- 
lowing arsphenamin  administration  has  been  variously  explained.  It  is 
not  necessarily  attributable  to  stale  distilled  water  or  to  salt  diuresis. 
Luithlen  and  !Mucha  have  explained  it  as  due  to  a  destructive  action  of 
the  drug  upon  the  pathological  tif^sues  of  syphilis.  A  new  cause  for  some 
cases  has  been  found  in  an  alkaline-soluble  substance  extractable  from  new 
samples  of  so-called  '^pure  gum''  rubber  tubing.     (Stokes  and  Busman.) 

Ferments. — Duncker  and  lodbauer  found  an  increased  catalase  action 
after  small  doses  of  arsenic,  larger  amounts  giving  negative  results.  This 
does  not  accord  with  the  decrease  after  phosphorus.  It  must  be  borne  in 
m'ind  that  catalytic  activity  of  the  blood  has  never  been  clearly  shown 
to  influence  directly  any  vital  process.  Lacquer  and  Ettinger  maintain 
that  small  doses  of  arsenic  increase  liver  autolysis,  which  is  retarded  by 
large  amounts. 

Iron. — Stockman  and  Grieg  have  shown  that  five  to  ten  milligrams 
of  iron  ingested  per  day  suffice  to  maintain  an  equilibrium.  The  effects 
of  iron  deficiency  are  described  by  Ilosslin(a).  Organic  iron  compounds, 
whether  or  not  the  metal  is  readily  ionizable,  offer  no  real  therapeutic 
advantage  over  the  inorganic  fonns. 

Like  arsenic  large  doses  of  iron  may  cause  renal  and  intestinal  irrita- 
tion with  anuria  and  diarrhea.  The  carbon  dioxid  content  of  the  blood 
is  reduced  w4th  toxic  doses  (Hans  Meyer). 

Munk  observed  no  changed  in  the  nitrogen  metabolism  of  dogs  fed 
0.3-0.5  gTam  daily. 

Mercury. — The  regular  occurrence  of  nephritis  and  of  glycosuria 
sharply  differentiates  the  effects  of  mercury  (as  well  as  of  uranium,  etc) 
from  those  of  arsenic  and  phosphoinis. 

Certain  effects  common  to  the  last  two  mentioned  poisons  are  seen 
also  after  small  doses  of  mercury,  especially  fat  deposition  and  red  blood 
cell  increase.     Schlesinger  demonstrated  these  results  in  cats,  dogs,  and 


75G  .    HENRY  G.  BARBOUE 

hens  fed  for  months  on  small  quantities  of  corrosive  sublimate.     Among 
ethers  Bieganski  demonstrated  similar  effects  in  man. 

Total  Metaholiartv, — The  total  metabolism  is  not  affected  in  fasting 
rabbits  (Schroeder). 

Protein  Metabolism. — Bock  and  others  found  the  nitrogen  metabolism 
unaltered  in  svphilitics  treated  with  mercury.  Noel  Baton  observed  a 
slightly  increased  nitrogen  excretion  in  a  dog.  Urea  and  uric  acid  may 
also  be  increased  after  small  doses.  Schroeder  and  others  have  obsei-ved 
some  nitrogen  retention,  presumably  of  nephritic  origin,  for  the  blood 
urea  content  is  increased  under  such  conditions. 

Carbohydrate  Metabolism, — Glycosuria  was  found  by  Schroeder  and 
almost  constantly  by  many  others.  Hyperglycemia  was  not  found  by 
Graf  or  Kissel  in  spite  of  the  rapid  disappearance  of  liver  glycogen. 
Franck  finally  showed  the  glycosuria  to  be  of  renal  origin.  Lactic  acid 
has  not  been  demonstrated  in  the  urine. 

Fat  Metabolism. — Fatty  infiltration  of  various  organs  is  frequently 
seen. 

Mineral  Metabolism. — Decalcification  of  bones  with  cachexia  and 
anemia  are  typical  of  chronic  poisoning. 

Prevost,  like  others,  found  that  mercury  may  produce  calcium  de- 
posits in  the  kidneys,  and  associated  them  with  a  diminution  in  bone 
calcium. 

Acid-Alkali  Metabolism.- — Hans  Meyer  first  showed  that  the  blood 
alkalinity  may  be  diminished,  and  MacNider(6)  found  an  acid  intoxica- 
tion in  cases  of  delayed  kidney  injury. 

Water  Metabolism, — Jendrassik,  the  modern  discoverer  of  calomel 
diuresis,  recommended  0.2  gram  doses  four  times  a  day.  In  cardiac 
dropsies  seven  to  eight  liters  of  urine  were  thus  obtained  daily  with  a  con- 
siderable washing  out  of  urea  and  chlorids. 

Fleckseder(&)  found  that  all  mercury  compounds  by  all  methods  of  ad- 
ministration produce  a  diuretic  effect  in  rabbits.  He  believes  that  mercury 
lessens  the  absorption  of  water  from  the  small  intestines ;  correspondingly 
larger  amounts  of  water  being  absorbed  from  the  colon,  diuresis  is  more 
readily  brought  about.  This  does  not  explain  calomel  action  in  cardiac 
dropsies.  The  blood  of  rabbits  becomes  hydremic,  but  in  man  the  hydremia 
seems  to  occur  only  with  the  dropsies.  Healthy  individuals  under  mercury 
may  exhibit  a  concentrated  blood  associated  with  diarrhea. 

Pleuritic  exudates  are  not  influenced  by  calomel. 

Body  Temperature. — Poisoning  from  inhalation  of  mercury  vapor  is 
accompanied  by  a  febrile  reaction  (Carpenter  and  Benedict).  Further- 
more fever  generally  accompanies  the  stomatitis  or  skin  ei-uptions  of  mer- 
cury poisoning,  while  in  collapse  there  is  of  course  a  profound  temperature 
fall. 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS       757 

Uranium. — In  uranium  intoxication  while  renal  and  capillary  per- 
meability appear  to  occupy  the  center  of  the  picture,  a  kinship  to  phos- 
phorus poisoning  is  still  discernible.  Edema,  due  to  capillary  poisoning, 
is  often  a  feature. 

Water  MetohoJism. —  Loconte  in  1854  described  general  anasarca  and 
ascites  as  a  result  of  the  hypodermic  administration  of  uranium  acetate. 
Altered  permeability  of  the  capillaries  was  suggested  by  Richter  as  re- 
sponsible for  these  chan<ie.s.  He  found  the  edema  not  connected  causally 
with  salt  retention.  Flecksoder(a)  excluded  the  renal  factor,  for  he  was 
able  to  produce  the  condition  by  giving  uranium  to  nephrectomized  ani- 
mals, which  do  not  develo]>  hydrops  without  the  poison.  Further  evidence 
of  altered  capillary  permeability  was  furnished  by  Bogert,  Mendel  and 
Underbill,  who  showed  that  uranium  interferes  with  the  restoration  of 
blood  volume  after  large  saline  infusions. 

Uranium  poisoning  is  associated  with  various  degrees  of  nephritis, 
and  suppression  of  urine  flow.  In  the  earlier  stages  the  oliguria  may  be 
partially  overcome  by  catl'oin  and  the  saline  diuretics  (Mosenthal  and 
Schlayer).  Diuretics  do  not,  however,  relieve  complete  uranium  anuria, 
according  to  MacNider((^j )  who  found  the  nephritis  associated  with  an  acid 
intoxication  as  evidencel  by  ketosis  and  a  lowered  alkali  reserve.  Inhibi- 
tion of  the  nephritis  with  bicarbonate  was  found  possible  under  some 
conditions. 

[MacNider  found  polyuria  (accompanied  by  glycosuria)  in  the  milder 
types  of  uranium  poisoning. 

Mineral  Metabolism. — Pearce,  Hill  and  Eisenbrey  found  a  decreased 
chlorid  excretion  in  uranium  nephritis.  Austin  and  Eisenbrey  were 
later  able  to  show  that  the  smallest  nephritic  doses  cause,  along  with 
the  polyuria,  some  increase  in  the  chloiids.  Uranium  (as  well  as 
chromatcs)  may  diminish  chlorid  excretion  by  40  per  cent  for  twenty-four 
hours. 

Protein  Metaholism. — The  nitrogen  excretion  also  ran  parallel  to 
diuresis  or  anuria  in  the  experiments  of  Pearce  and  others,  who  con- 
firmed the  findings  of  Chittenden  and  Lambert  that  uranium  increases- 
protein  catabolism,  as  sliDwn  by  augmented  nitrogen,  sulphate  and  phos- 
phate excretion,  ^losentl)al(c)  found  the  non-protein  blood  nitrogen  in- 
creased and  pointed  out  that  aside  from  renal  retention  this  might  be 
due  to  increase  in  the  catabolism  or  to  blood  concentration.  Karsner  and 
Denis  found  the  increase  in  non-protein  nitrogen  of  the  blood  parallel  to 
retention  of  phthalein. 

Watanabe(a)  finds  in  mild  uranium  nephritis  that  creatinin  is  less 
readily  eliminated  than  urea ;  the  opiX)site  relation  obtains  in  severe  types. 

Carhohydrate  Metaholism. — Uranium  glycosuria  was  discovered  by 
Leconte  and  has  been  sometimes  but  not  regularly  found  associated  with 
hyperglycemia.    Chittenden  and  Lambert  found  it  dependent  upon  a  sup- 


758  HEiSTRY  G.  BARBOUR 

plj  of  liver  glycogen.     Cartier  associated  it  with  intense  degenerative 
changes  in  the  liver.    He  failed  to  find  lactic  acid  in  the  urine. 

Fat  Metabolism. — The  degenerative  changes  in  the  liver  in  uranium 
intoxication  have  been  associated  by  MacXider  with  acid  poisoning.  Fatty 
infiltration  of  various  organs  is  common. 

Total  Metabolism  and  Temperature, — Chittenden  and  Lambert  found 
the  carbon  dioxid  output  increased  in  uranium-poisoned  dogs.  This  was 
associated  with  some  increase  in  body  temperature. 

Chromates  and  Cantharidin. — The  toxic  effects  of  chromates  as  well 
as  of  cantharidin  are  said  to  resemble  those  of  uranium.  (Austin  and 
Eisenbrey.) 

Lead,  Platinum,  Copper,  Zinc. — These  metals  are  poorly  absorbed  and 
their  effects  upon  the  metabolism  have  received  but  little  attention. 
(Loewi(6)). 

Radium. — Gudzent  maintains  that  the  inhalation  of  radioactive 
emanations  leads  to  an  increased  elimination  of  uric  acid  in  the  gouty,  due  • 
to  the  conversion  of  the  lactim  form  of  uric  acid  into  the  lactam. 

Contrary  to  these  and  other  claims  Fine  and  Chace(a)  failed  to  pro- 
duce any  effect  on  the  uric  acid  of  the  blood  by  radium  given  either  intra- 
venously or  by  inhalation.  Berg  and  Welker  state  that  radium  salts  given 
per  OS  increase  both  nitrogen  excretion  and  urine  volume. 

In  chronic  arthritis  McCrudden  and  Sargent(6)  could  find  no  effect  of 
radium  w^ater  upon  the  excretion  of  uric  acid,  total  nitrogen  or  water, 
although  they  state  that  the  creatinin  excretion  may  be  affected.  Recently, 
however,  Theis  and  Bagg  in  the  laboratory  of  S.  R.  Benedict  have  pro- 
duced a  marked  increase  in  the  uric  acid  excretion  of  Dalmatian  hounds 
by  intravenous  injection  of  active  deposit  of  radium. 

Theis  and  Bagg  found  further  that  the  active  deposit  of  radium  in- 
travenously injected  also  increased  the  total  nitrogen  output,  the  urea 
curve  running  parallel;  ammonia  excretion  was  relatively  as  well  as  abso- 
lutely increased.  Some  increase  in  creatinin  was  noted  after  the  in- 
creased temperature  had  returned  to  normal. 

Variable  results  have  been  observed  upon  the  respiratory  metabolism, 
little  effect  having  been  demonstrated  from  the  emanations.  Benczur  and 
Fuchs(&)  state  that  ingestion  of  100  times  the  usual  therapeutic  dose  of 
radium  has  caused  a  17  per  cent  increase  in  the  total  metabolism.  Alkaline 
radium  water,  on  the  other  hand,  is  said  to  diminish  the  gas  metabolism 
in  health  but  not  in  gout.     (Staehelin  and  Maase.) 

According  to  Darms  inhalation  of  radium  causes  a  rise  in  body  tem- 
perature followed  by  a  fall,  while  a  fall  followed  by  a  rise  is  seen  after 
ingestion.  . 

In  the  treatment  of  lymphatic  leukemia  Murphy,  Means,  and  Aub 
found  that  radium  affected  the  basal  metabolism  but  slightly  during  the 
marked  fall  in  the  leukocyte  count.    In  a  similar  case  Knudson  and  Erdos 


EFFECTS  OF  CEKTAUS"  DKUGS  AND  POISONS        759 

found  under  radium  thfrapy  very  lar^e  increases  in  the  excretion  of  total 
urea,  ammonia,  and  j)hosphate,  the  latter  sometimes  attaining  400  per 
cent  of  the  normal  %ui(\  The  slight  increase  in  uric  acid  excretion  was 
attributed  to  the  disintegration  of  nuclein  tissue  in  the  spleen. 

Phlorhizin. — Although  not  used  in  therapeutics  this  poison  is  of  great 
interest  on  account  of  the  type  of  glycosuria  it  produces.  Its  etfects  upon 
the  metabolism  resembh*  .somewhat  those  of  the  heavy  metals. 

Carbohydrate  Mcffiholism. — Mering,  the  discoverer  of  phlorhizin 
glycosuria,  found  dextrose  values  in  the  urine  as  high  as  eighteen  per  cent ; 
the  absolute  amount  may  be  very  large.  The  condition  is  characterized 
by  absence  of  hyperglycemia,  showing  that  it  is  essentially  of  renal  origin. 
Zuntz  showed  that  the  effect  upon  the  kidney  was  peripheral  rather  than 
central  by  injecting  the  poison  into  a  single  renal  artery  which  gave  rise 
to  glycosuria  at  first  on  that  side  alone. 

Although  the  important  factor  of  increased  glomerular  permeability 
has  recently  been  well  demonstrated  by  Brinkmann(a)  in  Hamburger^s 
laboratory  some  have  deemed  it  necessary  to  seek  further  for  the  origin 
of  such  large  amounts  of  sugar.  Pavy,  J^rodie  and  Siau,  for  example, 
maintained  that  the  kidneys  form  sugar  from  the  proteins  of  the  blood. 
Underbill,  however,  prc^duced  hyperglycemia  by  phlorhizin  in  animals  in 
which  the  renal  arteries  were  ligated,  thus  excluding  the  kidneys.  Le- 
pine(&)  has  long  championed  the  "virtual  sugar"  theory  in  which  much 
sugar  is  supposed  to  exist  normally  in  combination  with  blood  colloids, 
being  demonstrable  only  on  hydrolysis.  From  this  source  he  believes  sugar 
is  derived  in  phlorhizin  poisoning. 

At  all  events  the  glycogen  stores  are  never  entirely  exhausted  by 
phlorhizin,  even  during  fasting  (Sansum  and  Woodyatt(a)).  Epstein  and 
Baer  even  maintain  tluit  phlorhizin  stimulates  glycogenosis,  as  hepatic 
glycogen  seems  to  accumulate  when  the  kidneys  are  excluded. 

The  sugar  percentage  in  Brinkmann's  perfusate  being  sometimes 
higher  than  in  the  perfusion  fluid  and  no  opportunity  existing  for  re- 
absorption  of  water  the  renal  secretory  theoiy  must  still  be  given  some 
consideration. 

In  complete  phlorhizin  poisoning  Stiles  and  Lusk  found  that  dextrose 
given  subcutaneously  fails  to  increase  the  respiratory  quotient;  thus  the 
power  to  oxidise  sugar  becomes  lost. 

Protein  Metabolism. — The  body  being  deprived  of  the  sparing  influ- 
ence of  sugar  there  is  often  a  very  marked  rise  in  the  protein  metabolism. 
Reilly,  Nolan  and  laisk  have  found  this  as  high  as  450  per  cent  of  normal 
in  dogs.  After  the  extra  sugar  w^as  flushed  out  the  D:N  ratio  in  this 
species  was  found  to  bo  3.05  as  against  2.8  in  rabbits,  cats,  and  goats. 
58.7  per  cent  of  the  protein  is  therefore  excreted  as  dextrose. 

Fat  Metabolism. — Mcring  in  his  experiment j  noted  fatty  infiltration 
of  the  liver  when  starving  animals  were  phlorhizinized.     This  was  asso- 


760  HEA^RY  G.  BARBOUR  .     - 

ciated  with  increased  ammonia  excretion  and  ketosis.  Moritz  and  Praus- 
nitz  found  that  it  could  he  prevented  hy  carbohydrate  feeding.  Feeding 
butter  fat  or  butyric  acid  will  increase  it.  Bang(t)  finds  that,  although 
the  fat  of  the  liver  is  increased,  the  blood  fat  remains  unaltered. 

Total  MeiahoUsm. — The  heat  production  was  found  increased  by  Lusk, 
who  attributes  the  change  to  the  specific  dynamic  action  of  the  increased 
protein  metabolism.  Recently  Hari  and  Aszodi  have  observed  a  marked 
increase  in  the  energy-  exchange  and  body  temperature  of  starving  dogs 
after  subcutaneous  injection  of  0.05  gram  per  kilo  of  phlorhizin.  Op- 
posite effects  were  noted,  with  relatively  larger  doses,  in  rats.  These 
authors  believe  that  since  the  increases  protein  catabolism  occurs  in  both 
cases  it  cannot  be  held  to  account  for  the  increased  heat  production  in 
dogs.  They  therefore  postulate  for  phlorhizin  a  specific  action  upon  the 
heat  regulating  centers. 

VI.    Narcotics 

The  Mai  metabolism  is  reduced  by  all  narcotic  agents,  whether  classed 
as  anesthetics  or  hypnotics,  during  the  stages  in  which  sleep  is  present. 
(For  details  see  Jaquet.)  This  is  the  natural  result  of  diminished  muscu- 
lar activity.  The  reverse  may  easily  be  demonstrated  in  the  stage  of 
excitement  produced  by  some  narcotic  drugs. 

The  body  temperature  also  has  a  tendency  to  fall  during  drug  narcosis; 
as  is  well  knoAvn  this  effect  may  result  seriously  if  precautions  to  consei-ve 
bodily  heat  are  not  observed.  Since  anesthetized  mammals  also  become 
more  easily  overheated  than  normal  animals  they  may  be  described  as 
poikilothermic.  This  has  been  attributed  to  inhibition  of  the  regulatory 
influence  of  the  ^^heat  centers."  .  (See  Gottlieb,  in  Meyer  and  Gottlieb.) 

Whether  hydremia  regularly  results  from  the  hyperglycemia  and 
anuria  which  commonly  accompany  the  action  of  all  narcotic  dmgs  is  not 
known,  but  seems  indicated  from  the  reduction  in  hemoglobin  described 
by  DaCosta  and  Kalteyer.  Hydremia  would  contribute  toward  a  poikilo- 
thermic condition. 

The  narcotics  will  be  further  discussed  under  the  following  heads: 
General  anesthetics,  hypnotics,  alcohol,  opiates. 

General  Anesthetics.  Chloroform  and  Ether. — Protein.  Metaholism.. 
— The  total  nitrogen  excretion  is  considerably  increased  both  by  ether 
and  chloroform,  as  was  first  noted  by  Strassmann.  Tanigiiti  and  others 
have  found  an  increase  in  the  chlorids  and  phosphates  as  well.  Hawk 
and  Kleine  found  an  increase  in  neutral  sulphur.  Pringle  found  the  nitro- 
gen excretion  diminished  (renal  effect'^)  during  the  anesthesia,  but  de- 
cidedly increased  during  the  following  twenty-four  to  foi-ty-eight  hours. 

Hawk(&)  found  that  the  total  nitrogen  increase  may  amount  to  forty- 
five  per  cent.     It  is  usually  considerably  smaller.     Chlorofonn  \si\^  espe- 


EFFECTS  OF  CERTAIN  DRUGS  A^"D  POISOKS       YCl 

cially  stiiflied  by  Ilowland  and  Ricliards  and  by  Lindsay  (a).  The  excre- 
tion of  ammonia,  allantoin,  diamino-acids,  polypeptids,  crcatinin  and  or- 
ganic sulphur  was  found  augmented;  the  urea  and  monamino-acids  were 
decreased.  Increas(Ml  urea  as  well  as  total  nitrogen,  and  ammonia  has  l)een 
found  by  Aloi,  however. 

Rouzaiid  has  recently  reported  interesting  blood  studies  in  surgical 
cases  before  and  after  chloroform.  The  average  urea  content  of  the  blood 
was  found  increased  from  0.048  per  cent  to  0.075  per  cent.  Under  ether 
the  blood  urea  was  still  higher.  This  investigator  also  noted  an  increased 
urea  concentration  in  the  urine. 

Davis  and  Whipple  have  accomplished  rapid  reconstniction  of  liver 
cells  in  chloroform  poisoning  by  feeding  either  carbohydrate  or  fat.  In 
both  cases  the  beneficial  results  w^ere  attributed  to  a  sparing  effect  upon 
the  protein  metabolism. 

Carbohydrate  Metabolism, — Rosenbaum  observed  the  rapid  disappear- 
ance of  glycogen  from  the  liver  under  the  influence  of  chloroform.  Heins- 
berg  found  this  effect  associated  with  hyperglycemia. 

Pfluger(c)  states  that  glycosuria  is  compai'atively  rare  after  surgical 
anesthesia ;  Pavy  and  Godden  prevented  chloroform  glycosuria  by  sodium 
carbonate.  IIawk(6*)  described  ether  and  chloroform  glycosuria  in  dogs 
and  found  it  more  intense  when  the  animals  were  well  fed. 

King  and  his  pupils  found  that  ether  glycosuria  is  independent  of  the 
splanchnic  nei-ves,  but  does  not  occur  if  the  liver  be  excluded  from  the 
circulation.  King,  Moyle  and  Ilaupt  proved  that  both  hyperglycemia  and 
glycosuria  could  be  produced  by  intravenous  injections  of  ether  wdthout 
causing  asphyxia  which  was  thus  excluded  from  a  primary  causal  relation. 
Ross  and  Hawk  showed  that  ether  glycosuria  is  not  due  to  lowering  of 
the  body  temperature. 

Sansum  and  Woodyatt(a)  made  the  interesting  observation  that  both 
ether  and  nitrous  oxid  increase  the  glycosuria  and  D  I'N  ratio  in  phlorhizin 
diabetes;  the  ^^extra  sugar"  is  ascribed  to  glycogenolysis  through  tissue 
asphyxia.  Ross  and  ^IcGuigan  observed  a  greater  ether  hyperglycemia  in 
dogs  on  a  pure  meat  diet  than  when  carbohydrate  was  added.  Tliey  ob- 
tained the  phenomenon  in  the  absence  of  asphyxia  or  excitement.  The 
di astatic  power  of  the  sonim  was  found  unaltered.  Watanabe(&)  believes, 
however,  that  the  blood  diastases  increase  slightly  just  after  the  anesthesia. 

Chlorofonn  hyperglycemia  was  clearly  shown  by  Scott  to  accompany 
the  glycosuria.  Marshall  and  Rowntree(&)  have  found  that  chloroform 
diminishes  the  tolerance  to  levulose  and  galactose  as  well  as  to  dextrose. 

Killian  has  found  that  patients  under  ether  or  chloroform  exhibit  an 
increase  in  both  the  sugar  and  diastase  content  of  the  blood,  together 
with  a  decrease  in  the  alkali  reserve.  All  three  of  these  tendencies  can 
be  reversed  by  the  administration  of  20-30  grams  sodium  bicarbonate. 

According  to  recent  work  of  Keeton  and  Ross  ether  hyperglycemia  is 


762  HENRY  G.  BARBOUR 

not  prevented  either  by  Eck  fistula  or  the  reversed  operation ;  unilateral 
splanchnicotoiny  exercises  some  inhibiting  influence,  bilateral  more.  This 
appears  largely  due  to  an  influence  upon  the  adrenals  which  become  im- 
plicated as  in  asphyxial  glycosuria.  Rouzaud  found  an  average  blood 
sugar  content  of  0.12  per  cent  in  surgical  chloroform  anesthesia,  ether 
giving  a  similar  result. 

Fat  Metahjlism. — Ro5enfeld(a)  (b)  and  others  described  fatty  infil- 
tration of  liver,  heart  and  kidneys  after  chloroform.  The  fatly  and  other 
changes  of  the  liver  have  been  extensively  studied  by  Whipple  and  his 
pupils.  This  investigator  ascribes  to  the  hepatic  lesions:  icterus,  disap- 
pearance of  fibrinogen  from  the  blood,  diminution  of  liver  lipase  (with  in- 
crease of  plasma,  kidney  and  muscle  lipase)  and  the  occasional  excretion  of 
leucin  and  tyrosin,  as  well  as  the  other  metabolic  changes  of  chloroform 
poisoning.  These  claims  appear  well  supported  by  the  analogy  to  phos- 
phorus poisoning. 

That  the  blood  fat  is  increased  under  ether  more  than  any  other  anes- 
thetic was  maintained  by  Bloor(c),  who  found  a  rise  of  40  to  100  per  cent. 
Its  w^ater-solubility  was  considered  the  factor  which  favors  ether  in  this 
regard.  Berczeller  gives  30  per  cent  as  the  maximum  increase.  Unless 
animals  had  been  stuffed  previously  with  fat  food,  chlorofonn  was  found 
ineffective  until  the  second  or  third  day  when  an  "after  rise"  in  blood 
fat  occurred,  which  Bloor -ascribed  to  the  liver  necrosis. 

On  the  other  hand,  a  lowering  of  the  percentage  of  blood  fat  is  de- 
scribed by  Murlin  and  Riche ;  the  intensity  of  this  effect  was  found  pro- 
portional to  the  degree  of  narcosis.  Mann  has  found  the  cholesterol  con- 
tent of  the  blood  unchanged  under  surgical  ether. 

Etherizati(;^i  of  dogs  for  from  one  to  one  and  a  half  hours  on  succes- 
sive days  has  been  found  by  Ducceschi(a)  (b)  to  produce  a  marked  in- 
crease in  the  cholesterol  of  the  serum.  This  may  persist  for  several  days 
after  the  treatment.  IsTo  untoward  effects  were  noted  in  a  twenty-five  day 
experiment.  Chloroform  under  similar  conditions  caused  death  within 
eleven  days;  the  cholesterol  remained  high  two  or  three  days  only,  assum- 
ing a  subnormal  level  thereafter. 

Acid-Alkali  Metabolism. — IMarked  increase  in  the  titration  acidity  of 
the  urine  after  long  chloroform  narcosis  was  described  by  Kast  and  Mester 
and  others.  Becker  described  acetonuria  and  pointed  out  the  inadvis- 
ability  of  administering  chloroform  to  diabetics.  Thomas  maintained  that 
while  the  titration  alkalinity  of  the  blood  was  diminished  the  carbon 
dioxid  content  remained  unaltered.  This  was  ascribed  to  "carbon  dioxid 
congestion,"  or  insufiicient  ventilation.  Abram  described  acetonuria  after 
both  choloroform  and  ether.  Aloi  recently  found  beta-oxybutyric  acid  in 
nine  out  of  eleven  cases  of  chloroform  anesthesia. 

Ether,  chloroform,  or  nitrous  oxide  may  reduce  the  Pt,  of  the  blood 
to  7.0  (neutrality),  according  to  jMenten  and  Crile. 


EFFECTS  OF  CERTAm  DRUG.S  AND  POISONS       763 

Graham  has  made  interesting  studies  of  chloroform  acidosis  illiistrat- 
iug  the  protective  effects  of  alkali.  The  diminished  alkali  reserve  of  the 
blood  has  been  discussed  in  the  section  on  alkalies. 

Buckmaster  has  found  the  total  gas  content  of  the  blood  increased  by 
10.2  per  cent  under  slight  chlorofoirn  anesthesia.  When  the  anesthesia 
was  complete  this  was  increased  to  20.2  per  cent.  The  extra  gas  is  nearly 
all  carbon  dioxid,  but  there  is  also  a  low  oxyhemoglobin  content  (40  per 
cent  reduction). 

Henderson  and  Haggard  have  made  the  important  observation  that 
the  effects  of  ether  upon  the  alkali  reserve  (as  indicated  by  the  carbon 
dioxid  capacity)  of  the  blood  are  dependent  largeHy  upon  how  the  anes- 
thetic affects  the  respiration.  Ether  in  lower  concentration,  so  adminis- 
tered as  to  cause  hyperpnea,  produces,  acapnia,  lowering  the  alkali  reserve. 
On  the  other  hand,  concentrations  of  ether  high  enough  to  depress  the 
respiration  result  in  increasing  the  alkalinity  of  the  blood.  (Compare 
morphin.) 

Water  Metabolism. — Oliguria  or  anuria  have  long  been  recognized 
accompaniments  of  surgical  anesthesia. 

Rouzaud  finds  oliguria  more  pronounced  with  chloroform  than  with 
ether  in  man,  in  connection  with  his  studies  on  hyperglycemia  and 
azotemia.     He  recommends  after-treatment  with  diuretics. 

MacNider(c),  however,  has  just  reported  some  facts  relating  to  anuria 
under  anesthetics  which  would  tend  to  discourage  the  use  of  diuretics  and 
point  rather  to  preventive  measures.  Dogs  were  anesthetized  with  ether, 
chloroform,  or  chloroform  and  alcohol  (Grehant's  anesthetic).  Ether 
anuria  was  found  attributable  to  low  blood  pressure  and  rarely  associated 
with  depletion  of  the  alkali  reserve.  Only  in  the  latter  case  are  diuretics 
ineffective.  On  the  other  hand,  chloroform  anuria  (with  or  without 
alcohol)  is  invariably  associated  with  loss  of  alkali,  the  kidney  becoming 
quite  impervious  to  diuretics. 

Alkali  preliminary  to  operative  anesthesia  is  therefore  recommended 
by  MacNider  from  a  new  viewpoint — to  protect  the  kidney. 

Mineral  Metabolism. — Kast  found  that  chloroform,  like  some  other 
poisons,  increased  the  chlorid  excretion  more  in  chlorid-poor  animals 
than  in  others. 

Ferments. — Burge  maintains  that  anesthetics  lower  the  blood  catalase 
content.  Reimann  and  Becker  found  it  increased  in  35  per  cent  and  de- 
creased only  in  05  per  cent  of  their  cases. 

Hypnotics. — Chloral. — Mild  chloroform  action  is  suggested  by  many 
of  the  effects  of  chloral,  although  the  former  is  not  derived  from  the  latter 
in  vivo  as  Liebreich  supjmsed.  Chloral  glycosuria  was  described  by  Eck- 
hardt.  Harnack  and  Remertz  found  that  chloral  increases  both  nitrogen 
and  sulphur  excreti<m,  but  later  and  to  a  lesser  degree  than  does  chloro- 
form.   Abl  found  an  increased  uric  acid  excretion. 


764  HEXEY  a  BAKBOUR 

Sollmann  and  Hatcher  pointed  out  'that  severe  chloral  coma  in  ani- 
mals is  followed  by  anorexia,  marasmus  and  loss  of  weight.  They  de- 
scribed the  loss  of  heat-regulating  power,  Ginsberg  the  anuria  and  Winter- 
stein(&)  the  decreased  oxvgen  consumption.  Cushny(a)  describes  a  low- 
ering of  the  carbon  dioxid  threshold  for  respiration  after  chloral  and  otlier 
hypnotics. 

Amylene  Hydrate  diminishes  the  excretion  of  nitrogen,  according  to 
Peiser. 

Sid  phonal. — Stokvis  identified  the  discoloration  of  the  urine  after 
sulphonal  as  due  to  hematoporphyrin. 

Parald child, — Pow(fll  states  that  "hypnotic"  doses  of  paraldehyd 
lower  the  blood  sugar  in  dogs  without  affecting  the  nitrogen  excretion, 
while  "anesthetic"  doses  increase  the  foraier  and  decrease  the  latter. 

Uretham — Chittenden  observed  that  small  doses  of  iirethan  decrease 
the  nitrogen  excretion,  larger  amounts  having  the  opposite  effect.  Under- 
bill (c)  found  that  this  hypnotic  sensitizes  rabbits  to  epiuephrin  glycosuria, 
while  Bang(e)  succeeded  in  producing  hyperglycemia  with  large  doses  of 
urethan  itself.  This  is  stated  to  have  been  independent  of  the  liver 
glycogen  as  well  as  of  the  adrenal  secretion. 

Alcohol. — As  Atwater  and  Benedict  (a)  have  shown,  over  98  per  cent 
of  ingested  alcohol  is  completely  oxidized  to  carbon  dioxid  and  water  in 
the  body.  Its  effects  upon  the  metabolism  are  not  extensive.  The  litera- 
ture up  to  1903  will  be  found  reviewed  in  the  report  of  Abel,  Atwater, 
Billings,  Bowditch,  Chittenden  and  Welch. 

Total  Metabolism. — Reichert  found  the  total  metabolism  in  dogs  un- 
changed by  moderate  doses. of  alcohol.  In  Higgins^(&)  experiments  on 
man  the  oxygen  consumption  was  shown  to  remain  unaltered  after  doses  of 
30-45  c.c.  except  in  one-fifth  of  the  cases;  in  these  a  slight  increase  was 
observed.  Twenty  to  forty  per  cent  of  the  total  metabolism  was  due  to 
combustion  of  alcohol.  Large  doses  act  like  other  narcotics  in  diminish- 
ing oxidations  and  paralyzing  heat  regulation. 

Protein  Metabolism. — ^lendel  and  Ililditch  in  dogs  and  man  found 
that,  while  moderate  doses  spare  protein,  loss  of  nitrogen  occurs  when 
large  quantities  of  alcohol  are  administered.  The  partition  of  urinary 
nitrogen  remains  constant  except  that  "toxic"  doses  result  in  an  increased 
elimination  of  purins  and  of  ammonia,  accompanying  other  evidence  of 
perverted  metabolism,  as  indicated  by  the  appearance  of  levorotatory  com- 
pounds in  the  urine. 

Salant  and  Hinkel  obsen-ed  in  ^'subacute  intoxication"  in  w^ell-fed 
dogs  a  diminished  excretion  of  total  nitrogen  and  sulphur,  a  much  greater 
decrease  of  inorganic  sulpliates  and  phosphates,  and  a  tendency  to  chlorid 
retention.     Xeutral  and  ethereal  sulphur  were  increased. 

Carbohydrate  Metabolism. — Allen  has  been  unable  to  verify  the  claims 
of  some  authors  that  alcohol  creates  a  diabetic  tendencv.     Such  was  not 


EFFECTS  OF  CERTxVIX  DRUGS  AND  POISONS        765 

obsei-ved  in  cats  and  guinea  pigs  given  either  small  or  large  quantities  of 
alcohol  for  periods  up  to  one  week  in  duration. 

In  diabetics  Benedict  and  Foruk  ohsers'ed  that  replacement  of  fifty 
to  eightv  iirjims  of  food  fat  hv  isodynamic  quantities  of  alcohol  lessened 
the  excretion  of  sugar,  acetone  and  nitrogen.  Higgins,  Peabody  and  Fitz, 
however,  could  not  prevent  the  appearance  of  acidosis  in  normal  persons 
on  a  carb«jhydrate-free  diet  by  giving  alcohol.  IMosenthal  and  Harrop 
found  that  the  addition  of  alcohol  to  a  carbohydrate-free  diet  does  not 
alter  the  nitrogen  balance  in  diabetes.  No  positive  value  in  this  condition 
has  been  demonstrated. 

Fat  MctahoUsm. — The  fatty  degeneration  resulting  from  alcohol  was 
described  by  Rosenfeld.  Ducceschi  found  that  repeated  doses  of  alcohol 
sometimes  tripled  the  total  fat  of  the  liver  in  association  with  an  increase 
in  its  cholesterol  and  total  solid  content.  The  adrenals,  on  the  other  hand, 
lost  forty  per  cent  of  their  cholesterol,  but  gained  slightly  in  total  solids 
and  fat. 

Reproduction  avd  Growth. — No  effects  of  chronic  alcoholism  upon  the 
offspring  in  man  have  been  demonstrated  as  due  to  the  poison  itself. 
Stockard  has  observed  the  production  of  defective  offspring  in  guinea 
pigs  and  other  species,  but  Nice,  on  the  other  hand,  finds  in  white  mice 
that  the  offspring  are  normal  and  the  growth  of  the  alcoholic  lines  exceeds 
that  of  non-alcoholic  descendants. 

Opiates. — The  opiates  differ  particularly  from  other  narcotics  in  their 
tendency  to  increase  rather  than  to  reduce  the  alkali  reserve  and  in  the 
absence,  in  general,  of  changes  in  the  fat  metabolism.    ' 

Total  Metabolism. — Various  investigators  have  found  the  respiratory 
exchange  reduced  under  morphin,  but  to  this  no  unusual  significance  at- 
taches since  the  reduction  is  essentially  parallel  to  the  narcotic  effect. 
Higgins  and  ]\Ieans,  as  well  as  Barbour,  Maurer  and  von  Glalm,  have 
observed  that  sixteen  milligrams  of  morphin  sulphate  will  usually  cause 
a  definite  depression  of  oxidations  even  when  given  after  a  fasting  indi- 
vidual has  been  lying  practically  motionless  for  from  one  and  a  half  to 
two  hours.  The  latter  group  of  investigators  were  able  to  diminisb  or 
prevent  this  effect  by  simultaneous  administration  of  forty-milligram 
doses  of  tyramin  hydrochlorid.  Heroin  (diacetyl  morphin)  in  five- 
milligram  doses  does  not  appear  to  affect  the  metabolism  (Higgins  and 
Cleans),  and  the  results  of  earlier  observers  with  heroin  and  codein 
(Dreser)  and  other  morphin  derivatives  appear  to  lack  much  positive 
significance. 

Body  Temperature. — The  effects  of  morphin  upon  the  heat-regulating 
mechanism    were   extensively   studied   by  Reichert,   who   demonstrated 
that  neither  the  depression  nor  the  antagonistic  pyretic  effect  of  cocain 
could  be  produced  after  an  operation  intei-fering  with  the  caudate  nucleus 
of  the  corpus  striatum.     (For  the  effects  upon  total  metabolism  and  body 


766  HEXRY  G.  BARBOUR 

temperature  which  ai'e  coiiinion  to  narcotics  see  the  introduction  to  this 
chapter.) 

Protein  Metabolism. — Boeck  found  a  six  per  cent  diminution  in 
urinary  nitrogen  in  dogs,  but  Luzzato  maintains  that  it  is  augmented 
by  morphin  in  both  fed  and  fasted  animals,  especially  the  latter. 

Carbohydrate  Metabolism. — Rapid  disappearance  of  glycogen  from 
the  liver  was  noted  by  Rosen baum  and  morphin  glycosuria  has  been  fre- 
quently described.  Hyperglycemia  and  glycosuria  were  both  found  with 
large  doses  by  Luzzato.  The  effects  were  not  obtained  in  animals  accus- 
tomed to  morphin.  Higgins  and  Cleans  with  therapeutic  doses  observed  a 
very  slight  hyperglycemia  and  some  decrease  in  the  respiratory  quotieiit. 
The  latter  seems  attributable  to  the  lowered  ventilation. 

Glycosuria  may  be  simulated  by  the  appearance  of  other  reducing 
substances  in  the  urine  after  moi^phin.     (Spitta.) 

Diabetes. — Good  clinical  observers  claim  that  the  glycosuria,  together 
with  thirst  and  polyuria,  can  be  markedly  diminished  by  the  use  of 
morphin.  In  this  connection  Klercker(rf)  has  shown  that,  while  opiates 
have  no  effect  on  hyperglycemia  of  hepatogenous  origin,  they  may  inhibit 
alimentary  hyperglycemia.  !MacLeod  suggests  that  this  is  due  to  retarded 
absorption  induced  by  the  depressant  effect  of  morphin  upon  the  alimen- 
tary  canal. 

Morphin,  according  to  Kleiner  and  Meltzer(a.),  increases  the  renal 
elimination  of  intravenously  injected  dextrose,  but  retards  the  return  of 
the  blood  sugar  to  its  previous  level,  whence  these  investigators  concluded 
that  morphin  increases  the  permeability  of  the  kidney  cells  while  decreas- 
ing the  same  kind  of  permeability  of  the  capillary  endothelia  elsewhere  in 
the  body. 

Ross  (a)  recently  obtained  marked  hyperglycemia  by  the  injection  into 
dogs  of  10  milligrams  (per  kilo)  of  morphin.  In  thirty  minutes  the  blood 
sugar  was  increased  by  59  per  ce^t,  in  45  minutes  by  ,60  per  cent,  in 
one  and  one-half  hours  by  77  per  cent.  Ether  administration  begun  one- 
half  hour  after  morphin  did  not  cause  as  much  increase  in  the  blood 
sugar  as  if  morphin  had  not  been  used,  but  the  final  degree  of  ether  hyper- 
glycemia was  the  same  with  or  without  morphin. 

Fat  Metabolism. — Murlin  and  Riche  found  the  blood  fat  decreased 
under  morphin. 

Acid-Alkali  Metabolism. — Filehne  and  Kionka  observed  a  diminution  ' 
in  blood  oxygen  but  increased  carbon  dioxid  after  morphin.  The  latter 
is  indicative  of  depression  of  the  respiratory  center  which  was  first  shown 
by  Loewy  to  be  less  sensitive  to  carbon  dioxid  after  morphin.  The  high 
carbon  dioxid  content  of  the  blood  is  indicative  of  the  presence  of  a  greater 
alkali  reserve. 

The  alkali  resei-ve  increase  is  proven  by  the  increased  alveolar  carbon 
dioxid   (shown  by  Higgins  and  Cleans,  who  observed  the  same  under 


EFFECTS  OF  CERTAm  DRUGS  AND  POISOj^-S   767 

heroin,  and  by  Barbour,  Maurer  and  von  Glahn),  the  alkaline  urine  of 
dogs  after  morphin  (Underbill,  Blathervvick  and  Goldschmidt),  and  the 
increased  carbon  dioxid  capacity  of  the  blood  after  morphin  (Henderson 
and  Haggard,  Hjort  and  Taylor).  Henderson  and  Haggard  interpret  the 
phenomenon  as  illustrative  of  the  power  of  the  respiratory  mechanism  to 
exert  an  influence  upon  the  alkali  reser\'e  of  the  blood.  The  extra  alkali 
must  be  obtained,  of  course,  at  the  expense  of  the  tissues. 

This  effect  of  morphin  is  probably  of  value  in  the  prophylaxis  of 
operative  acidosis  (preventing  acapnia  with  its  consequent  loss  of  blood 
alkali),  but  the  bicarbonate  prophylaxis  possesses  the  advantage  of  fur- 
nishing new  alkali  to  combat  the  acid  production  from  various  sources. 
The  superiority  cf  opiates  over  other  narcotics  may  be  related  to  their 
protecting  effect  upon  the  alkali  of  the  blood. 

Water  Metabolism. — Ginsberg  found  that  morphin  decreases  the 
urine  flow  in  dog-s,  a  property  cominonly  exhibited  by  anesthetics.  Opiates 
seem  to  promote  the  retention  of  water  in  the  body  by  their  action  upon 
most  of  the  secretions.  The  prevention  of  the  exudation  associated  with 
colocynth  diarrhea  (Padtberg(6))  is  pertinent  in  this  connection.  Fur- 
thermore, Bogert,  Mendel  and  Underbill  found  the  drug  very  potent  in 
prolonging  the  retention  of  injected  saline  in  the  circulation.  This  hy- 
dremic tendency  accords  with  its  temperature-depressing  capacity. 


VII.    Antipyretics 

Antipyrin,  Acetanilid,  Phenacetin,  the  Salicylates,  Quinin,  Cinchophen 
(Atophan),  and  Related  Substances. 

In  general  the  antipyretics  resemble  the  narcotics  in  producing 
analgesia,  anuria,  hyperglycemia  and  increased  pi-otein  metabolism.  They 
differ  from  the  last  in  failing  to  induce  narcosis,  glycosuria  or  fatty 
changes.  Furthermore,  given  in  therapeutic  doses,  they  exhibit  their 
hydremic,  antipyretic  and  oxidation-depressing  effects  only  in  patho- 
logical conditions  associated  iviili  fever.  Significant  changes  in  the  acid- 
base  metabolism  have  not  been  demonstrated  in  connection  with  their 
action. 

Total  Metabolism. — A  large  number  of  researches,  involving  the 
methods  both  of  direct  and  indirect  calorimetiy,  have  been  made  \ipon 
the  total  metabolism  and  heat  balance  under  antipyretic  drugs.  It  may 
safely  be  regarded  as  established  that  antipyretic  drugs,  in  man  at  least, 
do  not  act  primarily  by  diminishing  the  total  oxidations.  Furthermore, 
marked  increases  in  the  heat  elimination  can  be  demonstrated.  - 

In  normal  individuals  so  far  as  is  known,  therapeutic  doses  of  none 
of  the  enumerated  substances  reduce  the  respiratory  exchange  at  all.  The 
quinin  group,  however,  has  occasionally  been  held  to  do  this.    In  hitherto 


768  HENRY  G.  BARBOUR 

unpublished  work  Barbour,  Harris,  and  Plant  have  in  normal  fasting 
persons  found  the  heat  production  increased  in  two  experiments  in  which 
one-half  gram  was  taken  and  practically  unchanged  in  two  others.  These 
experiments  accord  with  those  of  Zuntz  as  well  as  of  Liepelt,  who  with 
large  doses  raised  the  total  metabolism.  Means  and  Aub  found  quinin 
of  no  value  in  reducing  the  basal  metabolism  in  exophthalmic  goiter. 

/  With  acetyl-salicylic  acid  in  one  gram  doses  there  is  produced  in 
normal  individuals  approximately  a  six  per  cent  increase  (Barbour  and 
Devenis).  Wood  and  Reichert  found  the  metabolism  increased  in  dogs 
after  large  doses  of  sodium  salicylate,  which,  according  to  Stiihlinger, 
also  increases  it  in  guinea  pigs. 

Denis  and  Means  found  after  repeated  doses  of  sodium  salicylate  a 
fifteen  per  cent  increase  in  the  metabolism  in  one  out  of  three  surgical 
convalescents:  the  others  exliibited  no  change. 

With  very  large  doses  (two  to  three  grams)  of  antipyrin  Liepelt  suc- 
ceeded in  producing  a  reduction  in  the  oxygen  intake  varying  from  three 
to  seven  per  cent.  In  the  carbon  dioxid  output  was  found  a  greater 
diminution,  probably  attributable  partly  to  retention.  There  was  with 
these  doses  no  significant  temperature  change.  Even  with  antipyrin, 
however,  there  must  often  be  an  increase  in  the  heat  production.  It 
usually  raises  the  temperature,  for  example,  in  nonnal  dogs  and  rabbits 
in  doses  which  in  fever  are  antipyretic;  furthermore,  it  has  a  similar 
and  more  decided  effect  in  decerebrate  rabbits.  This  latter  finding  of 
Barbour  and  Deming  was  confirmed  by  Isenschmid,  :who  also  imitated 
it  with  sodium  salicylate. 

In  fever  the  total  metabolism  is  definitely  depressed  by  therapeutic 
doses  of  the  antipyretics,  the  natural  result  of  cooling  the  body.  With 
antipyrin  Riethus  observed  reductions  ii\  the  oxygen  intake  YeiTylng 
from  two  to  thirty  per  cent. 

After  one  gram  doses  of  acetyl-salicylic  acid  Barbour  observed  an 
average  diminution  of  3.5  per  cent  in  the  heat  production  in  associa- 
tion with  a  drop  of  nearly  1°  C.  in  the  temperature;  heat  elimination  is 
greatly  increased  (see  Fig.  4).  Similar  changes  occur  under  phenacetin 
and  antipyrin. 

Quinin  in  fever  has  usually  reduced  the  total  oxidations  in  man  and 
animals  when  the  temperature  was  aifected,  for  example,  in  a  case  of 
erysipelas  studied  by  Riethus.  Tuberculosis  and  many  other  febrile  con- 
ditions respond  to  quinin  by  a  rise  in  temperature  and  oxidations  rather 
than  by  a  fall.  The  contention  that  quinin,  which  is  far  from  being  a 
universal  antipyretic,  reduces  temperature  primarily  by  diminishing  the 
heat  production,  certainly  does  not  hold  for  human  beings. 

Senta  found  that  various  antipyretics  reduce  the  oxidations  in  isolated 
muscles  of  mammals  and  birds,  quinin  and  salicylic  acid  being  the  most 
efficient  in  this  respect. 


EFFECTS  OF  CERTAIiSr  DRUGS  AND  POISOlSrS        769 

Protein  Metabolism. — After  antipyrin  the  nitrogen  excretion  is  not 
much  changed  in  man  or  in  dogs.  In  fever  it  is  often  found  reduced 
(Miiller).     This  effect  inay,  however,  he  sinuilated  hj  renal  retention. 

Salicylates  increase  the  elimination  of  nitrogen,  as  has  been  repeatedly 
demonstrated.  Goodbody,  for  example,  found  urea  and  ammonia  both 
increased.  According  to  Wiley  repeated  ingestion  of  salicylate  results 
in  some  loss  of  weight  and  of  nitrogen. 

Singer  found  both  nitrogen  and  uric  acid  excretion  increased  after 
acetyl-salicylic  acid  in  rabbits.  Denis (c)  and  many  others  have  found 
the  uric  acid  excretion  increased  under  salicylates.     According  to  Fine 


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Fig.  4.  Effects  of  acetyl  salicylic  acid  on  patient  with  tuberculous  abscess; 
broken  line,  oxygen  c.c.  per  minute;  lighter  horizontal  line,  carbon  dioxid  c.c.  per 
minute;  heavier  horizontal  line,  calories  produced  per  minute;  dotted  line,  calories 
eliminated  per  minute;  continuous  curve,  body  temperature.  Drug  administered  at 
arrow.     (H.  G.  Barbour,  Arcli.  Int.  Med.,  1919,  XXIV.) 


and  Chace(6)  this  is  due  to  increased  permeability  of  the  kidneys,  for  the 
blood  uric  acid  is  lowered. 

Hanzlik  has  thoroughly  reviewed  the  literature  on  salicylates.  With 
Scott  and  Reycraft  he  demonstrated  an  accumulation  of  urea  in  the  blood 
(associated  with  renal  impairment  and  edema)  after  administration  of 
full  therapeutic  doses  of  sodium  salicylate. 

Acetanilid  in  four  to  five  gram  doses  increased  the  nitrogen  metab- 
olism of  Kumagawa's  dogs  by  over  80  per  cent.  Chittenden  in  normal 
men  found  the  nitrogen  excretion  unaltered,  but  the  urea  was  diminished 
by  10  to  20  per  cent.  Sulphates,  phosphates,  and  chlorids  were  not 
significantly  altered. 

Quinin  reduces  the  nitrogen  metabolism  definitely,  as  shown  by  Koor- 
den  and  Zuntz  and  many  others.  Loewi  found  the  percentage  of  urea 
nitrogen  slightly  decreased. 

Reproduction  and  Growth. — Riddle  and  Anderson  have  shown  that 
quinin  fed  to  laying  ring  doves  reduces  the  size  of  the  eggs,  the  yolks 


770  HENBY  G.  BAEBOUR 

particularly  being  affected.  They  believe  that  the  size  attained  is  gov- 
erned by  restrictions  placed  upon  the  protein  metabolism. 

Carbohydrate  Metabolism. — According  to  Lepine  and  Porteret  and  to 
^N'ebelthau  antipyretics  (antipyrin  and  acetanilid)  are  capable  of  pro- 
moting  the  storage  of  glycogen  in  both  liver  and  muscles.  Starkenstein's 
claim  that  antipyretics  prevent  the  mobilization  of  liver  glycogen  by 
epinephrin  has  been  disproved  by  Mansfield  and  Purjesz  who  found  that 
antipyretics  exert  no  demonstrable  effect  upon  the  somewhat  variable  curve 
of  epinephrin  hyperglycemia.  Noorden  examined  the  claim  that  salicy- 
lates decrease  the  sugar  output  in  diabetes  and  failed  to  establish  it. 

Herter  (cited  by  Underbill)  observed  the  production  of  glycosuria 
after  painting  salicylate  upon  the  pancreas  of  a  dog.  l^o  other  case  of 
glycosuria  due  to  any  of  this  group  of  drugs  appears  to  have  been  re- 
ported. Wacker  and  Poly  have,  however,  described  a  rise  in  the  blood 
sugar  content  in  rabbits  and  tuberculosis  patients  after  phenacetin  and 
Silberstein  found  hyperglycemia  after  giving  quinin  to  dogs. 

Barbour  and  Herrmann  demonstrated  that  hyperglyceinia  (without 
glycosuria)  occurs  in  both  normal  and  ^^coli  fever"  dogs  after  acetyl- 
salicylic  acid,  sodium  salicylate,  antipyrin  and  quinin.  The  following 
averages  were  obtained: 

DEXTROSE  CONCENTRATION  IN  BLOOD 


Before 

Maximum 

Antipyretics 

After  Antipyretics 

% 

% 

0.137 

0.18G 

0.139 

0.218 

Average  of  13  normal  dogs 
Average  of  10  fevered  dogs 

Since  the  blood  of  the  normal  dogs  became  slightly  concentrated  and 
that  of  the  fever  dogs  diluted  by  the  various  dnigs  the  absolute  increase 
in  the  blood  sugar  content  of  the  latter  was  somewhat  larger  than  would 
appear  from  the  concentration. 

Antipyretic  drugs  cause  no  significant  changes  in  the  respiratory 
quotient. 

Water  Metabolism. — Barbour  and  Herrmann  foimd  after  antipyretics 
a  hydremia,  as  indicated  by  the  hemoglobin  contentj  in  "coli  fever"  but 
not  in  normal  dogs,  as  has  just  been  stated.  This  is  induced,  at  least  in 
part,  by  the  osmotic  action  of  the  extra  blood  sugar.  The  reason  that 
the  hydremia  is  not  seen  in  the  noi-mal  dogs  appears  to  be  that  fever 
dogs  are  possessed  of  a  store  of  available  water  in  the  tissues  which  is 
not  normally  present.  This  contention  is  supported  by  Barbour  and 
How^ard's  demonstration  of  an  increase  in  the  percentage  of  blood  solids 
during  the  initial  rise  of  "coli  fever,"  without  diuresis.  Furthermore, 
water  would  be  liberated  with  the  increased  protein  catabolism  of  fever. 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS       771 

In  Hanzlik's  demonstration  of  salicyl  anuria  one  sees  a  further  reason 
why  the  hyperglycemia  tends  to  keep  the  volume  of  the  blood  high. 

Hirscht'eld  niaiiitains  that  antipyretics  relieve  diabetes  insipidus  and 
Gaulier  finds  that  salicylates  diminish  the  excretion  of  chlorids.  These 
and  various  other  observations  tend  to  support  the  belief  that  salicylates 
induce  oliguria. 

In  Hanzlik's  non-febrile  cases  the  hemoglobin  remained  constant. 
Barbour  has  found  the  hemoglobin  percentage  diminished  in  fever  patients 
during,  the  antipyretic  action  of  both  acetyl-salicylic  acid  and  antipyrin. 

The  role  of  the  excess  sugar  in  producing  hydremia  is  illustrated  in 
Barbour  and  Howard's  results  with  dextrose  in  normal  and  fever  dogs. 
Intravenous  dextrose  injections,  which  in  normal  animals  produce  a  slight 
blood  dilution  with  no  temperature  change,  will  dilute  the  blood  two  or 
three  times  more  extensively  in  fever  animals  coincidently  with  a  marked 
antipyretic  action.  These  eifects  are  short-lived  when  much  sugar  is  used. 
The  sugar  runs  off  in  the  urine  presently  and  may  leave  the  blood  more 
concentrated  and  the  temperature  higher  than  ever. 

Theory  of  the  Mechanism  of  Fever  Reduction  by  Drugs.-^AW  antipy- 
retics act  by  increasing  the  heat  elimination ;  reduction  in  heat  production 
is  incidental.  Antipyretics  increase  the  blood  sugar  concentration.  In 
fever  extra  water  being  available  in  the  tissues,  these  drugs  produce 
^plethora ;  factors  other  than  hyperglycemia  may  contribute  to  this  result. 
Plethora  promotes  the  dissipation  of  heat  by  radiation  and  surface 
evaporation.  (Sweating  is  not  essential  to  antipyretic  action  which  pro- 
ceeds unabated  in  the  presence  of  atropin  antidiaphoresis.)  In  health 
no  plethora  occurs, — consequently  there  is  no  antipyretic  effect. 

The  earlier  work  on  the  relation  of  ''heat  centers"  to  antipyretic  action 
is  well  presented  by  Gottlieb  in  Meyer  and  Gottlieb's  pharmacological 
treatise. 

Barbour  and  Wing  have  showed  that  local  applications  of  antipyrin, 
chloral  or  quinin  to  the  heat  centers  in  rabbits  all  gave  better  antipyretic 
effects  than  the  same  doses  by  the  intravenous  or  subcutaneous  routes. 

Hashimoto  later  found  that  the  antipyretic  action  of  both  antipyrin 
and  salicylate  is  enhanced  by  heating  the  centers  but  annulled  by  cooling. 
After  quinin  only  heat  was  found  effective,  cold  having  no  effect.  The 
effects  of  heat  and  cold  were  prevented  by  morphin,  as  indeed  tlie  present 
author  has  often  noticed  to  be  true  of  ether. 

Vasomotor  effects  figure  largely  in  these  "heat  center"  reactions  which 
it  is  expected  can  be  correlated  ultimately  with  the  blood  dilution  theory. 

Acid-Alkali  Metabolism. — ^IMeyer  found  no  change  in  the  alkalinity 
of  the  blood  with  salicylates.  In  fatal  poisoning,  however,  Walter  found 
a  low  carbon  dioxid  content.  Acetonuria  is  reported  by  Langmead  and 
by  Lees  from  large  doses  of  salicylates,  and  in  children.  Piccini  found 
that  phenacetin  and  acetanilid,  and,  to  a  lesser  extent,  antipyrin,  reduced 


772  HENKY  G.  BAEBOOR 

the  arterial  oxygen  in  dogs,  the  carhon  dioxid  being  reduced  to  a  slight 
extent.    In  general  then  the  tendency  is  toward  the  side  of  acidosis. 

Quinin  and  its  congeners. — Although  it  is  not  a  dependable  anti- 
pyretic in  many  instances,  Solis  Cohen  has  recommended 'the  use  of  quinin 
in  pneumonia;  the  initial  dose  is  1-1.6  grams  of  the  quinin-urea  hydro- 
chlorid,  to  be  followed  by  1  gram  doses  every  three  hours  until  the  tem- 
perature is  reduced  to  102°  F.,  which  may  require  a  day  or  two.  Cahn- 
Bronner  maintains  that  in  certain  lung  inflammations  treated  with  0.5 
gram  doses  of  quinin  subcutaneously  an  early  antipyretic  effect  was  seen 
and  the  mortality  reduced  to  one-fourth.  It  may  be  of  some  real  etiotropic 
value  in  this  condition. 

In  malaria  the  drug  only  prevents  "chills"  and  further  symptoms 
rather  than  modifying  the  temperature  curve  after  it  has  begun  to  rise. 
Certainly  it  does  not  compare  favorably  with  other  antipyretics  in  mild 
fever.  Quinin  is  probably  only  antipyretic  in  nearly  or  quite  toxic  doses, 
when  it  acts  very  similarly  to  other  types  of  antipyretic  drugs. 

Ethylhydrocuprein  has  a  lesser  antipyretic  effect  than  quinin,  as  shown 
by  Smith  and  Fantus. 

Cinchophen  (Atophan). — Cinchophen,  according  to  Starkenstein  and 
Wiechowski,  reduces  the  temperature  of  normal  rabbits  by  several  degi-ees. 
Its  real  therapeutic  value  perhaps  lies  more  in  its  analgesic  properties 
(which  it  shares  with  other  antipyretics)  than  in  its  influence  upon  the 
purin  metabolism.  For  example,  a  number  of  compounds  chemically 
related  to  cinchophen,  but  possessing  no  influence  upon  uric  acid  excretion 
were  found  by  Klemperer  to  diminish  in  time  and  intensity  the  inflam- 
matory phenomena  of  acute  gout  attacks.  Boeck  as  well  as  Rotter  has 
described  the  action  of  a  number  of  other  derivatives. 

Purin  Metabolism. — Nicolaier  and  Dohrn  introduced  cinchophen  for 
the  treatment  of  gout,  having  noted  that  three  grams  given  daily  to 
normal  individuals  increased  the  uric  acid  excretion  sometimes  up  to  200 
per  cent  of  the  normal.  (6-gram  doses  tripled  the  output.)  The  in-_ 
creased  excretion  begins  within  an  hour,  the  maximum  being  reached 
within  two  hours  (Griesbach  and  Samson).  The  uric  acid  concentration 
shows,  according  to  IIaskins(6)  (c),  a  compensatory  decrease,  sometimes 
during  administration. 

The  increase  of  uric  acid  is  often  so  great  that  it  precipitates  in  the 
urine  before  it  is  passed.  Haskins  has  in  fact  shown  that  cinchophen  in- 
terferes with  the  urate-solvent  action  of  the  urine. 

Zuelzer (?>)  maintains  that  the  urate  excretion  is  more  prolonged  in 
gout  than  in  health. 

Among  the  theories  advanced  to  account  for  the  action  of  cinchophen 
are  increased  destruction  of  nucleo-protein  (Schittenhelm  and  Ullman) 
and  conversion  of  absorbed  uric  acid  into  a  filterable  form  (Frank  and 
Pietrulla).     Since,  however,  Folin  and  Lyman (6)  were  able  to  show  a 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        773 

decrease  of  blood  uric  acid  parallel  to  the  urinary  uric  acid  increase,  little 
need  is  found  for  an  explanation  beyond  that  of  increased  permeability  of 
the  kidney  for  this  metabolite.  According  to  McLester  the  blood  uric  acid 
eventually  attains  an  irreducible  minimum. 

Fine  and  Chace  have  shown  that  when  the  administration  of  the  drug 
is  stopped  the  initial  blood  concentration  is  restored  in  from  two  to 
four  days. 

According  to  Starkenstpin  and  Wiechowski  the  allantoin  excretion  is 
reduced  and  the  total  formation  of  purin  bodies  is  inhibited.  The  same 
authors  maintain  that  piqiire  and  asphyxial  glycosurias  are  inhibited  as 
by  calcium,  and  that  the  drug  besides  an  antipyretic  possesses  an  anti- 
phlogistic action,  entirely  inhibiting  mustard  oil  chemosis. 


VIII.     Ammonia,  Amins,  Alkaloids,  Purins,  Etc* 

Ammonia. — Underbill  and  Goldschmidt  showed  that  organic  ammon- 
ium salts  are  quickly  and  completely  transfonned  into  urea.  The  fate 
of  the  inorganic  salts  is  more  complicated.  While  a  part  are  converted 
into  urea  another  portion  is  excreted  unchanged.  Still  a  third  part  of 
the  inorganic  salts  are  temporarily  retained,  following  which  an  augmented 
nitrogen  excretion  is  noted. 

Grafe  found  that  ammonium  salts  increase  oxidations  in  rabbits. 

Hydrazin. — Underbill  and  Kleiner  (a)  showed  that  this  poison  pro- 
duces fatty  degeneration  of  the  liver.  Underbill  and  Murliu  showed  that 
it  increases  the  respiratory  quotient  of  fasting  dogs,  the  increased  combus- 
tion of  sugar  accounting  for  the  hypoglycemia  which  occurs.  It  does 
not  specifically  aifect  the  heat  production, 

Ethylenediamin. — This  proteinogenous  amin  lowers  the  body  tempera- 
ture of  rabbits:  a  tolerance  to  this  effect  is  acquired  within  a  few  days. 
(Barbour  and  Hjort.) 

Iso-amylamin,  Phenylethylamin,  and  Tyramin. — xVll  of  these  increase 
the  nitrogen  metabolism,  especially  in  thyroidectomized  animals  (Abelin). 
Tyramin  increases  the  total  metabolism  in  man,  lowering  the  alveolar  car- 
bon dioxid,  as  shown  by  Barbour,  Maurer  and  von  Glahn.  These  effects 
are  antagonistic  to  morphin  action.  Phenylethylamin  and  tyramin  raise 
the  body  temperature  of  dogs.  Morita  found  that  tyramin  and  similar 
drugs  cause  glycosuria,  and  Iwao  that  tryamin  produces  hemosiderosis 
in  rabbits. 

Beta-tetrahydronaphthylamin. — This  is  the  most  powerful  pyretic 
poison  known.  Mutsch  and  Pembrey  have  shown  that  it  increases  the 
carbon  dioxid  excretion  but  not  that  of  nitrogen.  DeCoi-ral  maintains 
that  it  causes  hyperglycemia  and  increases  the  hyperglycemia  caused 
by  narcotics. 


^74  HEXKY  a  BiVKBOUR 

The  Amino  Acids. — Increase  of  the  total  metabolism  and  body  tem- 
perature (Liisk(e)),  also  the  uric  acid  metabolism,  by  the  amino  acids  has 
been  well  established  (Lewis  and  Doisy). 

Atropin,  Pilocarpin,  etc. — Total  Metabolism. — Edsall  and  Means  as 
well  as  Iliggins  and  Cleans  found  the  respiratory  exchange  increased 
after  milligram  doses  of  atropin  in  human  subjects.  On  the  other  hand, 
Keleman,  employing  large  doses  in  dogs,  finds  a  decrease  in  the  carbon 
dioxid  output.  This  antagonizes  the  ten  per  cent  increase  in  the 
metabolism  which  he  has  found  after  pilocarpin,  confirming  the  ob- 
servations of  Frank  and  Voit(&).  The  relative  role  of  secretory  and 
smooth  muscle  activity  has  been  discussed  by  Loewi.  An  energetic  pilo- 
carpin sialorrhea  may  deplete  the  blood  fluid  sufficiently  to  cause  a  rise  of 
temperature  with  consequent  increase  in  the  total  metabolism. 

Protein  Metabolism, — Either  fifteen  milligrams  of  pilocarpin  or  ten 
milligrams  of  atropin  increased  the  nitrogen  excretion  in  Eichelberg's 
experiments.  There  was  a  slight  phosphate  increase  as  well.  With 
scopolamin  de  Stella  observed  in  two  rabbits  and  two  dog's  a  consistent  fall 
in  nitrogen,  chlorids,  phosphates,  and  water  in  the  urine.  Uremia  has 
been  described  in  miiscarin  poisoning  by  Clark,  Marshall  and  Rowntree, 
who  found  it  due  to  renal  impairment. 

Furin  Metabolism. — Abl  found  that  atropin  prevents  the  uric  acid  in- 
crease after  cinchophen ;  IMendel  and  Stehle  found  the  postprandial  uric 
acid  increase  inhibited  by  the  same  drug. 

Carbohydrate  Metabolism. — Raphael  and  others  have  described 
glycosuria  in  atropin  poisoning.  Pitini,  as  well  as  MacGuigan(a),  has  ob- 
served that  large  doses  increase  the  blood  sugar.  The  conception  was 
at  one  time  prevalent  that  atropin  was  of  value  in  the  treatment  of  diabetes 
and  in  fact  that  it  inhibited  glycogenolysis.  Mosenthal(fc)  has  shown  that 
the  view  that  atropin  increases  the. tolerance  for  sugar  is  unsupported  by 
valid  evidence. 

Ross(&)  finds  that  atropin  reduces  markedly  the  ether  hyperglycemia, 
for  example,  from  a  forty-one  per  cent  increase  to  a  nine  per  cent  increase 
in  the  first  fifteen  minutes,  and  from  a  fifty-seven  per  cent  increase  to  a 
twenty-one  per  cent  increase  in  the  first  hour.  Atropin  alone  did  not 
affect  the  blood  sugar  content. 

According  to  MacGuigan  pilocarpin  may  cause  a  delayed  reduction 
in  the  blood  sugar  content.  In  massive  doses  atropin  fails  to  lessen  the 
hyperglycemia  due  to  stimulation  of  the  celiac  plexus. 

Mushroom  (miiscarnn)  poisoning  may  provoke  renal  glycosuria,  ac- 
cording to  Alexander. 

Water  Metabolism. — Pilocarpin  has  no  direct  action  upon  the  urine 
(J.  B.  MacCallum),  but  owing  to  the  great  loss  of  fluid  by  other  channels 
Asher  and  Bruck  state  that  it  usually  diminishes  the  water  and  chlorids. 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISOlSrs       775 

Cow  has  shown  that  a  number  of  supposed  effects  of  these  dmgs  upon 
the  renal  fimction  simply  arise  from  actions  upon  the  ureteral  muscula- 
ture. 

After  repeated  injections  of  large  doses  of  pilocarpin  Waterman  ob- 
served both  diuresis  and  glycosuria,  attributing  these  to  increased  renal 
permeability. 

It  is  not  unusual  for  three  liters  of  sweat  to  be  removed  by  pilocarpin 
diaphoresis,  thus  eliminating  2.5  grams  of  nitrogen.  In  nephritis  this 
could  amount  to  eight  grams,  thus  affording  notable  relief  for  the  kidney. 
(Sollmann.) 

Body  Temperature. — Both  pilocarpin  and  atropin  may  cause  hyper- 
thermia, the  former  by  secretory  (especially  salivary)  dehydration  and 
smooth  muscle  and  gland  stimulation  (Reichert),  the  latter  by  central 
stimulation,  perhaps  associated  with  depression  of  tki  sweat.  Atropin 
does  not,  however,  hinder  the  action  of  antipyretic  drugs. 

Strychnin. — This  alkaloid  may  be  classed  as  an  asphyxial  poison  for 
the  reason  that  such  effects  as  it  exerts  upon  the  metabolism  are,  in  part 
at  least,  due  to  oxygen-lack.  In  view,  however,  of  its  most  characteristic 
action  being  a  direct  stimulation  of  the  central  nen'ous  system  it  is  natural 
to  invoke  this  stimulation  in  explanation  of  the  glycogen  discharge  which 
strychnin  produces. 

Carbohydrate  Metabolism. — The  knowledge  of  hepatic  glycogenolysis 
and  glycosuria  as  a  result  of  strychnin  poisoning  dates  back  to  the  work 
of  Schiff  (1859).  Zuntz  made  use  of  the  drug  to  demonstrate  the  forma- 
tion of  glucose  from  the  protein  metabolism.  After  ridding  a  rabbit  of 
glycogen  by  strychnin  convulsions  he  kept  the  animal  fasting  and 
chloralized  for  one  hundred  and  nineteen  hours.  During  this  time  5.25 
grams  of  sugar  were  excreted  in  the  urine,  and  yet  1.286  grams  of 
glycogen  were  still  found  in  the  liver  and  muscles.  This  must  have  arisen 
from  protein. 

Araki  observed  that  strychnin  causes  lactic  acid  as  well  as  glucose  to 
appear  in  the  urine,  and  classified  it  as  an  asphyxial  poison,  as  did 
Starkenstein. 

Lepine(a)  states  that  strychnin  glycosuria  is  unknowu  in  man. 

According  to  Blum  strychnin  is  able  to  free  the  liver  of  glycogen  if 
either  both  vagi  or  both  splanchnic  nerves  are  cut.  lie  concludes,  there- 
fore, that  glycogenolysis  resulting  from  excessive  muscular  work  is  brought 
about  through  the  blood. 

Lusk  has  shown  that  stryc'linin  and  other  convulsions  cause  the  appear- 
ance of  lactic  acid  in  the  blood,  to  which  phenomenon,  however,  an  adequate 
glycogen  store  is  essential. 

The  alveolar  carbon  dioxid  tension  is  unaltered  by  strychnin  in  thera- 
peutic doses  (up  to  4.5  milligrams)  in  man,  according  to  the  results  of 
Higgins  and  Means.     These  investigators,  as  well  as  Edsall  and  Means, 


776  HEKKY  G.  BARBOUR 

were  also  unable  to  produce  any  change  in  the  total  metabolism  by  such 
doses. 

Some  Other  Convulsants — Camphor. — Edsall  and  I^Ieans,  also  Hig- 
gins  and  Cleans,  have  observed  a  slight  increase  in  the  total  metabolism 
in  man  after  0.4-0.5  gram  subcutaneous  injections  of  camphor.  The  only 
change  observed  by  these  investigators  in  the  alveolar  carbon  dioxid  tension 
was  a  slight  diminution  in  one  case.  This  accords  with.  Wieland's  find- 
ing that  camphor  lowers  the  respiratory  threshold  for  carbon  dioxid  in 
rabbits.  The  latter  observed  a  similar  result  from  coriamyrtin  (a  picro- 
tox in-like  convulsant). 

Since  camphor  is  excreted  in  the  urine  in  combination  with  glycuronic 
acid  (Schmicdeberg  and  Hans  ]^^eyer)  it  is  of  some  importance  that  this 
defensive  mechanism  should  be  intact  when  the  drug  is  administered  in 
large  amounts;  its  toxicity  is  said  to  be  higher  when  glycuronic  acid 
formation  is  disturbed  through  starvation  or  'deprivation  of  oxygen.  In 
Chiray's  experiments  glycuronic  acid  was  produced  by  administering 
camphor  by  mouth  or  the  injection  of  camphorated  oil  in  dogs^  rabbits, 
giiinea  pigs  and  man.  The  reaction  reached  a  maximum  at  about  the 
third  hour.  With  marked  insufficiency  of  the  liver  there  was  no  resjDonse 
to  the  ingestion  of  0.5-1.0  gram  of  camphor. 

Camphor  administration  to  dogs  by  Mandel  and  Jackson  resulted  in 
deci*eased  glycuronic  acid  production  after  glucose  feeding,  meat  caus- 
ing an  increase.  A  proteinogenous  origin  of  glycuronic  acid  was  thus 
indicated. 

Santonin. — The  increase  in  uric  acid  excretion  after  santonin  is 
attributed  by  Abl  to  intestinal  irritation. 

Body  Temperature. — Many  so-called  "convulsant  poisons,"  including 
strychnin,  santonin,  picrotoxin,  camphor,  phenol,  etc.,  have  been  shown 
by  Harnack  to  produce  characteristic  changes  in  the  heat  regTilation.  The 
salient  result  is  a  fall  in  body  temperature.  Small  doses  cause  in- 
creased heat  loss  and  a  slightly  smaller  heat  production. 

Larger  doses  cause  increased  metabolism,  through  muscular  action, 
(both  heat  production  and  loss  being  thus  increased).  Paralytic  doses 
diminish  the  heat  production  very  greatly. 

The  temperature  accordingly  varies,  but  the  smallest  and  the  largest 
doses  lower  it  decidedly.  The  heat  loss  is  seen  especially  in  small  and 
young  animals,  larger  animals  showing  some  temperature  rise  with  the 
medium  doses. 

Curare. — This  poison  as  is  well  known  paralyzes  all  voluntary  motor 
nerve  endings.  Asphyxia  therefore  results  by  the  interference  thus  pro- 
duced  wdth  the  external  respiratory  mechanism.  The  salient  feature  of 
its  action  upon  the  metabolism  is  the  glycosuria,  discovered  by  Claude 
Bernard.  Penzoldt  and  Fleischer  first  called  attention  to  the  importance 
of  asphyxia  as  a  causative  factor.     Araki  pointed  out  its  relatioji  to  tljc 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        777 

liver  glycogen.  MacLeod  failed  to  produce  glycosuria  either  by  asphyxia 
or  by  curare  in  Eck-fistula  dogs  after  ligation  of  the  hepatic  artery. 
Since,  however,  he  was  unable  to  prevent  curare  glycosuria  entirely  by 
employing  adequate  artificial  respiration,  some  other  factor  besides 
asphyxia  must  be  involved.  . 

Diminution  in  the  total  metabolism  was  claimed  by  Rohrig  and  N. 
Zuntz  and  others,  who  found  a  decrease  of  fifty  per  cent  in  the  respiratory 
exchange  of  rabbits.  But  O.  Frank,  Voit  and  Gebhard  found  no  essential 
difference  between  normal  and  curarized  dogs  when  precautions  were 
taken  to  keep  the  body  temperature  from  falling.  Tangl  has  recently 
confirmed  this  observation. 

The  nitrogen  metabolism  has  been  stated  to  be  reduced  by  curare, 
but  this  effect  appears  to  have  been  simulated  by  a  simple  delay  in  excre- 
tion (Voit). 

Body  Temperature. — The  experiments  of  Rohrig  and  Zuntz  were  the 
first  in  which  it  became  clear  that  curarized  mammals  become  poikilo- 
thermic  at  ordinary  room  temperatures. 

Krogh  states  that  the  curve  of  oxygen  absorption  as  influenced  by 
body  temperature  is  the  same  in  anesthetized  cold-blooded  animals  as 
in  the  curarized  dog. 

.  Cocain. — Body  Temperature  and  Heat  Production. — The  hyper- 
thermia which  cocain  induces,  while  accompanied  by  greatly  increased 
muscular  movements,  can  best  be  accounted  for  by  the  loss  of  much  fluid 
from  the  blood.  (Unpublished  work  of  the  author.)  The  temperature 
rise,  according  to  Mosso,  can  be  prevented  by  curare  or  chloral  but  not  by 
tho  antipyretics.  In  dogs  Reichert  found  that  ten  milligrams  of  cocain  pt*r 
kilo  given  subcutaneously  caused  in  one  hour  a  mean  maximum  increase 
of  146.0  per  cent  in  heat  produced  and  a  mean  maximum  rise  of  1.81°  hi 
temperature.  He  obsen^ed  that  cocain  is  sufficiently  powerful  to  counter- 
act the  profound  depressant  actions  of  raorphin  upon  heat  production  and 
body  temperature.  The  action  is  a  central  one,  not  occurring  in  the  absence 
of  the  cerebral  hemispheres  and  basal  ganglia. 

In  one  experiment  by  Kopciowski  in  a  fasting  human  subject  a  small 
do^o  of  cocain  diminished  the  carbon  dioxid  output  by  thirteen  per 
cent. 

Nitrogen  and  Fat  Metabolism. — ^Faestro  described  a  nitrogen  reten- 
tion in  rabbits  associated  with  oliguria.  Large  doses  (20  milligrams  per 
kilo),  as  shown  by  I^nderhill  and  Black,  lower  both  nitrogen  and  fat 
utilization  in  dogs. 

Carbohydrate  Metabolism. — Cocain  glycosuria  occurs  infrequently. 
Schaer  states  that  the  hyperglycemia,  in  cats  at  least,  when  present  is 
due  to  excitement.  In  well-fed  dogs  and  rabbits,  but  not  in  the  starving 
condition,  Underbill  and  Black  found  a  marked  increase  in  the  lactic 
acid  of  the  urine.     They  were  inclined  to  associate  this  with  muscular 


t^ 


778  HEXKY  G.  BARBOUE 

activity  and  to  ascribe  its  origin  to  more  than  a  single  antecetlent.  The 
ammonia  output  appeared  to  bear  little  relation  to  the  lactic  acid  elimina- 
tion. 

Purins. — The  chief  therapeutic  value  of  the  purin  bases  lies  in  their 
diuretic  property  which  quite  possibly  plays  the  chief  role  in  all  of  their 
effects  upon  the  metabolism. 

Water  Metabolism. — In  purin  diuresis  the  water  of  the  urine  is  in- 
creased proportionately  more  than  the  solids,  which  also  show  an  absolute 
increase.  The  extent  of  water  excretion  depends  much  upon  the  supply. 
Widmer(a),  for  example,  has  shown  that  caffein  diuresis  is  abundant  in  | 

dropsical  conditions,  but  fails  altogether  with  dry  feeding.     On  the  other  | 

hand,  during  the  diuresis  of  diabetes  mellitus  E.  Meyer  has  shown  that  | 

caffein  produces  no  further  effect.     The  reputed  superiority  of  theobromin  I 

and  theocin  as  compared  with  caft'ein  Sollmann  ascribes  to  the  fact  that  | 

the  last  mentioned  is  possessed  of  more  toxic  side  actions  which  prohibit  % 

its  being  administered  in  such  large  amounts.  % 

Schroeder(??)  observed  that  the  water  content  of  rabbit's  blood  is  de-  f 

creased  by  ten  per  cent  after  an  effective  caffein  diuresis.  Spiro  states 
that  theocin  also  lessens  the  absolute  amount  of  water  in  the  blood  besides 
the  percentage  concentration  of  sodium  chlorid. 

The  secretory  theory  of  caffein  diuresis  was  advanced  by  Schroeder. 
It  received  strong  support  from  the  experiments  of  Richards  and  Plant, 
in  which  it  was  shown  that  when  the  in  vitro  perfusion  flow  is  kept  con-  f ' 

stant  caffein  increases  the  artificial  urine.     On  the  other  hand,  there  is  S] 

a  mass  of  evidence  which  relates  purin  diuresis  to  an  increased  circula- 
tion through  the  kidneys.  For  a  full  discussion  of  the  mechanism  the 
reader  is  referred  to  Cushny's  monograph.  ^ 

Nephritic  Conditions. — Pearce,  Hill  and  Eisenbrey  and  others  have  1;- 

show^n  that  the  diuresis  fails  to  occur  in  experimental  glomerular  nephritis.  J.  I 

Christian  has  found  theocin  of  little  diuretic  value  in  nephritis  except 
in  cardiorenal  cases  with  edema.  Here  he  finds  that  it  increases  the 
sodium  chlorid  excretion  and  works  best  when  given  with  digitalis  or 
intermittently. 

MacXider  finds  purin  and  other  diuretics  ineffective  in  anurias  pro- 
duced by  anesthetics  except  in  those  cases  of  ether  anuria  where  the  alkali 
reserve  has  not  been  depleted.  T 

Zondek  has  recently  observed  that  in  cases  of  high  grade  hydropic  :^ 

nephritis  many  diuretics  of  the  xanthin  group  cause  a  decreased  flow  >? 

(with  greater  concentration)  of  the  urine.  This  phenomenon,  which  as 
yet  lacks  confirmation,  is  attributed  to  "fatigue"  of  the  renal  vessels. 

To  produce  full  caffein  diuresis  in  man  II.  L.  Taylor  finds  that  at 
least   0.5   gram   four  times   a   day   is   necessary.      Theobromin-sodium-  || 

salicylate  may  safely  be  given  in  doses  twice  as  large.  j^ 

In  the  human  experiments  of  IMeans,  Aub  and  DuBois  (see  below) 


k 


EFFECTS  OF  CERTAIN  DRUGS  AND  POISONS        779 

the  percentage  of  heat  lost  in  the  vaporization  of  water  from  the  luno-s 
and  skin  was  not  significantly  altered  by  caffein. 

Bodij  Temperature. — Binz  appears  to  have  discovered  that  caffein 
hyperthermia,  which  is  not  usually  intense,  regularly  results  when  con- 
siderable (loses  are  administered  to  animals  and  man.  Pilcher  found 
that  the  lowered  temperature  of  moderate,  but  not  of  deep  narcosis,  could 
be  successfully  combated  with  caffein.  Karelkin  stt\tes  that  the  temper- 
ature increase  is  much  greater  in  thyroidectomized  than  in  noi-mal 
dogs.  The  diuretic  effect,  which  concentrates  the  blood,  is  probably  re- 
sponsible for  the  rise  in  temperature,  but  this  should  be  determined  by 
experiment. 

^landel  observed  a  correlation  between  purin  excretion  and  tempera- 
ture-fall in  fevers.  He  produced  fever  in  monkeys  by  xanthin  injections; 
xanthin,  if  given  with  salicylate,  failed  to  raise  the  temperature. 

Total  Metabolism. — Edward  Smith  in  1859  by  a  very  large  number 
of  carefully  conducted  experiments  established  the  fact  that  caffein  in- 
creases the  carbon  dioxid  output.  The  rise  obtained  was  anywhere  from 
fifteen  to  thirty  per  cent.  Reichert  by  direct  calorimetry  in  dogs  observed 
greater  increases  in  the  heat  production.  Using  more,  modem  methods 
Edsall  and  ]\reans,  and  Iliggins  and  Cleans  found  increases  varj'ing  from 
three  to  fourteen  per  cent. 

Means,  Aub  and  DuBois  observed  in  four  normal  subjects  receiving  8.6 
milligrams  per  kilo  of  caffein  alkaloid  an  increase  of  from  seven  to 
twenty-three  per  cent  in  the  basal  metabolism.  In  these  elaborate  in- 
vestigations the  independent  methods  of  direct  and  indirect  calorimetry 
gave  results  which  agreed  within  one  per  cent. 

F.  G.  Benedict  and  Carpenter (6)  found  that  approximately  three  hun- 
dred and  twenty-five  grams  of  hot  coffee  will  increase  the  basal  metabolism 
eight  to  nine  per  cent. 

Nitrogen  Metabolism. — C.  Voit  concluded  from  his  experiments  that 
caffein  did  not  alter  the  nitrogen  balance,  although  there  was  possibly 
some  increase  in  the  urea  excretion.  Ribaut  found  the  nitrogen  excre- 
tion in  man  but  little  changed,  while  it  was  moderatcl}^  increased  in  dogs. 
In  three  of  their  subjects  Means,  Aub  and  DuBois  found  an  increase  in 
nitrogen  elimination  varying  from  six  to  thirty-seven  per  cent.  This  was 
attributed  to  the  diuresis. 

Farr  and  Welker  state  that  theocin  decreases  the  nitrogen  excretion" 
in  both  health  and  renal  disease. 

Creatin  and  creatinin  eliminatioji  were  found  but  slightly  altered  by 
Salant  and  Rieger. 

Purin  Metabolism. — Mendel  and  Wardell  have  shown  that  the  addi- 
tion of  strong  coffee  infusion  to  a  purin-free  diet  causes  a  marked  increase 
in  the  excretion  of  uric  acid.  This  increase  was  not  obtained  from  de- 
caffeinated coffee.     The  increase  was  fcmnd  equal  to  the  quantity  of  uric 


180  HENRY  G.  BARBOUR 

acid  which  would  be  obtained  by  the  demethylation  and  subsequent  oxida- 
tion of  from  ten  to  fifteen  per  cent  of  the  ingested  caffein. 

Astolfani  maintains  that  catfein  increases  hippuric  acid  synthesis. 

Carbohydrate  Metabolism. — There  is  commonly  a  slight  glycosuria 
(discovered  by  Jacobj)  during  caffein  and  theobromiu  diuresis.  It  de- 
pends on  the  pi-esence  of  liver  glycogen  according  to  Richter(6),  occurring 
only  when  there  is  considerable  hyperglycemia  (Hirsch).  It  is  usually 
prevented  by  section  of  the  splanchnic  nerves,  as  shown  by  Pollak,  and 
by  suprarenal  excision  (A.  Mayer).  Theobromiu  glycosuria  is  said  by 
Miculicich  to  be  inhibited  by  ergotoxin. 

Mineral  Metabolism. — The  pur  ins  may  increase  the  salt  excretion 
even  when  no  diuresis  is  produced,  e.  g.,  in  diabetes  (E.  Meyer).  Ac- 
cording to  Saccone,  on  the  other  hand,  theobromiu  and  caffein  may 
diminish  the  chlorid  excretion  independently  of  the  diuretic  effect,  in 
rabbits  Bock  found  that  theocin  increased  both  potassium  and  sodium 
output,  but  not  parallel  with  the  diuresis.  Sollmann  found  that  the 
chlorid-retaining  mechanism  which  becomes  broken  down  in  rabbits  re- 
mains unimpaired  in  dogs  and  man. 

Alkalinity. — Higgins  and  Means  found  that  caffein  diminishes  the 
alveolar  carbon  dioxid  in  man. 

Growth. — Nice  finds  that  caffein-fed  mice  exhibit  subnormal  activity. 
Caffein  increases  their  fecundity,  but  the  viability  of  the  young  is  re- 
duced. The  growth  of  the  young  is  only  inhibited  if  they  themselves  are 
fed  caffein. 

Catalase. — Burge  states  that  blood  catalase  is  increased  by  caffein 
and  theobromiu.  Blood  concentration  was  apparently  not  allowed  for. 
(Stehle(6)). 

Guanidin  Bases. — W'atanabe(c)  finds  that  the  metabolic  effects  in- 
duced by  guanidin  hydrochlorid  resemble  those  of  tetania  parathyi-eopriva. 
For  example,  besides  the  tetany  there  are  an  excess  ammonia  excretion,  a 
low  content  of  calcium  associated  w^ith  high  phosphates  and  a  hypoglyce- 
mia. Calcium  lactate  injection,  however,  fails  either  to  restore  the  blood 
sugar  content  or  abolish  the  tetany. 


IX.    Endocrin  Dru^s 

Epinephrin. — Total  Metabolism. — Hari  observed  a  diminution  in  the 
total  metabolism  when  epinephrin  was  injected  into  curarized  dogs,  either 
intravenously  or  intraperitoneally. 

Later  investigators,  however,  find  that  the  characteristic  action  is  to 
increase  the  total  oxidations  in  the  body;  for  example,  Tompkins,  Sturgis, 
and  Wearn  have  observed  that  the  basal  metabolism  is  increased  after 
epinephrin  not  only  in  normal  individuals,  but  in  hyperthyroidism  and 


EFFECTS  OF  CERTAm  DRUGS  AND  POISOXS       781 

in  soldiers  with  ^^irritable  heart."  The  metabolic  increase  runs  parallel 
to  the  circulatory  changes.  Sandiford  finds  in  man  that  0.5  cc.  per 
kilo  of  1-1000  epinephrin  injected  subcutaneously  invariably  causes  an 
increase  in  the  metabolic  rate.  She  attributes  the  increase  in  heat  pn>- 
duction  to  an  excess  of  carbohydrate  in  the  circulation  with  possibly  a 
direct  stimulation  of  the  cells  as  well.  (In  addition  acid  metabolites  from 
circulatory  stimulation  are  presumably  involved,  as  is  the  case  with  the 
increase  in  oxidations  produced  by  tyramin.) 

Evans  and  Ogawa  found  the  total  gas  exchange  of  the  heart  notably 
augmented. 

Catalase. — Burge(5)  states  that  the  injection  of  epinephrin  stimulates 
the  catalase  output  of  the  liver.  Stehle  believes  that  Burgees  results  here 
and  elsewhere  are  merely  an  expression  of  the  red  blood  cell  count ;  "high 
catalase''  would  then  be  equivalent  as  a  rule  to  blood  concentration,  *Tow 
catalase''  to  dilution. 

Body  Temperature, — It  has  long  been  known  that  large  doses  of 
epinephrin  cause  collapse  with  a  fall  in  body  temperature.  Freund  ob- 
served, however,  an  increased  temperature  in  rabbits  on  a  dry  diet  with 
little  change  in  temperature  on  a  green  diet.  His  correlation  of  epinephrin 
fever  to  that  produced  by  sugar  or  salt  has  been  mentioned. 

Hirsch  found  a  decrease  of  temperature  after  epinephrin,  ascribing 
it  to  lowered  heat  production.  Kondo  in  rabbits  found  no  effect  with 
small  doses,  but  depression  of  temperature  when  more  epinephrin  was 
given;  on  the  other  hand,  after  thyroid  preparations  or  peptone,  and 
sometimes  after  atropin,  epinephrin  raised  the  temperature.  Intracere- 
bral injections  in  his  hands  gave  a  marked  increase  in  temperature  with 
small  or  large  doses.  This  effect  was  somewhat  antagonized  by  antipryin 
or  by  thyroidectomy.  Barbour  and  Wing,  however,  reduced  the  tempera- 
ture by  intracerebral  injections  of  epinephrin. 

Hultgreen  and  Andersson  first  showed  that  adrenalectomy  reduced  the 
temperature.  Freund  and  Marchand  found  that  removal  of  both  adrenals 
results  in  gradual  diminution  of  body  temperature  and  that  the  blood 
sugar  at  the  same  time  may  fall  as  low  as  .01  per  cent. 

Water  Metabolism. — While  some  of  the  earlier  investigators  main- 
tained that  epinephrin  causes  diuresis,  it  is  now  generally  believed  to 
exert,  temporarily  at  least,  an  o])posIte  effect.  Gunning,  for  instance,  finds 
that  intravenously  given  in  all  effective  doses  epinephrin  lowers  the  urine 
flow  both  in  anesthetized  and  unanesthetized  dogs.  The  effect  is  probably 
associated  with  renal  vasoconstriction. 

Lamson  and  Keith  have  shown  that  epinephrin  increases  the  red  blood 
cell  count,  which  phenomenon  is  associated,  in  part  at  least,  with  dimimi- 
tinn  of  the  blood  volume.  The  water  passes  into  the  lymphatic  system, 
particidarly  of  the  liver.    In  some  species  these  effects  fail  to  appear. 

Carbohydrate  Metabolism. — Epinephrin  glycosuria  has  received  much 


782  .     HENRY  G.  BARBOUR 

attention  since  its  discovery  by  Blum.  Hyperglycemia  was  observed  by 
Zuelzer,  Vosburgh  and  Richards  and  others.  Doyon,  Morel  and  Kareff 
showed  that  glycogen  is  simultaneously  lost  from  the  liver.  IwanofT  dem- 
onstrated that  epinephrin  perfused  through  surviving  livers  stimulates 
sugar  foiTTiation,  thus  showing  that  the  point  of  action  is  peripheral.  The 
glycosuria  is  not  asphyxial,  but  nervouc  stimulation  of  the  adrenals  may 
contribute  to  asphyxial  glycosuria.     (MacLeod  and  Pearce.) 

Pollak(a)  finds  that  epinephrin  glycosuria  fails  after  repeated  injec- 
tions, as  the  glycogen  becomes  exhausted.  Kuriyama  has  shown  that  epi- 
nephrin does  not  interfere  with  the  storage  of  glycogen  by  the  liver,  earlier 
investigators  having  neglected  the  factor  of  malnutrition  in  their  animals. 
Lusk  demonstrated  that  epinephrin  docs  not  influence  the  oxidation  of 
injected  glucose;  in  dogs  the  respiratory  quotient  rises  to  unity  cither 
with  or  without  the  drug.  Furthermore,  Fuchs  and  Roth  obtained  the 
following  respiratory  quotients  in  human  beings  with  subcutaneous  injec- 
tions of  epinephrin  alone: 

Before:  0.85-0.87;  during  effect,  0.91-0.96;  after,  0.84-0.86. 
Evans  and  Ogawa  from  experiments  upon  isolated  mammalian  hearts 
concluded  that  epinephrin  does  not  alter  the  power  of  the  tissues  to  use 
carbohydrate. 

Protein  Metabolism. — Lusk  has  shown  that  there  is  no  significant 
chr:nge  in  the  protein  metabolism  after  epinephrin.  The  urea  changes 
noted  are  apparently  due  to  renal  effects.  Addis,  Bamett,  and  Shevky 
observed  increases  in  urea  after  subcutaneous  injections  of  epinephrin ;  but 
large  amounts  of  the  drug  decreased  the  urea  excretion  of  dogs.  Uric  acid 
and  allantoin  excretion  are  stimulated  by  large  doses,  according  to  Falta. 
Mineral  Metabolism. — Bulcke  and  Weiss  described  an  inhibition  of 
sodium  chlorid  excretion  under  epinephrin.  Schittenhelm  and  Schlccht 
found  that  in  "war  edema"  epinephrin  (which  apparently  failed  to  raise 
the  blood  pressure  under  the  conditions)  had  a  tendency  to  lower  the 
excretion  of  water  and  of  chlorids. 

Growth. — Chambers  observed  that  suprarenal  extract  increases  the 
rate  of  division  in  paramecia. 

Epinephrinemia  from  Drugs. — Stewart  and  Rogo-ff(fO  have  recently 
described  an  increased  output  of  epinephrin  from  the  adrenal  glands  under 
the  influence  of  a  variety  of  drugs.  These  results  must  often  be  taken 
into  account  in  the  interpretation  of  the  action  of  such  substances. 

Thjnroid  Gland  Substance. — To  combat  the  effects  of  thyroid  defi- 
ciency the  administration  of  thyroid  gland  substance  offers  one  of  the 
most  striking  achievements  of  modern  therapeutics.  The  first  patient 
thus  treated  has  just  died  at  the  age  of  seventy-one  after  enjoying  twenty- 
eight  years  under  continuous  treatment  by  Murray.  The  isolation  of 
thyroxin  by  Kendall  has  made  available  a  crystalline  substance  the  chemi- 
cal structure  of  which  is  under  investigation. 


EFFECTS  OF  CERTAIN  DRUGS  AISTD.  POISONS        783 

Total  Metabolism. — Recent  investigation  by  DiiBois,  by  Means  and 
Aub  and  others  have  shown  that  the  basal  metabolism  is  a  most  im- 
portant feature  of  Basedow's  disease.  It  was  first  emphasized  by  Magnus- 
Levy.  DuBois  showed  that  heat  production  is  fifty  per  cent  above  the 
normal  in  severe  and  seventy-five  per  cent  in  very  severe  cases.  This  test 
is  proving  of  value  in  indicating  the  proper  treatment. 

In  eight  cretins  Snell,  Ford  and  Rowntree  have  foimd  that  the  basal 
metabolism  varied  between  — 7  and  — 25.    By  administering  four  to  five 


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Fig.  5.    Effect  of  thyroxin  in  cretinism.     (A.  M.  Snell,  F.  Ford,  &  L.  G.  Rowntree, 
J.  Am.  M.  Assn.,  1920,  LXXV.) 


milligrams  of  thyroxin  every  few  days  these  investigators  have  been  able 
to  keep  the  metabolism  close  to  the  normal  range.     (See  Fig.  5.) 

Protein  Metaholism, — Thyroid  administration  increases  the  excretion 
of  nitrogen  as  shown  by  Rohde,  Stockholm  and  others.  The  appetite  is 
usually  improved,  but  there  is  rapid  loss  of  weight  (Leichtenstern).  The 
first  effect  is  on  fat,  the  proteins  being  drawn  upon  when  the  fat  is  re- 
duced to  a  certain  minimum.  On  a  meat-free  diet,  according  to  Krausc 
and  Cramer,  the  nitrogen  increase  concerns  especially  the  urea,  ammonia 
and  creatin,  the  uric  acid  and  creatinin  being  very  little  changed.  Kojima 
finds  that  thyroidectomized  rats  excrete  less  nitrogen  and  calcium  than 
normally.  Curiously  thyroid  feeding  in  such  animals  appears  to  reduce 
nitrogen  and  gaseous  metabolism  as  well  as  body  weight. 

Studzinsky  and  Kaminsky  found  that  thyroid  increases  the  urate 
excretion  in  hypothyroidism  but  not  in  normal  subjects. 

Carboliydrate  Metaholism. — Thyroidectomized  dogs  do  not  utilize 
sugar  as  well  as  normal  animals,  according  to  Underbill  and  Saiki.    This 


784  HENRY  G.  BARBOUE 

was  not  found  in  rats  by  Cramer  and  McCall.     Watanabe  finds  the  blood 
sugar  and  diastase  unaltered. 

Denis,  Aub  and  Minot  have  shown  that  glucose  tolerance  may  be  used 
as  a  diagnostic  test  iu  thyroid  disease.  The  blood  sugar  is  taken  as  the 
criterion. 

Fat  Metabolism-. — Thyroid  substances  must  be  employed  only  with 
great  caution  if  at  all  to  reduce  obese  conditions  not  due  to  thyroid 
deficiency. 

Growth. — Gudernatsch  discovered  that  thyroid  feeding  retards  growth 
but  hastens  development  in  frog  larvae. 

Pituitary  Substance. — Total  Metabolism. — No  significant  effect  upon 
the  basal  metabolism,  according  to  Snell,  Ford  and  Rowntree,  is  exerted 
by  the  administration  of  pituitary  substance. 

Water  Metabolism. — While  some  observers  have  described  fleeting 
diuretic  effects  with  pituitary  extract  its  most  striking  influence  is  an- 
tagonistic to  the  flow  of  urine.  This  is  seen,  for  example,  in  rabbits, 
which  under  the  influence  of  the  drug  give  no  significant  diuretic  response 
to  administration  of  large  amounts  of  water,  (llotzfeldt.)  Rees  finds 
no  alteration  of  the  daily  urine  output  in  cats  under  pituitary  treatment. 
The  antidiuretic  effect  lasts  but  several  hours.  Diuresis  due  to  continuous 
intravenous  injection  of  saline  was  not  aff'ected.  Konschegg  and  Schuster 
find  that  one  to  two  c.c.  given  to  normal  individuals  diminish  both  the 
volume  and  the  solids  of  the  urine,  the  effect  lasting  sixteen  hours. 

In  diabetes  insipidus  injections  of  pituitary  reduce  materially  the 
volume  of  urine  and  the  thirst. 

Barker  and  ]\Iosentlial  found  that  subcutaneous  daily  injections  of  at 
least  two  one  c.c.  doses  of  pituitary  extract  (pars  posterior  and  pars 
intermedia)  were  effective  in  diabetes  insipidus  over  a  long  period.  The 
urine  was  diminished  in  amount,  its  specific  gi*avity  raised ;  the  per- 
centages of  sodium  chlorid  and  of  nitrogen  became  increased.  Tcthelin 
treatment  was  not  successful  nor  was  the  posterior  lobe  exti'act  of  any 
value  by  mouth. 

Kennaway  and  Mottram  also  found  subcutaneous  injections  of 
pituitary  extract  effective  in  diabetes  insipidus  while  orally  it  was  value- 
less. 

Clausen  found  in  a  boy  of  nine  and  one-half  years  the  usual  reduction 
in  fluid  excretion  by  the  kidney  after  pituitary  treatment  in  diabetes 
insipidus;  the  hourly  chlorid  excretion  was  much  reduced.  The  hourly 
excretion  of  urea,  creatinin,  uric  acid  and  titratable  acids  was,  on  the 
other  hand,  but  slightly  affected. 

According  to  Leschke  midbrain  and  not  pituitary  disturbances  are 
responsible  for  diabetes  inspidus. 

The  galactagogic  effect  of  pituitary  is  probably  not  secretor}'  but  due 
merely  to  contraction  of  the  smooth  muscle  of  the  glands.     (Gaines.) 


J':FFECTS  of  certain  drugs  and  poisons        785 

Carbohydrate  Metaholism.^FitwitHYj  substance  does  not  alter  tlie 
blood  content  in  diastase  or  sugar.     (Watanabe.) 

Anterior  Pituitary  Lobe. — Robertson  found  that  feeding  the  anterior 
lobe  before  adolescence  retards  growth.  Fn  adult  animals  gi-owth  how- 
ever niav  be  renewed.  In  mice  growth  retardation  is  followed  by  accelera- 
tion, esj)ecially  when  tethelin  is  used. 

Partial  removal  of  the  anterior  lobe  of  the  pituitary  leads  to  obesity 
and  other  nutritional  derangements.  Total  metabolism,  body  temperature 
and  growth  become  subnonnal,  as  shown  by  Crowe,  Cushing  and  Homans, 
and  F.  G.  Benedict  and  Homans. 

In  arromegahjj  which  is  associated  with  hyperactivity  of  the  anterior 
lobe,  Bergeim,  Stewart  and  Hawk  found  no  change  in  the  nitrogen  or 
sulphur  metabolism,  but  have  described  a  retention  of  calcium,  magnesium 
and  phcsphonis. 

Labbe  and  Langlois  abolished  glycosuria  in  a  diabetic  acromegalic  by 
a  four  months'  course  of  hypophyseal  therapy.  The  polyuria  was  not 
affected. 

Other  Gland  Products — Thymus  Gland. — Feeding  thymus  to  am- 
phibian larva?  retards  development  while  hastening  growth.  (Guder- 
natsch. )  According  to  Uhlenhuth(a)  this  gland  secretes  the  substance 
which  induces  the  low  calcium  metabolism  of  parathyroid  tetany.  Th\inus 
injections  produce  emaciation  and  malnutrition  in  guinea-pig^,  according 
to  Olkon. 

Parathyroid  Gland. — The  relation  to  tetany  has  been  referred  to  in 
connection  wdth  calcium  salts.  Excision  of  the  gland  lowers  carbohydrate 
tolerance,  as  shown  by  Underbill  and  Hilditch.  Koch  (6)  found  that 
removal  of  the  parathyroid  leads  to  the  appearance  of  toxic  bases  (guani- 
din,  histamin,  etc.)  in  the  urine. 

In  para  thy  reoprival  tetany  injections  of  horse  parathyroids  reduced 
the  creatinin  excretion  from  1342  to  612  milligrams  per  day.  In  rats 
Kojima  found  the  calcium  excretion  increased  after  parathyroidectomy. 

Spleen. — Asher  and  his  pupils  have  recently  observed  that  removal  of 
the  spleen  augments  the  respiratory  exchange  in  rats.  He  regards  this 
organ  as  antagonistic  to  the  thyroid.  While  thyroidless  rats  appear  to 
tolerate  low  pressure  (oxygen-lack)  better  than  normal,  the  tolerance  of 
spleenle^s  animals  is  weakened. 

Prostate  Gland. — Macht  showed  recently  that  prostate  feeding  stimu- 
lates both  growth  and  development  in  amphibian  larvae. 

Testis. — Castration  of  male  rats  results  in  diminished  oxidations. 
(Agnoletti,  Kojima.)     Jean  found  an  increased  phosphate  excretion. 

Pineal  Gland. — In  animals  administration  of  pineal  extracts  \&  said 
to  hasten  growth  and  development.     (McCord.) 


The  Intravenous  Injection  of  Fluids Arlie  v.  Bock 

Introduction — The  Fluids  of  the  Body — The  Uses  of  Intravenous  Infusions — 
Intravenous  Infusions  to  Increase  the  Volume  of  Blood  and  Tissue  Fluid 
— Intravenous  Infusions  to  Increase  the  Buffer  Action  of  the  Blood  in 
Acidosis — Intravenous  Infusions  to  Combat  Toxemia — ^Intravenous  In- 
fusions to  Assist  in  Providing  for  the  Calorific  Kequirements  of  the  Body 
— Solutions  Used  for  Intravenous  Infusions — "Saline^'  Solutions — Gum 
Acacia  or  Gum-saline  Solutions — Gelatin  Solutions — Sodium  Bicar- 
bonate Solutions — Glucose  Solutions — Other  Solutions — Keactions  Due 
to  Infusions — Preparation  of  Infusion  Solutions  and  Technic  of  Adminis- 
tration. 


The  Intravenous  Injection  of  Fluids 

ARLTE  V.  BOCK 

BOSTON 

Introduction 

The  rapid  adoption  of  intravenous  therapy  has  resulted  from  the  devel- 
opment of  the  technic  of  venous  puncture.  The  simplicity  of  intravenous 
injection  for  the  administration  of  di-ugs  and  fluids  has  secured  for  this 
method  a  wide  field  of  usefulness.  In  the  following  pag-es  the  use  of 
immune  sera  and  of  drugs  will  not  he  considered,  but  attention  will  be 
paid  rather  to  the  use  of  injections  or  infusions  of  various  solutions  into 
the  blood  stream  for  the  treatment  of  certain  clinical  conditions. 


The  Fluids  of  the  Body 

Before  entering  in  detail  upon  the  subject  of  infusions,  the  role 
of  fluids  in  the  organism  will  be  briefly  discussed.  It  is-  estimated 
that  the  fluid  content  of  the  body  is  equal  to  from  60  per  cent  to  70 
per  cent  of  the  body  weight.  This  fluid  consists  of  the  blood,  the 
lymph,  and  the  tissue  fluid,  all  of  which  may  be  regarded  as  mobile  fluids, 
and  the  fluid  within  the  cells  which,  in  contrast  to  the  rest,  is  com- 
paratively fixed.  The  importance  of  water  in  the  maintenance  of  life 
has  been  emphasized  by  Starling(a),  who  points  out  that  all  of  the 
energies  manifested  by  living  cells  are  derived  from  substances  in  solu- 
tion, and  that  all  metabolic  changes  in  the  body  relate  to  changes  in  and 
between  substances  in  solution.  The  organism  as  a  whole  strives  to  main- 
tain a  fairly  constant  quantity  of  total  fluid,  as  well  as  to  guard  carefully 
the  chemical  constitution  of  the  fluid  in  the  various  systems.  This  control, 
although  exceedingly  complex,  since  it  involves  physical  and  chemical 
phenomena  of  an  infinite  order,  and  the  cooperation  of  highly  organized 
absorbing  and  excreting  organs,  is  nevertheless  remarkably  efl^cient. 

Starling  has  also  discussed  the  importance  of  the  body  fluids  in 
general,  from  the  point  of  view  of  the  variety  of  their  adjustments  to 
local  conditions,  by  which  the  cells  of  the  body  are  enabled  to  can-y 
out  the  functions  for  which  they   have  been   differentiated.     He  has 

787 


T88  ARLIE  V.  BOCK 

suggested  that  the  ability  of  man  to  withstand  changes  in  his  environ-        | 
ment,  such  as  extremes  of  heat  and  cokl,  is  due  to  adjustments  made  by         |t 
the  body  fluid  to  meet  the  altered  conditions.     It  is  this  facility  to  main-         || 
•tain  optimum  conditions  for  celluhir  activity,  together  with  the  rc<>;ulation 
of  the  total  volume  of  body  fluids  that  enables  all  higher  forms  of  life  to 
exist  in  comfort  within  the  environment. 

The  cellular  fluid  has  been  spoken  of  as  fixed,  in  comparison  with  the 
blood,  for  example.  There  is,  however,  a  constant  interchange  between 
the  cells  and  the  tissue  fluid  which  is  of  necessity  a  local  interchange. 
With  the  details  of  cellular  activity  the  present  discussion  is  not 
concerned. 

With  regard  to  lymphatic  fluid,  it  need  only  be  said  that  it  repre- 
sents tissue  fluid  collected  into  organized  channels,  to  be  returned  to  the 
cardiovascular  system  in  order  to  complete  the  major  part  of  the  cir- 
culatory exchange  of  fluid  in  the  tissues  which  began  with  the  passage  of 
nutrient  fluid  from  the  capillary  walls. 

The  tissues  everywhere  throughout  the  body  are  bathed  in  fluid  that 
fills  the  tissue  spaces.  Since  the  metabolism  of  tissue  cells  is  carried  on 
through  the  activity  of  this  medium  the  tissue  fluid,  in  a  sense,  becomes 
the  most  important  of  the  body  fluids,  as  Starling  suggests.  This  fluid 
traverses  the  system  of  tissue  spaces  that  form  a  rather  complete  circula- 
tory system  which,  as  Meltzer(6)  has  shown,  may  be  in  part  independent  of 
the  cardiovascular  system.  When  the  normal  quantity  of  tissue  fluid  is 
gi'eatly  altered  through  defect  in  absorption,  or  in  elimination  of  fluid,  or 
by  direct  loss  of  fluid,  there  are  definite  symptoms  traceable  to  such  a 
disturbance.  The  importance  of  the  tissue  fluid  which  is  the  last  vehicle 
for  the  transport  of  nutrient  material  to  the  cell,  and  the  first  to  receive 
the  waste  products  of  metabolism^  cannot  be  too  much  emphasized. 

Of  all  the  body  fluids,  the  blood  occupies  the  first  place  in  the  minds 
of  clinicians,  and  yet  it  is  only  one  unit  of  the  various  fluid  phases  within 
the  body.  It  exerts,  however,  the  controlling  influence  in  the  maintenance 
of  function  in  the  normal  organism.  It  is  the  main  highway  in  the  body 
for  distribution  and  elimination.  Of  its  many  characteristics  we  are 
here  concerned  mainly  with  the  question  of  the  volume  of  the  blood.  This 
is  roughly  one-eighth  of  the  total  fluid  in  the  body,  and  has  been  found  in 
the  normal  individual  to  be  a  surprisingly  constant  quantity,  subject 
only  to  minor  variations.  Even  in  disease  the  variation  from  the  normal 
quantity  is  not  often  gi-eat.  When  the  body  is  confronted  with  a  loss  of 
fluid,  such  as  may  occur  in  severe  diarrhea,  fluid  is  withdrawn  fiom  the 
tissue  fluid  to  the  blood.  This  is  done  in  an  eftort  to  maintain  nutrition 
of  the  higher  centers  at  the  expense  of  the  tissues  in  g-eneral.  Thus, 
individual  cells  may  begin  to  suffer  from  failure  of  nutrition  long  before 
the  blood  itself  shows  much  evidence  of  depletion  of  fluid.  This  mech- 
anism needs  to  be  appreciated,  since  conditions  in  which  actual  concen- 


THE  IXTRA VENOUS  INJECTIOX  OF  FLUIDS         781) 

tration  of  blood  occurs  are  usually  extreme  clinical  states  which  may  have 
been  avoided  by  the  administration  of  sufficient  fluid. 

The  intake  of  fluids  is  achieved  normally  by  absorption  from  the 
intestinal  tract.  This  absorption  occurs  independent  of  the  body  needs, 
and  any  excess  fluid  is  readily  eliminated  by  the  kidneys.  If  the  rate  of 
fluid  intake  exceeds  tbf  rate  of  elimination  through  the  kidneys,  the 
tissues  become  a  reservoir  temporarily  for  such  excess  fluid  which  is  later 
reabsorbed  from  the  tis:^iie  spaces  into  the  blood  and  passed  out  througli 
the  kidneys.  The  ingestion  of  large  quantities  of  water,  therefore,  has 
almost  no  effect  in  altering  the  quantity  of  circulating  blood  in  the  normal 
individual,  as  shown  by  Haldane  and  Priestley.  In  pathological  con- 
ditions the  same  regulation  of  blood  volume  tends  to  occur. 

Fluid  loss  from  the  body  occurs  to  a  certain  extent  through  the  lungs 
and  skin.  The  bulk  of  fluid,  however,  is  eliminated  by  the  kidneys.  The 
kidneys  are  responsive  to  changes  in  the  blood,  and  their  activity  in  the 
secretion  of  urine  is  the  l)est  index  as  to  the  state  of  water  balance  in  the 
body.  Experience  has  shown  that  if  the  intake  of  food  and  fluids  is 
sufficient  to  produce  a  daily  urine  output  of  at  least  1,500  c.c.  (for  an 
adult),  the  total  volume  of  body  fluids  is  approximately  normal.  When 
the  daily  urine  output  falls  below  1,500  c.c.  it  usually  does  so  because 
the  intake  of  fluids  as  such,  together  with  the  water  contained  in  the 
food  ingested,  is  not  great  enough  for  the  needs  of  the  body.  Cases  of 
anuria  due  to  nephritis,  and  cases  of  cardiac  failure  of  the  congestion  type, 
for  example,  are  exceptions  to  this  rule  for  obvious  reasons.  The  prac- 
tical importance,  therefore,  of  measuring  the  amount  of  urine  voided  in 
twenty-four  hours  in  almost  all  cases  of  acute  illness  is  that  it  provides 
direct  evidence  as  to  wliether  or  not  the  body  is  being  furnished  with  an 
adequate  supply  of  fluid. 


The  Uses  of   Intravenous  Infusions 

Intravenous  injectir;ns  are  employed  usually  for  four  main  purposes: 
(1)  to  increase  the  volume  of  the  blood  and  tissue  fluids  of  the  body;  (2) 
to  increase  the  buffer  action  of  the  blood  in  acidosis;  (3)  to  combat 
toxemia  by  what  is  generally  regarded  as  a  washing  out  process;  (4)  to 
assist  in  providing  for  the  calorific  requirements  of  the  body. 

1.  Intravenous  Infusions  to  Increase  the  Volume  of  Blood  and  Tissue 
Fluid. — The  following  conditions  ]nay  deplete  the  store  of  fluids  in  tJie 
body:  (A)  fluid  loss  by  (1)  hemorrhage,  (2)  abnormal  sweating,  (3) 
severe  diarrhea,  and  (-Ir)  polyuria;  (B)  insufficient  fluid  intake  by  (1) 
starvation,  (2)  inanition,  (3)  vomiting,  (4)  coma,  and  (5)  delirium. 
The  chief  symptom'  manifested  as  a  result  of  dehydration  of  tissues  in 
these  conditions  is  thirst,  which  constitutes  nature's  indication  for  treat- 


700  AELIE  V.  BOCK 

ment.  An  attempt  to  restore  the  fluid  loss  in  all  of  these  conditions  may 
be  made  by  giving  fluid  by  one  or  another  of  the  following  methods:  by 
mouth  or  rectum,  permitting  absorption  from  the  alimentary  tract;  by 
subcutaneous  injections,  intraj>eritoncal  injections,  or  intravenous  in- 
fusions.    The  method  adopted  will  depend  upon  individual  indications. 

In  the  case  of  acute  hemorrhage,  dikition  of  the  blood  rapidly  occurs 
by  transfer  of  tissue  fluid  to  the  vascular  system,  and  the  original  volume 
of  the  blood  plasma  is  promptly  restored,  if  the  hemorrhage  is  not  too 
great,  and  if  the  supply  of  tissue  fluids  is  normal.  The  chief  danger  in 
acute  hemorrhage  is  due  to  the  rapidity  with  which  blood  is  lost,  rather 
than  the  amount  of  blood  released  from  the  circulation.  If  hemorrhage 
occurs  so  suddenly  that  compensatory  mechanisms  such  as  vasoconstriction 
and  tissue  fluid  dilution  cannot  maintain  the  blood  pressure  at  a  safe  level, 
transfusion  of  blood,  or  intravenous  infusion,  may  be  immediately  urgent. 
Complete  collapse  of  patients  after  hemorrhage  is  often  the  result  of  the 
concurrent  factor  of  shock,  by  which  the  volume  of  blood  tends  to  be  still 
further  diminished.  "When  shock  is  present  the  transfusion  of  blood,  or 
the  infusion  of  a  fluid  substitute  for  blood,  may  be  obligatory.  A  falling 
blood  pressure  is  a  positive  indication  for  such  treatment  in  order  to 
relieve  the  anoxemia,^  particularly  of  the  vital  centers.  A  transfusion 
of  blood,  or  an  infusion  under  such  circumstances,  by  increasing  the 
volume  of  fluid  in  the  vascular  bed,  increases  the  volume  output  of  the 
heart  per  systole,  and  thus  tends  to  restore  the  arterial  pressure  to  a 
normal  figiire.  If  a  state  of  shock  has  existed  for  several  hours  the 
transfusion  of  blood  should  ahvays  be  carried  out  in  preference  to  other 
intravenous  therapy.  In  cases  of  hemorrhage,  in  addition 'to  transfusion 
or  infusion,  an  abundant  fluid  intake  by  the  alimentary  tract. should  be 
maintained  in  order  to  satisfy  completely,  not  only  the  blood  plasma 
volume,  but  the  supply  of  tissue  fluid  as  well.  The  increased  efliciency 
of  the  circulation,  and  the  good  effect  upon  the  rate  of  blood  regenera- 
tion as  a  result  of  a  forced  fluid  intake  in  cases  of  hemorrhage  has  been 
recently  discussed  by  Bock  and  Robertson. 

The  question  of  the  use  of  infusion  for  the  treatment  of  acute  hemor- 
rhage and  shock  presents  a  problem  not  common  to  other  conditions  for 
which  infusions  may  be  indicated,  namely,  the  necessity  for  an  immediate 
increase  in  the  total  mass  of  circulating  blood.  Eeduction  in  blood  volume 
below"  a  certain  level  lesults  in  a  fall  of  blood  pressure,  accompanied  by 
the  attendant  diflriculties  which  this  failure  of  the  circulation  imposes  upon 
the  organism.  In  order  to  restore  the  efliciency  of  the  circulation,  the 
volume  of  the  blood  must  be  largely  restored  as  rapidly  as  possible  either 
by  transfusion  of  blood  or  by  the  intravenous  infusi(m  of  a  fluid  sub- 
stitute.     In   addition   to   the  transfusion   of  blood,   which    is   the  most 

*A  comprehensive  discussion  by  J.  S.  Ilaldane  of  the  cause  and  effect  of  anoxemia 
or  oxygen  wsmt  may  be  found  in  the  British  Med.  Jour.,  1919,  2,  pp.  65-71. 


THE  IiVTRAVEXOUS  INJECTIOX  OF  FLUIDS         TOi 

effective  measure,  many  solutions  liave  bec^n  used  to  accomplisli  this  end. 
In-the  case-of  a  fluid  substitute  for  blood,  tlie  solution,  according'  to  Bav- 
liss(r),  should  possess  the  same  viscosity  as  blood,  in  order  to  raise  the 
blood  pressure  to  a  noraial  level,  and  to»exert  the  same  osmotic  pressure 
as  the  colloids  of  the  blood  plasma,  which  will  prevent  the  loss  of  fluid 
from  the  circulation.  If  a  solution  possesses  these  properties  it  will  tend 
to  maintain  tlu^  blood  pressure  at  a  nomial  level  for  many  hours,  because 
the  Vidume  of  fluid  injected  remains  in  the  blood  vessels  for  an  indefinite 
time.  In  order  to  insure  this  result,  the  solution,  furthermore,  must  be 
colloidal  in  nature,  since  the  capilhiry  walls  are  relatively  impervious,  to 
colloids.  The  best  solution  of  this  nature  yet  pro|K)sed  is  one  containing- 
gum  acacia,  to  the  strength  of  G  per  cent  to  7  per  cent  in  0.0  per  cent  saline 
(gimi-saline),  as  described  by  Eaylissfr).  Iious  and  Wilson,  on  the  other 
hand,  state  that  a  fluid  substitute  for  blood  neetl  not  have  the  same  viscosity 
as.  whole  blood.  They  removed  as  much  as  75  j>er  cent  of  the  hemoglobin  of 
rabbits  by  bleeding  and  replaced  the  v(dume  by  rabbit^s  plasma.  Xo  great 
change  was  observed  in  the  behavior  of  these  animals.  However,  the  fact 
remains  that  no  artificial  sohition  of  low  viscosity  used  up  to  the  present 
time  has  proved  to  be  so'uscful  for  the  treatment  of  hemorrhage  and  shock 
as  the  solution  recommended  by  Bayliss. 

Of  other  colloidal  soluti(;ns,  gelatin  in  2..'>  per  cent  solution  as  recom- 
mended by  Hogan  in  1915  has  been  found  useful.  ^More  recently,  Erlanger 
and  Gasser  have  proposed  the  siuuiltaneous  use  of  hypertonic  gami-salt 
solution  and  hypertonic  glucose  solution.  They  have  nsed  an  18  per  cent 
solution  of  glucose  and  a  25  per  cent  solution  of  giim-saline  with  good 
results  for  the  treatment  of  hemorrhage  and  shock  in  dogs,  and  also  in  a 
small  series  of  hunum  beings.  The  beneficial  effects  thus  obtained  are 
explained  in  part  by  these  authors  as  due  to  the  internal  transfusion 
effected  by  the  hypertonic  sohition  of  glucose,  resulting  in  a  still  further 
expansion  of  the  Idood  volume.  This  secondary  increase  of  volume  is 
maintained  by  the  hydration»of  the  excessive  amount  of  gum  acacia  present 
in  the  circulation. 

The  failure  of  isotonic  salt  solution  to  maintain  blood  pressure  after 
hemorrhage  is  well  known.  Physiologists  have  long  ago  shown  that  the 
introduction  of  normal  saline  into  the  blood  stream  has  only  a  fleeting  effect 
upon  the  blood  pressure,  because  this  fluid  leaves  the  blood  stream  for  the 
tissues  and  urine  within  a  few  minutes  after  it  is  injected.  The  reason 
for  this  is  the  low  viscosity  of  the  scdution  as  compared  with  blood, 
together  with  the  fact  that  the  walls  of  the  capillaries  ai*e  especially 
permeable  to  all  erystall<;ids.  ^lodifications  of  normal  saline,  such  as 
Iiinger's  sohition,  liypert<rtiic.  and  hyj)otonic  salt  solutions,  share  the  same 
fate  as  iiornia!  saline. 

It  is  to  hv  remend)er(Ml  that  all  artificial  fluitls  are  substitutes  for 
blood,  and  that  in  the  treatment  of  hemorrhage,  transfusion  of  bloo<l  is 


Y92  AELIE  V.  BOCK 

the  most  efficient  therapy  in  all  severe  cases.     In  shock  without  hemor- 
rhage intravenous  injection  of  a  fluid  substitute  for  blood  is  indicated. 

In  conditions  other  than  hemorrhage  and  shock,  in  which  fluid  de- 
pletion occurs,  there  is  not  usually  the  urgent  necessity  for  an  inmiediate 
increase  of  the  volume  of  the  blood.  Dehydration  of  the  tissues  in  gen- 
eral, however,  is  always  a  serious  matter  and  demands  energetic  measures 
to  combat  the  deficit  of  fluid.  Such  fluid  loss  is  met  with  in  conditions 
mentioned  on  page  789.  To  increase  the  stoi^e  of  b<xly  fluids  in  such 
states  it  may  be  necessary  to  use  one  or  more  of  the  following  absorption 
routes:  from  the  gastro-intestinal  tract,  which  is  the  one  of  choice;  by 
subcutaneous  injection,  or  intravenous  infusion.  If  the  treatment  is 
necessary  because  of  vomiting,  for  example,  large  amounts  of  normal 
saline  may  be  absorbed  from  the  subpectoral  areas.  Injections  of  this 
type  may  be  repeated  as  frequently  as  absorption  occurs.  If  conditions 
prevent  the  use  of  the  alimentary  tract,  the  same  object  can  be  achieved 
with  more  comfort  to  the  patient  by  the  intravenous  injection  of  fluids 
such  as  normal  saline  or  glucose  solutions.  Intravenous  injection  of 
suitable  amounts  of  fluid  may  be  repeated  every  four  hours. 

2..  Intravenous  Infusions  to  Increase  the  Buffer  Action  of  the  Blood 
in  Acidosis.— It  is  not  intended  hero  to  discuss  the  question  of  acid 
intoxication  in  the  body.  However,  the  intravenous  use  of  solutions  of 
sodium  bicarbonate  in  combating  acidosis  requires  a  brief  discussion  of  the 
basis  for  the  use  of  alkali  in  this  condition.  IIenderson(&)  has  shown  the 
importance  of  the  phosphates  and  carbonates  in  maintaining  a  constant 
reaction  of  the  blood.  These  bases  exist  in  balanced  solution  in  the 
blood,  and  are  able  to  take  up  relatively  large  quantities  of  acid  or  alkali 
without  greatly  altering  its  normal  alkalinity.  This  mechanism,  together 
with  a  similar  action  of  the  proteins  of  the  blood,  constitutes  the  bufl^er 
action  of  the  blood.  For  practical  purposes  the  buffer  salts  may  be 
regarded  as  bicarbonates.  They  may  be  measured  in  terais  of  carbon 
dioxid,  with  which  they  con^bine,  by  the  method  of  Van  Slyke(&)  or  Y. 
Henderson  and  JMorris.  The  constancy  of  the  reaction  of  the  blood  is 
maintained  chiefly  by  the  elimination  of  carbon  dioxid  in  the  lungs, 
and  of  acid  radicals  by  the  kidneys.  In  each  cycle  of  blood  the  bases  thus 
tend  to  be  conserved  in  the  body.  In  pathological  conditions  extreme  de- 
pletion of  the  bases  may  occur  in  an  attempt  to  maintain  the  normal 
reaction  of  the  bloods  In  these  conditions  the  administration  of  alkali 
is  advocated  in  order  to  renew  the  lost  bases  from  the  blood  and  tissues, 
as  well  as  to  neutralize  non-volatile  acids  being  formed  in  the  body. 

Theoretically,  the  administration  of  an  alkali  such  as  sodium  bicar- 
bonate,  first  suggested  by  Stadlemann(a)  in  1883,  should  be  an  efficient 
means  of  restoring  the  alkali  reserve  of  the  lx)dy,  and  thus  become  an  aid 
in  the  treatment  of  the  acidosis  associated  with  diabetes.  The  earlier,  al- 
most universal,  use  of  bicarbonate  for  the  treatment  of  this  condition,  how- 


THE  INTRAVEXOUS  IX.TECTIOiT  OF  FLUIDS         793 

ever,  has  been  given  up,  not  only  because  it  does  not  control  the  acidosis  but 
also  because  it  produces  deleterious  effects.  Allen,  Stillman  and  Fitz 
found  that  high  dosage  of  bicarbonate  by  mouth  seemed  necessary  in  cer- 
tain case^,  but  that  its  intravenous  use  failed  to  save  any  patients  in  their 
series  of  cases.  They  emphasize  the  danger  of  the  abuse  of  sodium  bicar- 
lx)nate  in  the  treatment  of  diabetes,  and  in  general  deprecate  its  use  at 
all.  Joslin  has  also  discussed  the  harmfulness  of  sodium  bicarbonate  and 
does  not  use  it  in  the  treatment  of  diabetes. 

Beneficial  results  from  infusion  of  solutions  of  sodium  bicarbonate  in 
cases  of  acute  nephritis  complicating  cholera,  as  well  as  in  certain  types 
of  nephritis  from  other  causes  have  been  reported  by  Sellards.  The 
cases  of  chronic  nephritis  which  he  treated  required  the  intravenous  injec- 
tion of  as  much  as  150  grams  of  bicarbonate  to  produce  an  alkaline  reac- 
tion of  the  urine,  in  contrast  to  a  normal  tolerance  of  5-10  gi-ams  by 
mouth.  Howland  and  !Marriott(c)  also  have  found  sodium  bicarbonate  in- 
fusions useful  in  the  treatment  of  acidosis  incident  to  diarrheas  of  infancy 
and  childhood.  Its  use  is  advocated  by  Wright  and  Fleming  for  the 
treatment  of  gas  gangrene  in  which,  in  severe  cases,  there  is  a  gi'eat  re- 
duction of  the  alkali  resen^e.  Cannon,  Eraser  and  Hooper  used  bicar- 
bonate in  the  treatment  of  the  acidosis  accompanying  shock,  but  a  later 
paper  by  the  British  Medical  Research  Committee  asserts  that  the  restora- 
tion of  the  circulation  by  means  of  transfusion,  etc.,  renders  the  use  of 

alkali  unnecessary  in  this  condition. 

t/ 

Good  results  from  alkali  therapy  may  be  expected  usually  only  in  the 
treatment  of  cases  of  acute  acidosis,  the  development  of  which  has  been  so 
rapid  that  the  chemistry  of  the  body  has  not  had  time  to  compensate  for 
the  changed  conditions;  Examples  of  this  type  are  seen  in  methyl  alcohol 
poisoning  and  acute  uremia.  In  such  conditions,  in  addition  to  alkali 
therapy,  forced  elimination  is  also  essential. 

The  practice  of  administering  bicarbonate  as  routine  before  and  after 
surgical  procedures  has  no  justification  except  in  the  case  of  a  considerable 
deficit  of  alkali.  Caldwell  and  Cleveland  determined  the  change  in  the 
plasma  carbon  dioxid  before,  during  and  after  surgical  operations,  and 
concluded  that  the  diminution  in  the  alkaline  reserve  below  the  average 
nornnil  does  not  reach  the  point  at  which  the  earliest  clinical  symptoms 
are  observed  to  occur,  namely,  about  35  volumes  per  cent  of  carbon  dioxid. 
There  is  at  present  no  indication  for  the  use  of  bicarbonate  by  mouth, 
or  intravenously,  unless  an  alkaline  deficit  is  present  sufficiently  gi*eat  to 
produce  symptoms.  Solutions  of  bicarbonate  liave  no  more  efl*ect  in  main- 
taining blood  pressure  than  normal  saline,   according  to  Bayliss. 

If  treatment  with  sodium  bicarlwnate  is  instituted,  attention  should  be 
paid  to  the  reaction  of  the  urine.  When  this  reaction  becomes  alkaline, 
the  administration  of  the  alkali  should  be  stopped.  While  the  observ- 
ance of  this  rule  is  a  safe  one  for  the  majority  of  cases,  Palmer  and  Van 


704  ARLTE  V.  BOCK 

Slvko  liave  sliowii  that  in  pathological  conditions  there  is  rlanger  of  giving 
too  much  l>icarbonate  it"  the  achninistration  is  continu('(l  until  the  urine 
becomes  alkaline  in  reaction.  An  alkalosis  may  result  in  such  cases,  a 
condition  pr(.bably  not  more  desirable  than  the  previfaisly  existing  state 
of  acidosis.  For  example,  Wilson,  Stearns  and  Tluulow  have  shown 
tlie  existence  of  alkalosis  in  cases  of  tetany  following  parathyi-oidectomy. 
Tileston  has  produced  tetany  in  a  case  of  WeiTs  disea.-e  by  the  overad- 
ministration  intravenously  of  sodium  bicarbonate,  having  established 
thereby  an  alkalosis  of  moderate  degree.  The  onset  of  tetany  in  a  case 
of  bichlorid  {X)isoning  after  the  administration  intravenou^^ly  of  GO  gi-ams 
of  bicarbonate  has  been  reported  by  Ilarrop(a),  and  .\rarriott  and  Ilowland 
(see  Howland  and  Marriott  (?>))  have  frequently  observed  the  development 
of  symptoms  of  tetany  in  infants  during  the  course  of  bicarlx)nate  treat- 
ment. Palmer  and  Van  Slyke  suggest  that  the  administration  of  sodium 
bicarbonate  should  be  controlled  by  determinations  of  the  plasma  carbon 
dioxid.  The  alkali  should  not  be  pushed  beyond  a  level  of  about  70  vol- 
umes per  cent,  which  represents  the  level  of  plasma  carbon  dioxid  at  which 
normal  urine  becomes  alkaline  following  the  ingestion  of  bicarlwnate. 

3.  Intravenous  Inf2mons  to  Combat  Toxemia. — The  importance  of 
an  abundant  intake  of  fluids  in  the  treatment  of  acute  toxemia  is  beyond 
question.  The  fact,  however,  that  the  gastrointestinal  tract  is  the  natural 
route  for  the  absorption  of  fluid  is  too  often  overlooked  by  the  advocates 
of  intravenous  therapy.  ^Fany  intravenous  infusions  could  be  dispensed 
with  if  a  sufficient  supply  of  fluid  by  mouth  and  by  rectum  was  available. 
In  other  words,  the  failure  to  recognize  the  insufficiency  of  the  fluid 
supply,  as  w^ell  as  the  excessive  loss  of  fluid  that  may  occur  as  a  result  of 
sweating  in  a  given  case,  often  results  in  the  clinical  state  for  which  intra- 
venous infusions  become  necessary.  It  is  surprising  how  rapidly  and 
how  much  fluid  may  be  absorbed  from  the  alimentaiy  tract.  When  fluid 
depletion  prevails,  normal  saline,  isotonic  glucose  solution,  or  tap  water, 
in  amounts  cf  300  to  400  c.c.  may  be  given  by  rectum  every  hour  for  four 
or  Ave  doses,  and  may  be  repeated  every  three  hours  thereafter  if  neces- 
sary. It  should  be  recognized  that  many  of  the  conditions  requiring 
increased  fluids  are  ably  met  by  means  of  absorption  from  the  alimentary 
canal,  and  that  in  many  cases  in  which  intravenous  infusions  are  given, 
the  absorption  of  fluid  from  the  intestine  is  a  valuable  adjunct  in 
treatment. 

In  the  event  of  failure  to  maintain  a  sufficient  fluid  intake  by  other 
routes,  intravenous  infusions  in  toxemic  states  should  be  frequently  given. 
There  is  a  popular  belief  that  intravenous  injections  of  various  solutions 
are  capable  of  washing  out  toxins  from  the  blood  stream  and  indirectly 
from  the  tissues  as  well.  The  procedure  has  been  used  to  diminish  the 
toxemia  of  pneumonia,  typhoid  fever,  etc.  Enriquez  has  reported  good 
results  from  the  intravenous  use  of  hypertonic  glucose  solution  in   the 


THE  FXTRAVEXOUS  INJECTION  OF  FLUIDS         795 

treatment  of  a  i>i'(^at  variety  of  such  cciiditious.  There  is,  however,  no 
analytical  evidence  to  show  that  such  therapy  succeeds  in  removing  from 
the  body  substances  responsible  for  the  symptoms.  Even  if  dilution  of 
the  toxic  substances  does  occur,  which  is  doubtful,  it  does  not  follow  that 
their  removal  fr(  ni  the  body  is  a  necessars*  sequel.  All  of  the  symptoms 
of  toxemia  are  subject  to  spontaneous  changes  which  make  difficult  an 
attempt  to  ju<lge  the  value  of  any  sins^le  therapeutic  measure.  There  is 
no  reason  to  believe  that  intravenous  infusions  in  toxemic  conditions  have 
^•eater  value  than  an  abundance  of  fluid  absorbed  from  the  gastro- 
intestinal tract.  The  results  obtained  in  the  past  by  intravenous  therapy 
are  probably  due  to  the  greater  facility  with  which  the  functions  of  the 
body  are  carried  on  in  the  presence  of  an  adequate  supply  of  body  fluid. 

4.  Intravenous  Infusions  to  assist  in  providing  for  the  Calorific  Re- 
quirements of  the  Body. — The  use  of  glucose  solutions  for  intravenous 
therapy  has  been  fostered  because  of  the  availability  of  glucose  in  processes 
of  metabolism.  Unlike,  sodium  chlorid,  glucose  when  introiluced  into  the 
tissues  may  be  completely  burned,  and  has,  therefore,  none  of  the  toxic  ef- 
fects associated  with  sodium  chlorid  which  cannot  be  destroyed  in  the 
tissues.  The  fuel  value  of  glucose  makes  its  use  for  purposes  of  infusion 
desirable,  particularly  in  conditions  in  which  nutrition  for  various  reasons 
is  not  being  maintained.  Enriquez,  by  the  use  of  a  30  per  cent  sohition, 
has  introduced  intravenously  an  amount  of  glucose  equivalent  to  3,200 
calories  wdthin  twenty-four  hours.  Glucose  requires  simple  dehydration 
to  transform  it  to  glycogen,  and  it  is  a  physiologically  efficient  food  sub- 
stance. 

When  an  isotonic  solution  of  glucose,  5.52  per  cent,  is  injected  intra- 
venously, the  sugar  leaves  the  blood  stream  within  a  very  brief  period. 
If  a  hypertonic  solution  is  injected  there  is  a  tem]>orary  increase  in  the 
blood  volume  caused  by  the  withdrawal  of  fluid  from  the  tissues  that 
persists  until  balanced  osmotic  relations  are  again  established  between 
the  blood  and  tissues.  Usually  this  adjustment  happens  within  thirty 
minutes  after  the  injection,  but  it  may  require  as  long  as  two  hours,  as 
shown  by  von  Brasol,  Eiedl  and  Xraus,  Starling(a)  and  others. 
The  excess  sugar  is  usually  i-eadily  stored  in  the  tissues  as  Kleiner  found. 
The  amount  of  sugar  excreted  by  the  kidneys  is  variable.  Kleiner 
found  in  dogs  that  60  per  cent  of  the  injected  sugar  was  excreted  in  the 
urine,  but  the  degree  of  glycosuria  and  its  duration  depend  not  only  upon 
the  state  of  the  kidneys  and  the  rate  of  blood  flow,  but  upon  the  amount 
of  sugar  and  the  rate  at  which  it  is  injected  as  well.  After  intravenous 
injection  in  man,  at  a  tolerant  rate  of  300  c.c.  of  a  30  per  cent  solution, 
Enriquez  found  at  most  4-5  gi*ams  of  glucose  in  the  urine  during  the  first 
two  hours  after  the  injection  and  none  thereaftc]'.  Woodyatt,  Sansimi 
and  Wilder,  by  means  of  timed  injections,  have  determined  the  tol- 
erance in  man  for  sugar  as  0.85  gram  per  kilogram  per  Jiour.     For  a 


Y96  AKUE  V.  BOCK 

man  of  75  kilogi'ams  this  corresponds  to  63  grams  of  glucose  per  hour. 
No  sugar  appears  in  the  urine  and  no  diuresis  occurs  at  this,  or  subtolerant 
rates,  since  glucose  utilization  presumably  keeps  pacci  with  such  rates 
of  injection.  However,  if  the  rate  of  administration  is  increased  as  high 
as  5.4  grams  per  kilogram  per  hour,  glycosuria  with  an  active  diuresis 
occurs,  which  soon  leads  to  excessive  dehydration  of  the  body  unless  a 
large  amount  of  water  is  supplied. 

Essentially  the  same  phenomena  were  observed  in  dogs  by  Fisher  and 
Wishart  after  the  ingestion  of  glucose,  but  the  time  relations  necessarily 
extend  over  longer  periods  owing  to  the  longer  absorption  time.  Ililler 
and  Mosenthal,  however,  found  in  man  that  ingestion  of  100  grams  of 
glucose  did  not  produce  hydremia. 

The  routine  use  of  glucose  solutions,  instead  of  normal  saline,  is  now 
the  custom  in  certain  clinics.  There  is  much  to  be  said  in  favor  of  this 
change.  Yet  too  much  emphasis  has  been  placed  upon  the  food  value  of 
glucose  infusions.  An  intravenous  infusion  of  500  c.c.  of  a  10  per  cent 
solution  of  glucose  has  a  fuel  value  of  only  about  200  calorics.  If  such  an 
infusion  is  repeated  every  two  hours  in  twenty-four  the  total  calories 
amount  to  2,400.  If  solutions  of  greater  concentration  of  glucose  are 
used,  correspondingly  more  time  for  each  infusion  must  be  consumed  in 
injecting  the  fluid  if  diuresis  and  glycosuria  are  to  be  avoided.  As  a 
practical  measure,  therefore,  the  supply  of  the  total  calorific  needs  of  the 
body  by  means  of  intravenous  injections  of  glucose  is  limited  to  circum- 
stances of  an  exceptional  nature. 


Solutions  Used   for  Intravenous  Infusions 

The  use  of  normal  saline  for  intravenous  infusion  has  fonncd  the  basis 
for  the  development  of  other  solutions  for  purposes  not  sensed  by  saline. 
The  following  list  comprises  those  solutions  that  have  been  found  to  have 
the  greatest  range  of  usefulness  for  intravenous  injection:  (1)  ^'saline'' 
solutions;  (2)  gum  acacia  or  gum-saline  solutions;  (3)  gelatin  solutions; 
(4)  sodium  bicarbonate  solutions;  and  (5)  glucose  solutions. 

1.  "Saline''  Solutions. — A  solution  of  normal  saline  (0.85  per  cent 
sodium  chlorid)  was  first  used  for  intravenous  injection.  It  was  found 
by  Sherrington  and  Copeman  and  many  others,  to  leave  the  circula- 
tion within  a  few  minutes  after  injection.  This  is  due  to  the  rapid  diffu- 
sion of  both,  water  and  salt  until  the  differences  in  potential  between  blood 
and  tissues  are  again  adjusted.  When  used  intravenously  for  cases  of  low 
blood  pressure,  sodium  chlorid  has,  therefore,  only  a  transitory  effect  upon 
the  blood  pressure.  Fraser  and  Covvell  found  that  such  a  solution 
was  of  little  use  in  the  treatment  of  hemorrhage  and  shock  for  this  reason, 
and  their  experience  led  them  to  conclude  that  the  blood  soon  becomes 


THE  i:N'TRAVEiSrOUS  IXJECTIOX  OF  FLUIDS         70T 

more  concentrated  than  it  was  before  the  injection.  ISTevertheless,  normal 
saline  may  often  be  used  to  tide  a  patient  over  a  critical  cmergctiev  period, 
and  its  usefulness  in  building  up  a  tissue  fluid  reserve  is  established.  The 
work  of  Bogert,  Underbill  ^and  ^Iend(d  may  be  referred  to  in  this 
coniu^tion. 

Hypertonic  solutions  of  saline  tend  to  pnxluce  hydremia,  but  diffusion 
processes  quickly  reduce  the  level  of  salt  in  the  blood  to  the  normal,  and 
the  excess  of  water  is  likewise  returned  to  the  tissues,  a  small  amount 
being  eliminated  by  the  kidneys.  There  is  no  indication  for  the  intra- 
venous use  of  hypotonic  salt  solution. 

Sodium  chlorid  has  been  shown  by  Loeb(a),  Joseph  and  INFeltzer,  and 
others,  to  possess  toxic  properties,  and  clinical  experience  has  also  demon- 
strated this  fact.  According  to  Hort  and  Penfold,  undesirable  symptoms 
include  fever,  rigors,  subnormal  temperature,  diarrhea,  intestinal  hemor- 
rhages and  Cheyne-Stokes  respiration.  A.  S.  and  H.  G.  Griinbaum 
have  reported  several  deaths  due  to  edema  of  the  lungs  following  the 
injection  of  saline  solutions  in  postoperative  cases,  in  which  ether  was 
used  as  the  anesthetic,  and  in  which  nephritis  was  also  present.  On  the 
other  hand,  Joseph  and  Meltzer,  in  experimental  work  on  dogs,  rarely 
encountered  edema  of  the  lungs  which  could  be  attributed  to  sodium 
chlorid.  The  relation  of  salt  to  the  edema  associated  with  nephritis,  as 
suggested  by  Widal  and  Javal  and  others,  also  indicates  that  an  excess  of 
salt  may  be  a  source  of  injury  to  the  patient.  Cei-tain  histological  changes 
such  as  vacuolation  of  liver  cells,  alteration  of  red  corpuscles,  and  degen- 
erative changes  in  heart  muscle  and  capillary  walls  have  been  described 
as  due  to  salt.  To  the  former  idea  that  salt  possesses  only  osmotic  prop- 
erties must  therefore  be  added  that  of  its  chemical  activity. 

When  normal  saline  is  injected  attention  should  be  given  to  the 
amount  of  fluid  used.  This  should  be  ai^jn-oximately  1  per  cent  of  the 
body  weight,  if  rapidly  injected  into  the  circulation,  but  of  course  may 
far  exceed  this  amount  if  sufficient  time  is  allowed  for  the  infusion  period. 
There  is  almost  no  danger  from  embarrassment  of  the  circulation  unless 
very  large  amounts  of  fluid  are  injected  rapidly,  or  unless  an  injection 
is  undertaken  when  a  patient  is  suffei'iug  from  edema  of  the  lungs.  It 
is  to  be  remembered  that  the  capacity  of  the  vascular  system  is  normally 
nuich  greater  than  the  volume  of  the  blood.  The  ability  of  the  vascular 
bed  to  contract  and  expand  constitutes  a  valuable  compensatory  feature 
of  the  circulation,  as  Meltzer  has  suggested,  and  it  is  usually  adequate  to 
prevent  embarrassment  to  heart  action  from  intravenous  injection  of  fluid. 
However,  as  noted  above,  salt  infusions  immediately  after  anesthesia,  in 
cases  having  damaged  kidneys,  should  be  avoided,  as  well  as  giving  ex- 
cessive amounts  of  sodium  chlorid  as  shown  by  a  fatal  case  reported  by 
Brooks. 


708  AELIE  V.  BOCK 

2.  Gum  Acacia  or  Gum-Saline  Solutions. — The  use  of  giim  acacia  for 
infusion  purposes  is  a  development  of  the  demand  during  the  war  for  a 
fluid  substitute  for  blood  in  the  treatment  of  hemorrhage  and  shock.  Ac- 
cording to  Bayliss(c),  giim  acacia  is  a  polymerized  anhydrid  of  arabinose. 
Erlanger  and  Gasser  state  that  substances  similar  to  gum  acacia  are  widely 
distributed  in  the  plant  kingdom,  and  are  important  factors  in  the  nutri- 
tion of  herbivorous  animals.  When  ingested  by  man  these  substances  are 
readily  utilized  in  processes  of  metabolism.  Erlanger  and  Gasser 
state  that  about  one-half  of  the  amount  of  gum  acacia  injected  intra- 
venously is  utilized  by  the  organism  in  the  course  of  twelve  hours,  but  that 
some  of  it  remains  in  the  body  for  over  forty-eight.  Bayliss  obtained  tlie 
pentose  test  in  the  blood  twenty-four  hours  after  injection  of  gum-saline. 

Gum  acacia  may  be  obtained  either  in  the  powder  form  or  in  lumps 
(tears).  The  lump  form  is  usually  purer  than  the  powder.  For  the 
purpose  of  infusion,  Bayliss  found  that  a  solution  of  gum  between  6  per 
cent  and  7  per  cent  in  strength,  in  a  0.0  per  cent  solution  of  sodium 
chlorid,  has  the  same  viscosity  as  whole  blood,  and  the  same  osmotic 
pressure  as  the  colloids  of  the  plasma.  Such  a  solution  therefore  possesses 
properties  requisite  for  use  in  conditions  in  which  an  increase  in  blood 
volume  and  sustained  elevation  of  blood  pressure  are  desirable,  because 
it  remains  in  the  circulation  long  enough  for  the  circulatory  mechanism 
to  readjust  itself.  The  residts  obtained  by  the  extensive  use  of  gum-saline 
by  Drummond  and  Taylor (t?),  and  others,  justify  the  theoretical  and  ex- 
perimental considerations  put  foi-ward  by  Bayliss(c).  Certain  dangers  in 
connection  with  the  use  of  this  solution  will  be  referred  to  under  the  sul)- 
ject  of  reactions. 

The  quantity  of  gum-saline  which  Bayliss  recommended  for  injection 
is  750  c.c.  A  safe  rule  to  follow  for  this  solution,  as  with  others  for 
intravenous  use,  is  to  govern  the  amount  given  in  relation  to  the  body 
weight.  A  dose  equal  to  1  per  cent  of  the  body  weight,  to  be  repeated,  if 
necessary,  will  usually  meet  requirements.  If  a  greater  addition  to  the 
blood  volume  is  desirable,  more  than  this  may  be  given  with  safety.  Gum- 
saline  may  be  given  to  cases  in  shock  without  overburdening  the  heart. 
Its  use  should  be  limited  to  conditions  of  low  blood  pressure  as  a  result 
of  hemorrhage  and  shock.  It  is  not  a  substitute  for  red  corpuscles  and, 
therefore,  can  be  of  no  use  in  treatment  for  an  exsanguinating  hemorrhage, 
for  which  transfusion  of  blood  alone  is  indicated. 

The  use  of  the  combination  of  hypertonic  solutions  of  gum  acacia  and 
glucose,  as  recommended  by  Erlanger  and  Gasser,  has  not  yet  been  ex- 
tensively used  clinically.  When  slowly  injected,  the  great  viscosity  of  25 
per  cent  gum-saline  which  they  used,  apparently  does  not  contra-indicate 
its  use. 

3.  Gelatin  Solutions. — A  solution  of  gelatin,  2.5  per  cent,  in  noT-mal 
saline,  as  recommended  by  Ilogan  on  account  of  its  colloidal  properties, 


THE  INTRAVENOUS  INJECTION  OF  FLUIDS         TOD 

may  be  ii9ed  for  the  same  indications  as  gum  acacia.  Hogan  demon- 
strated by  blood  pressure  readings  and  rate  of  urinary  secretion  that  this 
'solution  remained  in  the  circulation  for  a  considerable  period  of  time. 
It  does  not,  however,  possess  the  same  viscosity  as  blood.  Furthermore, 
uidt^ss  special  care  is  taken,  heat  destroys  the  colloidal  properties  of 
gelatin,  upon  which  its  usefulness  in  this  connection  dejx?nds.  Steriliza- 
tion of  the  solution  also  is  difficult,  owing  to  the  frequent  presence  of 
spores  of  tetanus  bacilli.  In  spite  of  these  disadvantages,  gelatin  solutions 
may  be  of  gi-eat  use  if  they  are  made  with  the  precautions  suggested 
by  Ilogan. 

4.  Sodium  Bicarbonate  Solutions. — Sodium  bicarbonate  sohitions  in 
strengths  varying  from  2  per  cent  to  6  per  cent  are  customarily  made  up 
in  normal  saline.  When  such  a  solution  is  boiled  in  the  process  of  steril- 
ization, much  of  the  bicarbonate  is  converted  into  carbonate.  The  car- 
bonate is  caustic,  and  is  capable  of  producing  extensive  sloughing  of  sub- 
cutaneous tissues.  It  may,  however,  be  injected  safely  into  the  blood 
stream.  Carbonates,  as  such,  should  not  be  used  as  a  rule,  even  for  in- 
travenous injection,  because  of  the  possibility  of  infiltration  about  the 
vein  with  consequent  tissue  destruction.  After  •  boiling  a  solution  of 
sodium  bicarbonate,  carbon  dioxid  should  be  bubbled  through  the  solution 
to  reconvert  the  carbonate  to  bicarbonate.  Contrary  to  statements  in 
the  literature  (Stadleniann(a)),  not  only  is  the  alkalinity  of  a  bicarbonate 
solution  altered  by  boiling,  but  also  the  caustic  properties  of  carbonate  in 
such  solutions  cannot  be  neglected.  Joslin  is  authority  for  the  statement 
that  sterilization  of  bicarbonate  is  probably  not  necessary.  If  not  ster- 
ilized, it  should  be  handled  with  sterile  utensils  and  dissolved  in  sterile 
normal  saline.  Solutions  of  bicarbonate  or  carbonate  should  not  be  in- 
jected subcutaneously. 

Some  of  the  effects  following  the  injection  of  sodium  bicarbonate  are 
easily  measured.  The  carbon  dioxid  tension  of  the  alveolar  air  is  in- 
creased, the  carbon  dioxid  content  of  the  blood  rises,  and  urine  becomes 
alkaline  usually  when  the  tolerance  is  reached,  and  in  some  cases  of 
nephritis,  as  Sellards  has  shown,  diuresis  may  be  pronounced,  Allen, 
Stillman  and  Fitz  suggest  that  great  care  is  necessary  when  sodium 
bicarbonate  is  given  intravenously,  not  to  force  a  blood  having  low  alka- 
linity suddenly  to  one  having  a  noniial  or  above  normal  alkalinity.  A 
favorable  progress  is  indicated  if  the  level  of  bicarbonate  tends  gradually 
upward. 

5.  Glucose  Solutions. — Glucose  is  a  monosaccharid  which  shares  with 
fructose  the  characteristic  of  being  more  readily  assimilated  than  any 
other  sugar.  It  is  highly  soluble  in  water,  is  non-toxic,  and  may  safely 
bo  given  in  concentrations  up  to  30  per  cent  to  35  per  cent.  The  isotonic 
solution  is  one  of  r>.r)2  p{u-  cent  .  When  injected  into  the  circulation  in 
isotonic  or  hypertonic  solutions,  the  excess  of  sugar  is  i*apidly  eliminated 


800  AKLIE  V.  BOCK 

from  the  blood,  a  process  shown  by  many  obsei-vers  to  be  independent  of 
the  kidneys  and  other  abdominal  organs,  and  Kleiner  has  shown 
that.it  may  to  a  certain  extent  be  independent  of  vital  function.  How- 
ever, Bogeii;,  ITendel  and  Underbill,  and  Boycott  and  Douglas  have 
found  that  in  animals  suffering  from  acute  experimental  nephritis, 
the  injected  sugar  remains  for  a  longer  time  in  the  blrxxij  than  when  the 
kidneys  are  normal.  This  point  may  be  of  gi-eat  clinical  importance  when 
such  infusions  are  contemplated  for  cases  of  nephritis  in  man,  since  it  may 
be  associated  with  the  onset  of  diuresis  reported  by  several  observers  in 
cases  of  anuria. 

6.  Other  Solutions. — Certain  other  substances  less  widely  used  for 
infusion  purposes  may  be  mentioned.  Intravenous  infusions  containing 
calcium  and  barium  have  been  used  for  the  alleged  constricting  action  of 
these  substances  upon  arterioles.  Bayliss(c)  has  shown  that  this  action 
lasts  but  a  few  minutes  and  is,  therefore,  of  no  great  importance.  The 
use  of  calcium  for  the  treatment  of  tetany  has  been  suggested  by  McCal- 
lum  and  Voegtlin,  Wilson,  Stearns  and  Thurlow,  and  othei-s.  It  is 
also  useful  to  restore  to  normal  the  delayed  coagulation  time  of  the 
blood  in  cases  of  obstructive  jaundice,  as  shown  by  Lee  and  Vincent. 
Likewise,  the  intravenous  use  of  magnesium  sulphate  for  the  treatment  of 
tetanus,  and  for  purposes  of  anesthesia,  has  been  described  by  Meltzer(c) 
and  Auer  and  Meltzer. 


Reactions  Due  to  Infusions 

As  in  the  case  of  blood  transfusion,  the  intravenous  injection  of 
solutions  is  attended  with  a  certain  incidence  of  reactions.  In  the  pre- 
ceding discussion  many  of  these  have  already  been  mentioned.  The  more 
common  reactions  are  characterized  by  symptoms  similar  to  those  associ- 
ated 'with  protein  intoxication.  The  most  important  cause  of  these  reac- 
tions seems  related  to  the  water  used  for  the  solutions.  Chills  and  fever, 
resulting  from  intravenous  injections,  are  for  the  most  part  theoretically 
due  to  reaction  to  foreign  protein  contained  in  the  water.  In  certain 
instances,  reactions  after  infusion  may  be  accounted  for  by  the  fact  that 
the  solution  injected  was  in  effect  a  vaccine  and  the  resulting  chill  and 
fever  a  manifestation  of  a  non-specific  imnnine  reaction.  In  the  routine 
use  of  infusions  experience  has  shown  that  chills  and  fever  result  in  a 
small  percentage  of  all  cases  regardless  of  the  type  of  solutions  used.  It 
is  well  known,  however,  that  in  man  the  rapid  ingestion  of  very  large 
amounts  of  water  may  produce  the  same  type  of  reaction,  from  which  the 
disturbance  may  be  seen  to  be  a  very  fundamental  one  involving  the 
water  balance  of  the  body.  Hort  and  Penfold,  after  carefully  in- 
vestigating the  matter,  found  that  water  distilled  in  a  glass  retort  and  at 


THE  INTRA VET^OUS  INJECTION  OF  FLUIDS         801 

once  injected  did  not  produce  fever,  but  tended  to  cause  a  fall  in  tempera- 
ture. Samples  of  the  same  water,  collected  and  sterilized  with  all  the 
usual  precautions  and  allowed  to  stand,  produced  fever  upon  injection. 
The  cause  of  such  a  reaction  is  unexplained.  These  authors  recommend 
that  water  for  intravenous  use  should  he  recently  distilled  and  sterilized 
before  injection,  as  the  only  reliable  method  of  avoiding  fever.  All  water 
used  for  infusion  purposes  should  be  distilled  from  water  containing  aS 
little  organic  material  as  possible,  and  sterilized  at  once  after  distillation. 
It  should  then  be  preferably  stored  on  ice  if  not  imme<liately  used. 

The  bad  results  that  have  been  reported  following  the  use  of  gum- 
saline  can  generally  be  explained  by  investigation  of  the  individual  cases. 
They  have  been  found  to  be  due  to  the  use  of  impure  gum  acacia,  to  im- 
proper storage  of  gum-saline  after  it  has  been  made  up  for  use,  and,  as 
DeKruif  showed,  to  gross  infection  of  the  solution.  Gum  acacia  is 
protein-free  and  has  been  demonstrated  by  Bayliss  and  DeKruif  to  bo 
free  from  anaphylactic  phenomena.  Before  use  in  man,  the  toxicity  of 
the  stock  gum  acacia  should  be  tested  in  cats  or  guinea  pigs.  When  all 
precautions  have  been  observed  in  the  preparation  of  gum-saline,  chills 
have  occurred  in  5  per  cent  to  10  per  cent  of  cases  after  its  injection  into 
the  circulation.  The  failure  to  test  the  toxicity  of  the  stock  supply  of 
gum,  and  to  obsen^e  the  other  usual  precautions,  has  led  to  some  fatalities 
from  its  use. 

In  the  case  of  sodium  bicarbonate  injections,  reactions  may  consist  of 
convulsions  or  complete  collapse,  according  to  Joslin.  The  production 
of  tetany  after  bicarbonate  injections  has  already  been  discussed. 
Harrop(a)  has  called  attention  to  the  danger  of  the  intravenous  use  of 
bicarbonate  when  the  excretory  function  of  the  kidneys  is  impaired,  and 
especially  when  oliguria  or  anuria  is  present. 

Chills  and  fever  occurring  after  inti-avenous  injection  of  normal  saline 
are  usually  the  result  of  carelessness  in  preparation  of  the  solution.  The 
practice  of  employing  as  "normal  saline"  a  solution  of  boiled  water  plus 
an  indefinite  quantity  of  salt  is  not  to  be  advised. 


Preparation  of  Infusion  Solutions  and    Technic  of 

Administration 

If  the  general  principles  concerning  the  character  of  water,  purity  of 
substances  employed,  etc.,  already  discussed  are  followed,  no  special  points 
remain  to  be  mentioned  in  the  preparation  of  solutions  for  intravenous  use. 
The  exception  to  the  general  rule  concerns  the  preparation  of  gum-saline, 
which,  owing  to  difficulties  of  filtration  of  the  gimi,  requires  special  technic. 
A  full  description  of  the  method  of  preparation  of  gum-saline  is  given  by 
Telfer. 


802  ARLIE  V.  BOCE: 

Solutions  for  intravenous  use  should  always  be  made,  not  only  with 
care  as  to  the  character  of  water  used,  but  also  as  to  the  nature  and  con- 
centration of  substances  in  the  solutions.  Also,  great  care  must  be  taken 
in  filtration  to  remove  extraneous  or  undissolved  particles,  and  in  steriliza- 
tion. The  storage  of  all  solutions  on  ice  in  the  interim  before  using  them 
is  important.  Before  iujecticn  any  solution  should  be  warmed  to  body 
temperature.  In  the  case  of  fluids  having  no  gi-eater  viscosity  than  bh^od, 
the  rate  of  injection  is  not  significant  unless  excessive  amounts  of  fluid  ai*e 
given.  When  amounts  of  fluid  exceeding  1  per  cent  of  body  weight,  or 
when  solutions  of  high  viscosity  are  injecterl,  caution  as  to  the  rate  of 
injection  is  necessary.  Special  care  is  always  advisable  when  intravenous 
infusions  are  given  to  cases  of  nephritis. 

The  methods  for  administration  of  intravenous  fluid  are  numerous. 
The  simplest  of  these  depends  upon  gravity  to  force  fluid  into  the  vein. 
The  syringe  method,  with  a  three-way  stopcock,  so  widely  used  for  the 
administration  of  salvarsan,  is  one  of  the  most  satisfactory  and  efiicient 
methods.  The  apparatus  designed  by  Robertson  for  the  transfusion  of 
citrated  blood  is  also  adapted  for  use  with  other  solutions  than  blood.  In 
order  to  introduce  known  amounts  of  sugar  at  a  tolerant  rate,  the  method 
of  timed  intravenous  injections  by  means  of  a  pump,  as  devised  by 
Woody att,  Sansum  and  Wilder,  and  later  improved  by  W^oodyatt(&)  is  to 
be  recommended. 


t 


':#■ 


*: 


Artificial  Methods  of  Feeding  ..... Herbert  s.  Carter 

Gavage — ^Duodenal  Feeding — Bectal  Feeding — Formulae  for  Rectal  Feeding — 
Precautions  and  Technicin  Rectal  Feeding — Summary  of  Results  for 
Rectal  Feeding — Subcutaneous  Feeding — Intravenous  Feeding. 


Artificial  Methods  of  Feeding 


HERBEKT  S.  CARTER 

KEW    YORK 

There  are  times  when  the  need  for  some  method  of  nourishing  the 
body  by  other  than  the  normal  route  is  imperative,  and  has  led  investi- 
gators to  determine,  if  possible,  some  way  that  shall  be  reliable,  easy, 
and  capable  of  supplying  at  least  approximately  the  needs  of  the  living 
organism.  That  it  is  not  reasonable  to  expect  that  an  individual  could  bo 
permanently  nourished  in  any  artificial  way  (with  the  exception  of  gavage 
and  direct  feeding  in  gastrostomy)  goes  without  saying,  but  there  are  some 
occasions  in  which  an  adequate  method  is  indicated— as  every  clinician 
can  testify.  So  far,  the  results  of  experimentation  have  been  only  par- 
tially successful,  and  while  it  has  been  found  possible  to  supply  prac- 
tically about  one-third  the  caloric  needs  of  the  body,  principally  in  the 
form  of  carbohydrate,  the  problem  of  furnishing  the  necessary  protein 
seems  still  far  off. 

It  has  long  been  kno\vn  that  a  man  can  live  many  days  on  his  own 
protein  and  fat,  provided  he  is  given  water,  and  there  are  numerous  in- 
stances of  professional  starvers  who  have  gone  forty  to  fifty  days  without 
food,  and  have  come  back  promptly  to  normal  w'hcn  they  were  again  fed. 
In  this  way  we  have  gained  considerable  knowledge  of  the  metabolism  of 
starvation  over  extended  periods,  a  subject  which  forms  an  interesting 
chapter  in  biological  chemistry.  The  results  of  fasting  experiments  in 
man  and  animals,  Sherman  (a)  says,  "show  that  in  fasting  the  total  metab- 
olism continues  at  a  fairly  constant  rate  in  spite  of  the  fact  that  the 
energy  is  obtained  entirely  at  the  expense  of  the  body  material."  In  long 
fasts  there  has  been  found  a  somewhat  greater  decrease  in  heat  production, 
and  Sherman  says  other  factors  than  the  simple  spaiing  of  the  direct 
effect  of  food  come  into  play.  Then,  too,  each  type  of  food  exerts  a  more 
or  less  specific  influence  on  energy  metabolism,  less  sugar  being  required 
to  prevent  loss  of  body  substance  than  fat  or  protein — an  observation  of 
practical  importance  in  devising  artificial  methods  of  feeding. 

In  many  of  the  artificial  feeding  procedures  the  metabolism  of  the 
body,  as  shown  by  the  nitrogen  balance,  body  weight  and  findings  of  the 
respiratory  chamber,  differ  little  from  that  found  in  actual  starvation; 
and  although  the  patients  seem  to  be  deriving  constructive  benefit  from 

805 


806  HEKBEKT  S.  CARTER 

one  or  another  method,  accurate  data  of  scientific  investigation  shows  the 
bettered  condition  is  for  the  most  part  only  apparent. 
The  forms  of  artificial  feeding  to  be  discussed  are: 

1.  Gavage. 

2.  Duodenal  feeding. 

3.  Rectal  feeding. 

4.  .  Subcutaneous  feeding. 

5.  Intravenous  feeding. 

Gavage. — By  gavage  is  meant  the  introduction  of  food  either  through 
the  nose  or  mouth  by  means  of  a  flexible  rubber  tube.  This  is  an  exceed- 
ingly valuable  procedure  under  certain  conditions  and  gives  most  satis- 
factory results  because  the  food  reaches  the  gastrointestinal  canal  through, 
the  normal  route. 

Indications. — The  chief  indications  for  the  use  of  this  method  of 
feeding  are:  First,  in  unconscious  patients,  particularly  in  those  who 
have  lost  the  swallowing  reflex ;  second,  in  the  insane  who  refuse  nourish- 
ment ;  third,  in  conditions  of  ulceration  of  mouth  or  pharynx  with  painful 
deglutition;  fourth,  in  babies,  at  times,  who  have  had  cleft  palate  opera- 
tions; fifth,  in  anorexia  nervosa  where  it  is  necessary  to  feed  in  spite  of 
absolute  anorexia ;  sixth,  in  ^'hunger  strikes,'^  in  prisons ;  seventh,  in 
paralysis  of  deglutition. 

Metabolism. — The  metabolism  in  gavage  is  precisely  that  of  normal 
feeding,  except  that  the  preliminary  mouth  digestion  is  lacking.  On 
this  account,  foods  used  in  gavage  should  be  either  in  a  liquid  form 
or  so  finely  communicated  that  they  will  nm  through  the  tube  in  a 
liquid  medium.  The  food  requirements  should  be  calculated  for  each 
patient. 

As  the  psychic  stimulus  to  digestion,  so  far  as  taste  goes,  is  not  a 
factor  in  gavage,  it  is  only  necessary  to  combine  the  food  elements  in 
sufficient  amounts  and  proper  proportions  to  satisfy  the  nutritional  re- 
quirements cf  each  case,  calculating  the  caloric  value  of  the  foods  used 
on  the  basis  of  the  patient's  activities,  according  to  the  well  known  rulas. 
Thus  an  insane,  hyperactive  patient  will  take  many  more  calories  per  kg. 
than  one  lying  unconscious  in  bed,  therefore  it  is  imreasonable  to  ivy  to 
supply  food  formula)  ready  made. 

Foods  Used  hi  Gavage. — The  most  convenient  foods  used  in  gavage  are 
milk,  cream,  sugars,  butter,  oils,  meat  powders,  eggs,  cereals,^  cooked 
starch,  etc. 

Method  of  Performing  Gavage. — The  patient  should  be  placed  in  as 
comfortable  a  iK)sition  as  possible.  If  in  bed,  with  the  head  slightly 
raised;  if  out  of  bed  best  in  the  upright  position;  if  insane  or  resisting, 
tied  in  bed  or  to  a  chair,  llie  tube  should  be  lubricated  best  with  some. 
jion-greasy  emollient  and  slipped  down  the  throat  at  least  well  beyond 


ARTIFICIAL  METHODS  OF  FEEDIISTG  807 

the  epiglottis — although  not  necessarily  into  the  stomach.  An  ordinary 
stomach  tuhe  may  he  used  or  any  convenient  sized  catheter  to  which  is 
attached  a  glass  funnel.  If  the  tuhe  is  passed  through  the  nose,  a  small 
sized  catheter  must  he  used  and  the  end  passed  to  a  point  well  heyoud  the 
epiglottis.  Before  pouring  food  into  the  funnel,  one  should  listen  to  bo 
sure  that  the  patient  is  not  breathing  through  the  tube,  showing  it  to  be 
in  the  trachea — a  not  unusual  occurrence,  particularly  in  unconscious 
patients. 

The  number  of  feedings  given  during  the  day  will  depend  on  circum- 
stances; but  three  or  four  feedings  in  the  twenty-four  hours  should  be 
enough,  too  frequent  passage  of  the  tube  being  irritating  to  the  mucous 
membrane.  At  times  it  is  necessary  to  insert  a  mouth  gag  before  passing 
the  tube,  and  in  restless  patients  who  bite  the  tube  it  is  well  to  use  a  spool 
gag  with  a  good  flange,  passing  the  tube  through  the  hole. 

Duodenal  Feeding. — This  method  of  feeding  was  devised  by  Einhorn 
some  years  ago,  and  has  found  a  field  of  usefulness  in  certain  cases. 
It  has  been  recommended  especially  for  use  in  peptic  ulcer,  chronic  gastric 
dilatation  to  prevent  weight  on  the  gastric  walls,  allowing  them  gradually 
to  recover  their  tonus  and  contract,  provided,  of  course,  the  dilatation  is 
not  secondary  to  pyloric  obstruction;  in  cases  of  difficult  nutrition  on 
account  of  absolute  anorexia,  nervous  vomiting,  or  asthenia — also  in  severe 
hepatic  disease  when  it  is  supposed  to  reduce  the  congestion  of  that 
organ — although  this  is  a  questionable  result;  in  carcinoma  of  the  stomach 
where  the  ingestion  of  food  is  painful;  in  some,  forms  of  chronic 
indigestion. 

The  metabolism  of  duodenal  feeding  is,  of  course,  essentially  normal, 
and  follows  the  same  lines  as  in  gavage. 

Method  of  Introducing  the  Duodenal  Tuhe. — The  bulb  of  the  tube  is 
placed  in  the  patient's  mouth  and  a  swallow  or  two  of  water  is  given  to 
help  in  its  deglutition — care  being  taken  not  to  have  it  swallowed  too 
rapidly  as  it  might  curl  up  in  the  pharynx.  When  the  tube  is  in  the 
stomach  the  patient  is  placed  on  the  right  side,  and  the  tube  fed  in  its 
entire  length,  gradually  working  its  way  into  the  duodenum  by  grfivity. 
The  length  of  time  necessary  for  it  to  reach  the  duodenum  depends  on 
several  factors,  on  the  degree  of  gastric  acidity,  the  motor  power  of  the 
stomach  muscle  and  pylorospasm ;  entering  the  duodenum  most  rapidly  in 
hyiX)acidity  when  this  is  associated  with  good  muscle  tone  and  no  pyloric 
contraction  either  functional  or  organic.  In  favorable  circumstances,  it 
may  enter  the  duodenum  in  ten  to  twenty  minutes — possibly  two  or  three 
hours  for  normal  persons — up  to  twelve  or  thirty-six  hours  in  less  favor- 
able cases.  When  the  end  of  the  tube  has  passed  the  pylorus  it  is  diffi- 
cult to  obtain  any  fluid  and  what  few  drops  can  be  aspirated  with  a  syringe 
are  alkaline  and  usually  contain  bile.  If  the  tube  is  still  in  the  stomach 
the  fluid  will  probably  be  acid.     If  there  is  an  achylia  present  (and  this 


808  HERBEET  S.  CAHTER 

acid  test  of  no  use)  a  little  milk  can  be  given  by  mouth  or  some  colored 
fluid  and  aspirating  at  once;  if  the  tube  has  gone  beyond  the  pylorus  no 
colored  fluid  or  milk  will  be  obtained.  The  tube's  location  can  also  be 
determined,  if  necessary,  by  fluoroscopy  after  fllling  it  with  a  solution  of 
barium.  The  length  of  time  that  the  tube  is  left  in  situ  depends  on  the 
condition  for  which  it  is  used,  but  it  can  remain  for  from  twelve  to  fif- 
teen days  without  detriment,  keeping  the  mouth  clean,  by  washes  and 
brush. 

Duodenal  Feedings. — The  feedings  recommended  by  E inborn  consist 
of  milk  210-240  c.c.  (7  to  8  ounces),  one  egg,  a  tablespoonful  of  lactose 
(15  gm.  1/2  ounce).  If  the  bowels  are  made  too  loose,  reduce  the  lactose, 
and  when  it  is  necessary  to  increase  weight,  4  to  8  gin.  (1  to  2  drams)  of 
butter  may  be  added  to  each  of  the  eight  feedings  given  at  two-hour  inter- 
vals. For  those  patients  who  cannot  take  milk,  cereal  gruels  may  be  sub- 
stituted, made  thin  and  smooth  enough  to  pass  through  the  tube  readily. 
It  will  then  be  necessary  to  give  the  protein  of  the  diet  in  the  form  of 
meat  powders— egg  albumin — or  some  one  of  the  artificially  prepared 
protein  foods,  e.  g.,  plasmon,  70  per  cent  protein;  nutrose,  90  per  cent 
protein;  beef  meal,  77  per  cent  protein;  peptones,  e.  g.,  panopeptones, 
Witte's  peptones,  xVrmour's  or  Cranick's,  all  of  which  vary  from  1.5  to  10 
per  cent  nitrogen.  These  latter  peptones  may  easily  upset  the  digestion, 
causing  diarrhea,  and  are  therefore  suitable  only  for  short  periods.  Aleu- 
ronat,  a  vegetable  protein,  contains  80  to  90  per  cent  protein,  7  per  cent 
carbohydrate.  All  these  preparations  are  good  as  well  for  reenforcing 
the  milk  formulae. 

The  food  should  be  given  at  about  100°  F.,  slowly  either  by  the 
drop  method  or  by  a  syringe  directly  into  the  tube,  or  by  using  a  three- 
way  stopcock  drawing  the  food  up  fi-om  a  glass.  If  the  food  is  given 
rapidly,  it  distends  the  duodenum  and  causes  pain.  After  each  feeding 
saline  is  run  through  the  tube  to  cleanse  it,  followed  by  air.  This  is  very 
essential  or  the  tube  shortly  becomes  blocked  and  has  to  be  removed  for 
further  cleaning.  Einhornf?>)  reports  95  per  cent  of  ulcer  cases  healed 
at  once,  and  90  per  cent  after  two  years  in  132  cases,  and  other  favorable 
results. 

Buckstein(c)  reports  experiences  with  this  method  of  feeding,  using  an 
average  mixture  of  peptonized  milk  150  c.c.  (5  oz.),  glucose  70  gm.  (2% 
oz.),  2  eggs,  butter  40  gm.  (liy  oz.). 

Duodenal  Feeding — Routine  Einhoen  Feeding 

7:30  a.  m.     Oatmeal  gruel 180  c.c.   (6  oz,) 

One  ^^ 

Butter   15  gm.   (I/2  oz.) 

Lactose 15  gm.   (%  oz. ) 


^ 


AETIFICIAL  METHODS  OP  FEEDmG  809 

9 :30  a.  m.     Pea  soup 180  c.c.  (6  oz.) 

One  egg 

Butter 15  gm.   (%  oz.) 

Lactose    15  gm.  (%  oz.) 

11:30  a.  m.     Same  as  at  9:30  a,  m. 

1 :30  p.  m.     Bouillon 180  c.c.   (6  oz.) 

One  egg 

3:30  p.  m.     Oatmeal  giuel 180  c.c.  (6  oz.) 

Butter 15  gm.  (%  oz  ) 

One  egg 

Lactose 15  gm.  (l/^  oz.) 

5 :30  p.  m.     Same  as  at  9 :30  a.  m. 

9 :30  p.  m.     Bouillon 180  c.c  (6  oz.) 

One  egg 

Total  amount:  Calories. 

Oatmeal  gTuel 360  c.c.  (12  oz.)  1,476 

Eggs   8  800 

Pea  soup 720  c.c.  (24  oz.)  384 

Lactose 90  gm.  (  3  oz.)  369 

Bouillon   360  c.c.  (12  oz.)  39 

Butter 90  gm.  (  3  oz.)  715 


3,483 


This  diet  list  may,  of  course,  be  modified  downward  where  fewer 
calories  are  needed. 

Rectal  Pee/iing. — ^Rectal  feeding  has  been  employed  since  earliest 
times  in  one  form  or  another,  and,  later,  von  Leube  and  Biegel  kept 
patients  alive  for  considerable  periods  by  this  method,  in  one  case  almost 
a  year,  and  it  was  thought  it  was  possible  to  do  this  regularly  when  indi- 
cated. Modern  scientific  experimentation,  however,  has  shown  that  at 
best  it  is  a  form  of  partial  feeding  only,  and  results  in  subnutrition.  This 
form  of  artificial  feeding  is,  nevertheless,  the  most  efficient  that  we  pos- 
sess so  far,  and  has  a  field  of  usefulness  in  tiding  patients  over  periods 
when  mouth  feeding  is  impossible  or  inadvisable.  The  length  of  time 
it  should  be  employed  and  is  of  practical  use  is  from  one  to  eight  weeks, 
or  less ;  the  success  of  the  longer  periods  is  probably  due  to  causes  to  be 
dealt  with  later. 

Indicatimis. — The  indications  for  rectal  feeding  may  be  summed  up 
as  follows:  1.  In  temporary  obstruction  from  any  cause.  2.  Inability 
to  swallow,  as  in  stricture  of  the  esophagus.     3.  Gastric  diseases,  e.  g.^ 


810  HERBEKT  S.  CARTER 

ulcer,,  cancer,  pyloric  stenosis,  protracted  vomiting,  etc.     4.   Increasing 
emaciation. 

Physiology  of  Rectal  Feeding. — The  large  bowel  is  ordinarily  thought 
of  as  a  reservoir  whore  the  liquid  of  the  chyle,  including  the  salts,  is  ab- 
sorbed, where  the  bacteria  continue  to  break  down  cellulose,  and  the  feces 
are  compacted.  Little  if  any  enzyme  action  on  the  foods  is  carried  out 
except  in  the  ascending  colon,  where  the  small  intestine  digestion  is 
continued  for  a  short  time,  the  large  bowel  secreting  no  digestive  juices. 
The  substances  absorbed  are  those  which  travel  easiest  by  osmosis  and  in 
the  case  of  rectal  enemata  reverse  peristalsis  carries  any  food  solution  the 
wdiole  length  of  the  bowel  and  into  the  small  intestine  if  the  ileocecal 
valve  is  incompetent.  It  is  more  than  probable  in  the  cases  of  rectal 
feeding  that  have  been  kept  alive  for  months  the  success  of  the  procedure 
has  depended  on  this  factor  to  a  large  extent,  the  small  intestine  being 
responsible  for  the  greater  part  of  the  absorption. 

In  1902  Cannon  showed  by  bismuth  enemata  with  food  that  if  small 
in  amount  they  were  carried  only  to  the  cecum,  but  if  large  aud  thick, 
were  carried  into  the  small  intestine,  segmentation  taking  place  following 
antiperistalsis,  particularly  if  considerable  pressure  was  used  in  their 
introduction. 

Metabolism  of  Rectal  Alimentation. — As  rectal  feeding  has  been  sub- 
jected to  more  accurate  laboratory  methods,  the  clinical  obsei-vations  indi- 
cating almost  complete  nutrition  by  this  method,  have  of  necessity  been 
modified,  and  at  best  it  has  been  found  that  only  about  30  per  cent  of  the 
total  caloric  needs  of  the  body  can  be  supplied,  save  in  exceptional  cases. 

Of  the  different  food  elements  introduced  by  enema  it  is  necessary 
to  speak  more  in  detail  concerning  the  fate  of  protein,  carbohydrate,  fat, 
alcohol,  salts  and  water. 

Protein. — Almost  every  conceivable  form  of  protein  has  been  used  at 
one  time  or  another  in  rectal  feeding,  and  Bauer  and  Voit(c?)  in  1860 
proved  by  the  increase  in  urinary  nitrogen  that  protein,  when  properly 
prepared,  was  absorbed  to  some  extt^nt. 

Edsall  and  ]\Iiller(>)  found  in  two  patients  3.04  gm.  X  (10  gm.  P)  and 
3.8  gm.  X  (23.8  P)  absorbed;  Boyd  in  six  patients  receiving  an  avei-age 
of  44.0  gm.  protein  (7.1G  X)  there  was  absorbed  8.87  gui.  protein  (1.42 
X)  i.  e.,  20  per  cent  of  the  intake,  and  the  nitrogen  balance  was  in  every 
instance  a  negative  one.  Adler,  using  peptonized  milk  per  rectum,  gave 
3.0  gm.  X,  2  gm.  being  found  in  the  feces,  proving  that  approximately 
one-third  of  the  protein  was  absorbed. 

Short  and  By  waters  (/)  analyzed  reports  of  cases  fed  by  rectal  enema 
together  with  weight  charts  and  urinary  findings  and  concluded  that:  1. 
The  daily  output  of  urinary  nitrogen  from  patients  given  enemata  of 
peptonized  milk  and  eggs  (}K^ptonize<l  twenty  to  thirty  minutes)  showed 
that  almost  no  nitrogen  was  absorbed,  and  the  total  nitrogen  in  the  urine 


AETIFICIAL  METHODS  OF  FEEDIJSTG  811 

was  little,  if  any,  higher  than  that  sei'n  in  the  urine  of  fasting  men  or  of 
patients  who  received  only  saline  hy  rectum.  2.  ]\rocleni  physiological 
opinion  holds  that  proteins  are  ahsorhed  principally  as  aniino-acids,  and 
the  failure  of  the  rectum  to  absorb  ordinary  nutrient  enemata  is  largely 
diut  to  the  fact  that  peptones  are  usually  given  instead  of  amino-acids.  3. 
Chemically  prepared  amino-acids  or  milk  pancreatized  for  twenty-four 
hours,  so  that  the  amino-acids  are  separated,  allows  a  much  better  absorp- 
tion of  nitrogen  as  shown  by  the  high  nitrogen  output  in  the  uHne.  4.  The 
low  output  of  anunonia  nitrogen  shows  that  the  high  total  nitrogen  was 
not  due  to  the  absorption  of  putrefactiye  boilies  when  the  amino-acids 
were  used. 

Bauer  showed  that  peptones,  meat  juices  and  alkali  albuminates  were 
absorbed  by  rectum  but  only  when  salt  was  added,  also  that  propeptones, 
milk,  casein,  globulins  and  egg  albumin  salted  or  mixed  with  pepsin  were 
absorbed. 

From  the  foregoing,  it  is  seen  that  some  confusion  still  exists  as  to 
just  how  well  the  various  forms  of  protein  are  absorbed,  but  in  general  it 
may  be  said  that  "the  nearer  the  protein  molecule  approaches  its  ultimate 
fate  in  normal  digestion,  i.  e.,  as  amino-acids,  the  better  is  its  absorption." 
So  we  find  peptone  better  absorbed  than  albumin,  amino-acids  than  pep- 
tone, the  best  rate  of  absorption  being  seen  when  salt  is  added  to  the  enema. 
Amino-acids  may  be  most  conveniently  produced  by  the  pancreatization 
of  milk  for  24  houi*s,  in  which  condition  a  fair  amount  is  absorbed  but  not 
enough  to  prevent  a  constant  negative  nitrogen  balance.  There  are  also 
amino-acids  produced  chemically  from  beef,  but  they  are  not  so  well  borne, 
causing  rectal  irritation. 

Fats. — The  role  of  fats  in  rectal  feeding  is  a  very  minor  one,  and 
authorities  differ  again  as  to  this.  Friedenwald  and  Riirah  believe  that 
fat  in  fine  emulsion,  as  in  egg  yoke,  is  fairly  well  absorbed.  Short  and 
Bywaters  conclude  that  very  little,  if  any,  fat  is  absorbed,  which  agrees 
with  Brown's ((7)  observation  that  fats  given  by  mouth  increase  fats  in  the 
urine,  while  if  given  by  rectum  they  do  not.  There  is  no  objection  to 
using  a  finely  emulsified  fat  in  the  nutrient  enema,  but  there  is  little 
object  in  doing  so,  as  dextrose  is  well  absorbed  and  takes  the  place  of 
fats  in  sparing  protein. 

Carbohydrates. — These,  so  to  speak,  form  the  sheet  anchor  in  rectal 
feeding  and  experimental  evidence  is  definite  that  they  are  absorbed  fairly 
readily  when  offered  in  proper  form  and  concentration.  This  has  been 
proven,  as  in  giving  dextrose  the  respiratory  quotient  was  raised  and 
acidosis  diminished.  Even  raw  starch  has  been  used  and  not  found  in  the 
feces,  but  dextrinized  or  malted  starch  is  less  irritating  than  the  sugars, 
according  to  some  authorities,  and  may  be  used  in  their  stead.  Lactose 
is  poorly  absorbed,  as  sho^vTi  by  the  rapid  rise  of  ammonia  nitrogen  in 
the  urine  when  this  was  substituted  for  dextrose,  although  it  is  of  some 


812 


HERBERT  S.  CARTER 


use  in  milk  eneraata  by  its  action  in  reducing  feimentation.  The  mono- 
saccharids  are  all  well  absorbed  by  the  colon  in  considerable  quantities, 
and  of  them  dextrose  is  the  best  for  general  use.  Boyd  and  Robertson 
found  that  9/10  of  a  10  to  20  per  cent  solution  of  dextrose  was  absorbed 
up  to  40-50  gm.,  but  decided  that  a  total  of  30  gm.  was  less  apt  to  irri- 
tate the  colon.  Goodall  found  with  a  10  per  cent  solution  157  to  163  gm. 
was  absorbed  and  with  a  15  per  cent  solution  a  total  of  144  to  193  gm., 
not  more  than  0.5  to  1  per  cent  being  lost  by  bacterial  action.  Boyd  gave 
patients  an  average  of  55  gm.  dextrose  with  an  average  absorption  of  53 
gm.  Gompertz,  using  a  3  per  cent  solution  gave  60  gin.  dextrose  and 
found  52  gm.  absorbed  in  24  hours,  8  gm.  being  recovered  from  the  stools; 
using  a  10  per  cent  solution  200  gm.  were  given,  163  gm.  absorbed;  of  a 
15  per  cent  solution,  300  gm.  were  given,  144  gm.  absorbed  j  and  ali- 
mentary glycosuria  did  not  occur. 

For  the  most  part,  therefore,  it  has  been  found  that  solutions  of 
dextrose  up  to  5  per  cent  were  best  tolerated  and  can  be  used  over  con- 
siderable periods  without  irritation.  If  fennentation  is  a  factor  it  can 
be  controlled  by  adding  1  part  of  thymol  in  4,000  parts  of  the  solution. 

Salts  and  V/ater. — It  has  been  abundantly  proven  that  these  substances 
are  rapidly  absorbed  by  the  rectum  and  really  largely  accoimt  for  the 
success  of  rectal  feeding.  Gompertz (/O  did  experiments  with  both  potas- 
siinn  iodid  and  sodium  chlorid  and  found  both  well  absorbed.  Apparent 
gains  in  weight  are  no  doubt  due  in  some  instances,  as  Coleman  points  out, 
lo  water  retention. 

Formulae  for  Rectal  Feeding 

Among  the  most  easily  prepared  and  satisfactory  foods  for  rectal  feed- 
ing is  milk,  preferably  skimmed,  and  pancreatized  from  8  to  24  hours, 
after  which  enough  dextrose  is  added  to  make  a  5  to  10  per  cent  solution 
and  salt  5  gm.  to  the  liter.  The  milk  should  be  scalded  after  peptoniza- 
tion to  sterilize  it,  and  then  kept  on  ice.  Of  this  solution,  6-8  ounces  (180- 
240  c.c.)  may  be  given  by  rectum  every  four  to  six  or  eight  hours,  de- 
pending on  the  ability  of  the  patient  to  take  it.  This  may  also  be  given 
advantageously  by  the  Murphy  drip,  thirty-five  drops  to  the  minute,  three 
pints  or  more  being  given  this  way  in  twenty-four  hours. 

The  following  combination  of  dextrose,  alcohol  and  pancreatized 
milk  represents  a  fair  sample  formula,  although  in  some  patients  the 
alcohol  has  to  be  omitted  and  the  lower  percentage  of  dextrose  used» 


Dextrose   20  to  50  gm.- 

Alcohol 20  to  50  gm.- 

Pancreatized  milk  1,000  c.c.  - 

Salt 5  to     9  gm. 


■  80 

to 

205 

calories 

-140 

to 

350 

<i 

-650 

— 

650 

(( 

870  to  1,205 

tt 

ARTIFICIAL  METHODS  OF  FEEDIl!^G  813 

This  may  be  given  in  a  250  c.c.  dose  every  four. to  six  hours,  and  if  well 
tolerated  aids  materially  in  helping  the  patient  to  tide  over  an  emergency. 
By  omitting  the  milk,  the  solution  is  useful  in:  1.  Simple  exhaustion. 
2.  In  septic  conditions.  3.  As  an  antidote  to  chloroform;  in  phosphorus 
poisoning;  or  anything  that  causes  fatty  degeneration  of  the  liver,  e.  »•. 
toxemia  of  pregnancy.  4.  In  diabetic  acidosis  and  acetonemia.  5.  After 
abdominal  operations,  especially  in  undenaourished  or  desiccated!  in- 
dividuals. 

Instead  of  the  pancreatized  milk,  one  may  use  white  of  egg,  plasmon, 
casein,  somatose  or  aminoids,  etc.,  but  they  offer  no  particular  advantage 
over  milk  and  are  sometimes  irritating  to  the  rectum. 

Fitch (t)  recommends: 

Eggs,  two  whole 100  gm.  160  calories 

Dextrose,  l^/^  teaspoons  — .         6  gm.  30        " 

Pancreatized  milk,  10  oz 300  c.c.  210        " 

Salt,  y2  teaspoon 2  gm.  0        '^ 


400  calories 

Cornwall (;)  uses  two  formulae:  Xo.  1  contains  protein  20  gm.  in 
amino  acids,  glucose  90  gm.,  vitamins,  salt  and  water  1,500  cc,  and  TOO 
calories,  given  as  follows :  6  a.  m.,  glucose  30  gm.,  strained  juice  of  half  an 
orange,  soda  bicarbonate  2  gm.,  salt  2  gm.,  water  q.  s.  ad  300  c.c. ;  8  a.  m., 
150  e.c.  skimmed  milk  thoroughly  pancreatized ;  12,  same  as  at  8  a.  m. ; 
4  p.  m.,  same  as  at  6  a.  m. ;  6  p.  m,,  same  as  at  8  a.  m. ;  10  p.  m.,  same  as 
at  6  a.  m, ;  midnight,  .same  as  at  8  a.  m. 

Every  second  day,  at  4  a.  m.,  a  colon  irrigation  is  given  with  saline 
0.0  per  cent  solution,  and  the  glucose  enema  at  6  a.  m.  omitted.  The  per- 
centage of  glucose  may  be  reduced  or  increased  according  to  reaction.  A 
culture  of  acidophilic  bacteria  may  be  added. 

Formula  Xo.  2  supplies  700  calories,  salts,  vitamins  and  w^ater  1,800 
c.c,  but  no  protein,  as  follows :  6  a.  m.,  glucose  30  gm.,  strained  juice  of 
half  an  orange,  soda  bicarbonate  and  salt  of  each  2  gm.,  water '300  c.c. 
Repeat  this  at  10  a.  m.,  2,  6  and  10  p.  m.,  and  2  a.  ni. 

Precautions  and  Technic  in  Eectal  Feeding 

1.  The  rectum  must  he  kept  clean  by  a  saline  irrigalion  or 
enema,  once  a  day, 

2.  All  food  should  he  slerilized  he  fore  injecting, 

3.  If  the  rectum  hecomes  irritated,  give  a. rest  of  6  to  8  hours, 
or  use  only  saline  solution  for  a  time. 


814 


HERBERT  S.  CARTER 


4.  EnemnUi  should  he  given  ivifh  the  patietit  on  the  left  side,  or 
mth  the  foot  of  the  bed  raised  an  shorhblocks,  which  are  left  in  place 
for  an  hour  after  the  injection, 

5.  In  certain  cases  of  excesaire  peristalsis,  it  is  necessary  to  use 
o  to  10  drops  of  deodorized  tincture  of  opium  in  the  enemata. 

6.  Injections  should  he  given  slowly,  the  rectal  tube  IvJjncated 
and  passed  not  more  than  6  to  S  inches,  atul  the  reservoir  containing 
the  solution  should  not  he  more  than  18  inches  or  two  feet  ahove  the 
level  of  the  patient's  hack. 

7.  All  fluids  should  he  as  nearly  blood  temperature  as  possible 
on  enteHng  the  rectum.  This  can  he  facilitated  by  placing  an  electric 
light  bulb  in  the  reservoir  and  placing  a  hot  water  bag  over  the  feed 
tube  just  before  it  enters  the  rectum. 

If  the  Murpliy  drip  metlicxl  is  used,  Kemp  has  devised  a  special  heat 
retaining  hottle  to  use  and  has  worked  out  the  following  table  for  deter- 
mining* the  temperature: 


Table  of  Temperature  of 
Fluid  in  Bottle 


190*  F. 
160*  F. 
150*  F. 
110"  F. 


Length  of  Tube 


30  inches 


Number  of  Drops 
per  ^Unute 


60 

20  or  less 
40-50 
150-200 


Temp,  in  Rectum 


Ub"  F. 
100*  F. 
100*  F. 
105*-110°  F. 


Summary  of  Results  of  Rectal  Feeding. — 1.  Only  about  25  to  35 
per  cent  of  nourishment  required  to  maintain  nitrogenous  equilibrium 
and  weight  is  absorbed  per  rectum. 

2.  ^[etabolism  experiments  show  that  even  under  the  best  of  con- 
ditions this  method,  although  the  best  we  have,  results  in  subnutrition, 
and  is  really  semi-starvation. 

3.  As  a  practical  method,  it  should  not  be  relied  upon  to  bring  up  a 
patient's  condition  as,  e.  g.,  for  an  operation  except  where  there  has  been 
actual  starvation  as  in  a  marked  esophageal  or'  pyloric  stenosis.  It  is  a 
false  prop. 

4.  It  is  useful  in  tiding  over  short  periods  when  from  one  reason  or 
another  it  is  necessary  to  give  the  patient  water,  salts,  and  some  nourish- 
ment in  the  form  of  protein  and  carbohydrates. 

5.  Its  usefulness  is,  therefore,  limited,  more  so  than  many  people 
suppose. 

Subcutaneous  Feeding. — There  are  occasions  when  this  form  of  feed- 
ing would  be  of  great  value  even  f(U'  a  f(nv  days  if 'it  could  be  done  com- 
fortably and  otliciently,  dnit  as  yet  it  has  not  been  possible  to  accomplish 
this  with  any  degree  of  satisfaction.  Although  considerable  experimenta- 
tion has  been  done  towards  this  end,  at  present  the  rectal  method  is  much 


I 


AETIFICIAL  METHODS  OF  FEEDmo  815 

more  satisfactory  and  useful  and  the  future  will  have  to  detemiiiie  the 
possibilities  of  subcutaneous  feeding,  although  a  certain  amount  can -be 
done  in  this  way  now.  Any  substance  used  must  be  capable  of  direct 
assimilation,  non-irritating  and  easy  of  sterilization. 

Protein. — I^rotein  has  been  used  in  many  different  forms,  as  e^g 
albumin,  peptone,  alkali  albuminate  and  propeptones,  but  it  was  found  that 
all  these  forms  of  protein  lead  to  severe  local  reactions — abscess  formation 
and  breaking  down  of  the  tissues.  Experimentally  (A:),  it  was  found  pos- 
sible in  dogs  by  small  and  repeated  injections  of  skimmed  milk  peptonized 
one  and  a  half  hours,  to  supply  a  certain  amount  of  protein,  the  nitrogen- 
ous balance  showing  a  loss  of  only  0.8  to  0.5  gm.  per  day.  These  injections 
were  toxic  and  particularly  so  unless  the  dose  was  begun  low  and  very 
gradually  increased,  so  that  this  form  of  protein  is  not  practical  and 
should  not  be  used.  Ascitic  fluid  and  blood  serimi  have  also  been  used 
with  better  result  and  a  certain  amount  of  protein  can.  be  supplied  and 
made  use  of  vnthout  toxic  symptoms,  although  large  doses  were  found  to 
cause  renal  irritation.  Blood  serum  contains  practically  1  per  cent 
protein,  and  ascitic  fluid  0.17  to  1  per  cent,  hence  in  order  to  supply 
sufficient  protein  it  w^oidd  be  necessary  to  give  even  on  the  basis  of 
Chittenden's  low  estimate  of  0.12  gm.  nitrogen  per  kilo  daily,  840  to 
4,200  c.c.  of  fluid  for  a  man  weighing  70  kg.,  depending  on  whether  blood 
serum  or  ascitic  fluid  was  used,  certainly  too  large  an  amount  td  be  readily 
obtained  or  used  on  account  of  mechanical  objections.  At  the  same  time, 
it  is  possible  to  use  from  300  to  400  c.c.  daily  probably  without  detriment 
to  the  organism,  although  the  urine  should  be  watched  for  signs  of  renal 
irritation.  In  dogs,  even  large  amounts  were  used  and  apparently  utilized, 
although  there  w^as  always  a  negative  nitrogen  balance  in  two-  or  three-day 
periods  of  from  0.04  to  4.35  gm.  nitrogen;  in  starvation  the  balance  being 
for  two  days,  3.83  gm.  nitrogen  daily (Z). 

When  serum  or  ascitic  fluid  is  aseptically  drawn,  it  can  be  used  safely ; 
if  there  is  any  question  it  should  be  heated  to  55°  C,  which  makes  it 
opalescent,  but  does  not  coagulate  it. 

Horse  serum  heated  to  65°  C.  in  amounts  of  100  to  120  c.c.  was  used 
by  Salter(y»),  who  noted  that  the  urinary  nitrogen  was  increased.  This, 
however,  is  not  an  homologous  serum  and  could  not  be  used  for  nutritional 
purposes  without  first  testing  the  patient  for  serum  reaction,  and  is  not 
suitable  for  hypodermic  feeding. 

Fats. — Fat  injections  have  been  tried  in  various  fonns  but  too  few 
accurate  metabolic  estimations  have  been  carried  out  to  place  the  matter 
on  a  firm  footing.  Von  Leube  used  subcutaneous  oil  injections  20  to  30 
gm.  at  a  time  two  or  three  times  daily,  and  concluded  that  the  oil  was 
absorbed  and  metabolized  as  evidenced  by  lowered  excretion  of  nitrogen 
in  the  urine.  Absorption  is  very  slow,  and  care  nnist  be  taken  not  to 
inject  the  oil  into  a  vein  which  of  course  would  result  in  fat  embolism. 


816  HERBERT  S.  CARTER 

Mills (n),  who  has  done  much  work  on  this,  and  presents  the  hest  historical 
resume  of  the  subject,  finds  that  -fats  similar  in  composition  to  fats  of 
the  body  are  l)est  absorbed,  enuilsions  l>etter  than  plain  oils,  the  best 
being  a  3'  to  5  per  cent  emulsion  of  egg  lecithin  in  sterile  water.  Sixty 
grams  of  oil  may  thus  be  given  slowly.  He  also  used  oils  of  lard,  cocoanut 
and  peanut  oil  e^mulsificd  with  egg  lecithin,  and  proved  that  fats  introduced 
subcutaneously  may  be  burned  directly,  sparing  body  fat,  and  may  be 
either  retained  in  the  body  in  their  own  form  or  may  be  reconstiiicted 
into  body  fat. 

Lard,  according  to  Winteraitz,  can  be  given  by  subcutaneous  injection, 
but  is  of  slight  usefulness  except  in  an  emergency. 

Carhohydrdles. — The  only  form  of  carbohydrate  which  has  been  suc- 
cessfully used  has  been  dextrose.  Voit(o)  in  1890  found  he  could  inject  a 
10  per  cent  solution  without  producing  glycosuria,  although  it  was  too 
painful  a  process,  caused  too  much  tissue  infiltration  and  was  not  prac- 
tical. Kausch  used  a  2  per  cent  solution,  injecting  as  much  as  1,000  c.c. 
In  an  8  to  10  per  cent  solution  it  was  promptly  excreted  in  the  urine, 
although  it  produced  no  renal  irritation.  It  was  also  observed  by  him 
that  the  poorer  the  patient's  nutrition,  the  better  was  the  sugar  borne. 
Gautier  found  he  could  use  60  to  80  gm.  in  1,000  c.c.  of  sterile  noi-raal 
saline  solution,  and  that  it  was  well  absorbed;  but  this  furnishes  only 
about  240  to  320  calories,  which  is  not  more  than  a  fraction  of  the  neces- 
sary amount.  A  four  and  one-half  per  cent  solution  of  dextrose  is  isotonic 
with  the  blood,  and  would  seem  the  best  strength  to  use. 

Salts  and  Water, — The  hypodermic  method  of  getting  water  and  salts 
into  the  system  has  long  been  used  with  complete  success  and  has  formed 
one  of  the  easiest  and  safest  ways  of  supplying  these  necessary  elements 
when  the  normal  i-oute  is  closed.  This  can  be  given  as  sterile  noniial  saline 
solution  (0.6  to  0.0  per  cent)  or  in  the  following  solution,  which  forais 
a  more  complete  reproduction  of  the  saline  elements  in  normal  serum : 

Sodium  Chlorid 0.0      gm. 

Calcium  Chlorid 0.026  '' 

Potassium  Chlorid 0.01     " 

Aq.  destil .  90.064  " 

Taken  then  altogether,  it  can  easily  be  seen  that  as  yet  the  subcutaneous 
method  of  maintaining  nutrition  is  of  minor  importance  and  practically 
about  all  that  can  be  done  is  to  supply  a  small  amount  of  protein  in  the 
form  of  bkxKl  serum  or  ascitic  fluid  (with  a  little  emulsified  fat  given 
separately?)  and  dextrose  in  a  4.5  per  cent  solution  in  normal  saline. 
The  serum  or  ascitic  fluid  may  prove  of  benefit  eventually  in  treating 
certain  diseases,  e.  g.,  cholera  where  the  loss  of  fluids  and  nitrogen  is 
excessive,  care  being  taken  to  rule  out  the  presence  of  syphilis  or  tubercu- 
losis in  the  donor  before  using  either ;  but  even  here  the  intravenous  route 


AETIFICIAL  METHODS  OF  FEEDII^G  817 

is  better  and  more  satisfactory.     It  must  also  be  said  that  for  short  periods 
the  intravenous  route  is  better  for  giving  glucose  solutions  also. 

Intravenous  Feeding. — The  intravenous  method  of  giving  medication 
for  varying  conditions  has  come  into  vogue  more  and  more,  and  is  now  an 
established  method  of  practice.  The  ax>plication  of  this  principle  to 
supplying  nourishment  to  tlie  body  is  of  very  recent  date,  and  a  field  of 
usefulness  has  been  opened  that  may  be  fruitful  of  very  definite  results, 

There  are  certain  dangers  connected  with  this  method  that  do  not 
obtain  in  other  forms  of  artificial  feeding  and  must  be  taken  into  account. 
Embolism  is  a  possibility,  but  is  probably  of  slight  moment  with  anything 
like  surgical  cleanliness  and  is  certainly  a  rare  occurrence  in  giving  medica- 
tion. Overfilling  of  the  blood  vessels  is  another  potential  danger,  and 
with  a  weakened  heart  muscle  must  be  kept  in  mind,  and  the  amount  in- 
jected into  the  vein  carefully  regulated  as  to  speed  of  introduction  and 
total  quantity  used. 

Indications. — The  chief  indications  for  this  form  of  feeding  may  be 
summoned  up  as  follows:  1.  When  all  other  routes  are  closed.  2.  In 
conditions  of  severe  acidosis.  3.  In  severe  acute  infections.  4.  To  pro- 
duce massive  diuresis.  The  last  three  indications  are  to  meet  medical 
rather  than  nutritional  demands. 

Protein. — The  use  of  protein  by  the  intravenous  route,  except  in  the 
form  of  serum,  is  still  in  the  experimental  stage  and  no  refej'cnce  can  be 
found  in  recent  literature  bearing  on  the  subject.  Woodyat  reports  that 
he  and  his  collaborators  have  been  doing  experimental  work  with  proteins 
but  is  not  yet  ready  to  publish  it.  It  would  seem  a  simple  matter  to  supply 
protein  in  a  limited  way  intravenously  by  using  human  serum,  but  the 
difficulty  would  naturally  arise  in  securing  a  supply  to  carry  on  the  food 
requirements.  Horse  serum  could  be  used  for  a  short  time,  provided  the 
individual  was  not  sensitive  to  it.  The  process  is  still  in  a  speculative  and 
experimental  stage  with  as  yet  no  definite  solution  of  the  problem  of 
supplying  easily  the  protein  requirements  of  the  body  by  this  method. 

Fat. — From  what  is  knowii  of  fat  embolism  it  would  seem  that  the 
giving  of  fat  by  the  intravenous  i-oute  was  pretty  definitely  precluded,  and 
although  a  3  per  cent  lard  emulsion  has  been  used  experimentally  in  ani- 
mals, it  is  not  without  danger  and  should  not  be  used  in  man. 

Carbohydrates. — ^Again,  as  in  the  rectal  and  sulxiutaneous  methods  of 
feeding,  carbohydrate  in  the  form  of  dextrose  is  the  most  easily  used  and 
readily  absorbed  and  forms,  so  far,  the  only  important  constituent  of  this 
method  of  artificial  nutrition. 

Woodyat,  Sansum  and  Wilder,  by  means  of  a  special  apparatus,  de- 
scribed in  the  Journal  of  Biological  Chemistry,  tested  glucose  tolerance  by 
intravenous  injection,  and  showed  that  by  delivering  it  at  a  uniform  rate 
of  speed  in  10  to  50  per  cent  solutions,  a  rate  closely  corresponding  to  0.85 
gm.  of  glucose  per  kilo  of  body  w^eight  and  hour  of  time,  for  from  six  to 


818  nERBERT  S.  CARTER 

twt^lve  hours,  it  was  possible  to  give  such  sohitions  without  producing 
glycosuria  or  diuresis.  The  following  conclusions  were  drawn  from  these 
experiments : 

1.  A  man  weighing  70  kg.  may  receive  and  utilize  63  gm.  of  glucose 
by  vein  per  hour  without  glycosuria,  which  equals  252  calorics  per  hour 
or  6,048  calories  per  day,  which  is  about  twice  his  resting  requirements. 

2.  This  is  in  accordance  with  BlumenthaFs  conclusions  in  animal 
experiment  by  repeated  small  doses. 

3.  These  experiments  discredit  the  idea  that  the  glycogenic  function 
of  the  liver  is  indispensable  for  the  utilization  of  sugar. 

4.  The  theory  that  any  large  amount  of  glucose  given  by  vein  always 
causes  glycosuria  and  diuresis  must  be  given  up. 

5.  The  tolerance  limit  of  levulose  was  0.15  gm.  per  kilo  the  hour; 
galactose  about  0.1  gm. ;  lactose  practically  zero. 

6.  When  glucose  is  given  intravenously  faster  than  0.9  gm.  per  kg. 
the  hour,  glycosuria  appears,  then  later,  diuresis,  these  are  all  of  practical 
importance. 

7.  If  given  faster  than  0.85  gm.  per  kg.  the  hour,  "the  unburned 
glucose  begins  to  accumulate  in  the  tissues  and  pass  out  chiefly  in  the 
urine  and  carries  water  with  it,"  extensive  diuresis  resulting. 

To  make  12.5  gin.  glucose  pass  out  of  the  body  via  the  kidney  at 
least  100  c.c.  of  water  is  necessary ;  if  too  much  water  is  given,  there  is 
danger  of  mechanically  stopping  the  heart. 

In  the  practical  application  of  these  conclusions  to  intravenous  feed- 
ing, it  would  seem  imwise  and  unnecessary  to  try  to  supply  the  limit  of 
the  body  tolerance  0.85  gm.  i>er  kg.  the  hour,  and  that  the  most  that  can 
be  done  is  to  furnish  a  fraction  of  this  limit,  enough  to  partially  spare 
the  protein  destruction,  and  prevent  marked  acidosis.  To  furnish  not 
over  one-half  the  caloric  needs  of  the  body  at  rest,  e.  g.,  for  a  man  of 
TO  kg.,  using  an  isotonic  glucose  solution  (4.5  per  cent),  it  would  be 
necessary  to  give  305  gm.  glucose  in  24  hours,  using  6,800  c.c.  of  the 
solution,  altogether  too  large  an  amount  even  if  divided  up  into  two  or  three 
injections.  If  a  10  per  cent  solution  were  used,  it  would  require  3,050  c.c, 
and  if  given  at  the  rate  of  63  gm.  per  hour,  it  would  require  4.8  hours  to 
give.  This,  of  course,  could  be  done,  but  could  not  be  kept  up  for  more 
than  a  few  days  (even  dividing  the  dose  into  three  of  1.6  hours  for 
each  dose)  on  account  of  the  inability  to  use  the  veins  over  and  over 
again.  So  far  as  using  the  special  pum[>  described  by  Woodyat  goes, 
this  wx)ul(l  hardly  be  practical  in  humans,  but  the  solution  could 
be  given  from  an  irrigator  ke})t  warm  by  a  jacket,  and  warming 
the  S(;luti()n  just  before  it  enters  the  vein  by  passing  the  tube  under  a 
hot  water  bottle,  using  about  180  drops  per  minute.  The  same  rate  of 
llow  and  tem})erature  curve  could  be  used  as  recommended  in  Kemp's 
table  (see  rectal  fecMling,  ]).  814).     The  solution  in  which  the  glucose  is 


AKTIFICIAL  METHODS  OF  FEEDING      ,.^        810 

dissolved  should  be  a  normal  O.J)  per  cent  saline,  freshly  distilled  and  ster- 
ilized. This,  of  course,  furnishes  no  protein  and  the  patient  would  have 
to  bum  his  own  protein,  although  a  certain  amount  would  be  spared  on 
account  of  the  glucose.  Whether  later  it  will  be  found  possible  to  incorpo- 
rate blood  serum  or  some  form  of  araino-acid  compound  to  supply  the 
protein  of  the  diet  must  remain  for  future  investigation.  Intravenous 
feeding  must  at  best  be  only  for  very  temporary  use  in  exceptional  cases. 
The  use  of  glucose  solutions  for  the  other  demands  mentioned  will  be 
found  under  their  appropriate  heading  in  Diabetes  Mellitus,  Acute  Infec- 
tions, and  Renal  Disease,  q.  v. 


Transfusion  of  Blood  .  •  George  R,  Minot  and  Artie  V.  Bock 

Introduction — General  Effects  of  Anemia  on  the  Body — Beneficial  Effects  of 
Transfusion — The  Effect  upon  the  Oxygen  Capacity  of  the  Blood — The 
Effect  upon  the  Blood  Volume — The  Effect  upon  the  Factors  of  Coagu- 
lation— The  Effect  upon  Blood  Regeneration — The  Effect  upon  Immune 
Bodies — The  Effect  upon  the  Basal  and  Nitrogen  Metabolism — The 
Effect  upon  the  More  Immediate  Symptomatology — Indications  for 
Transfusion — Conditions  in  Which  Transfusion  is  a  Necessity — Con- 
ditions in  Which  Transfusion  is  Often  Desirable — The  Amount  of  Blood 
to  be  Transfused — The  Choice  of  a  Donor — Reactions  from  Transfusion 
— Reactions  Due  to  Recognized  Incompatibility— rReact ions  Not  Due  to 
Recognized  Incompatibility — Methods  of  Transfusion. 


M 


Transfusion  of  Blood 

GEORGE  R.  MIXOT 

AND 

ARLIE  V.  BOCK 

BOSTON 


L    Introduction 

Transfusion  of  blood  is  a  standard  therapeutic  measure.  Its  useful- 
ness has  outgrown  the  older  conception  that  it  is  only  an  emergency  opera- 
tion. •  Holtz  has  traced  the  history  of  transfusion  back  to  Cardanus'  woi'k 
in  1556.  The  simplification  of  transfusion  methods  has  made  it  possible 
for  those  not  particularly  trained  in  surgical  technic  to  transfer  blood 
from  one  individual  to  another,  while  the  possibility  of  avoiding  hemolysis 
by  preliminary  tests  has  eliminated  the  chief  risk.  In  spite  of  these  facts, 
the  majority  of  physicians  still  regard  transfusion  as  a  fonnidable  opera- 
tion. It  is  our  purpose  here  to  discuss  the  transfusion  of  blood  from 
different  aspects,  especial  emphasis  being  placed  upon  the  physiological 
principles  that  form  the  basis  for  its  use  in  therapeutics. 


11.    General  Effects  of  Anemia  on  the  Body 

In  order  to  appreciate  some  of  the  effects  of  transfusion  in  cases  of 
anemia  it  is  desirable  to  consider  briefly  certain  disturbances  which  occur 
when  there  is  a  diminished  amount  of  circulating  hemoglobin  in  the  body. 
In  general,  it  may  be  said  that  anemia  impoverishes  the  functions  of  all 
the  organs  of  the  body  and  produces  certain  deleterious  changes.  Well 
known  clinical  raanifestations  indicate  the  existence  of  the  condition. 
These  vary  according  to  the  degTco  of  the  anemia,  but  they  may  include 
dyspnea,  palpitation,  gastro-intestinal  disorders,  disturbance  of  kidney 
function,  symptoms  referable  to  tlie  central  nervous  system,  and,  in 
extreme  cases,  complete  prostration  may  result.  The  latter  condition  is 
often  regarded  as  cardiac  failure,  the  underlying  anemia  having  been 
overlooked. 

Very  little  definite  knowledge  is  at  hand  to  show  the  relation  of  such 
clinical  manifestations  to  altered  function  of  the  body.    Strauss (6),  quot- 

821 


822  GEORGE  R.  MINOT  AND  ARLIE  V.  BOCK 

ing  the  work  of  Von  Noorden,  Krause,  Ribbert,  and  others,  states  that  the 
fatty  infiltration  and  d^eneration  of  tissues  occurring  in  chronic  anemia 
is  an  indirect  result  of  the  low  hemoglobin  content  of  the  blood.  He 
assumes  that  the  excessive  effort  of  the  tissue  cells  to  procure  oxygen 
from  the  anemic  blood  proditccs  such  an  alteration  in  the  cells  as  to 
predispose  them  to  fatty  infiltration.  Until  recently  the  only  available 
metabolic  observations  in  anemia  were  those  made  upon  scattered  cases  by 
various  observers,  and  those  which  concern  the  effect  of  acute  hemorrhage 
in  animals.  No  precise  agreement  in  either  series  of  observations  is 
apparent.  There  often  has  been  found  in  anemia  of  all  types  a  negative 
nitrogen  balance,  usually  not  great  The  notable  exceptions  to  this  finding 
occur  in  the  work  of  Von  Xoorden,  Goldschmidt,  and  his  associates,  Moseu- 
thal(rf)  and  Minot(a).  The  problem  of  nitrogen  excretion  after  hemor- 
rhage in  normal  animals  is  somewhat  different,  but  Haskins  and  others 
have  found  an  increase  in  protein  metabolism  which  is  only  temporary. 

Studies  of  basal  metabolism  in  anemia  have  also  shown  great  varia- 
tions. Anemia  does  not  necessarily  result  in  a  sluggish  metabolism,  since 
the  demand  for  oxygen  may  be  somewhat  gi-eater  than  in  health.  Meyer 
and  DuBois  determined  the  metabolism  in  five  cases  of  pernicious  anemia 
and  found  an  increase  of  from  2  per  cent  to  33  per  cent.  Tompkins, 
Brittingham  and  Drinker  have  shown  that  the  basal  metabolism  in  anemia 
may  vary  within  normal  limits,  or  be  above  or  below  normal.  Although 
they  found  no  close  parallelism  between  the  degi*ee  of  anemia  and  the  basal 
metabolism,  they  concluded  that  the  cases  of  anemia  with  acute  symptoms 
have  a  high  metabolism  while  the  chronic  cases  have  a  diminished  oxygen 
consumption.  Zuntz(&)  and  his  associates  showed  that  muscles  poorly  sup- 
plied with  oxygen  are  functionally  less  efficient.  Accessory  muscles  are 
therefore  called  upon  for  the  accomplishment  of  any  task,  as  in  respira- 
tion, thus  increasing  the  demand  for  additional  oxygen,  a  factor  which 
may  account  for  part  of  the  increased  metabolism  in  some  cases,  according 
to  Meyer  and  DuBois.  Lusk(/i.)  expresses  the  view  that  the  general  oxida- 
tion of  the  body  is  normally  maintained  in  anemia  provided  the  anemia 
is  not  of  extreme  severity,  and  that  lack  of  oxygen  renders  the  anemic 
individual  incapable  of  great  muscular  work  without  quick  exhaustion. 

In  view  of  the  fact  that  in  anemia  the  body  suffers  from  decreased 
function  of  many  organs,  and  in  view  of  the  possibility  of  a  noraial  or 
augmented  metabolism  in  the  presence  of  anemia,  the  question  arises  as 
to  how  the  oxygen  requirements  of  the  body  may  be  met.  Certain  phe- 
nomena may  be  mentioned  which  may  for  long  periods  of  time  paitially 
compensate  for  the  oxygen  deficit.  These  are  increased  rate  of  blood  flow, 
increased  ventilation  by  the  lungs,  and  increased  utilization  of  oxygen 
in  the  blood.  Often  the  immediate  purpose  of  transfusion  is  to  relieve 
the  body  of  these  excessive  compensatory  efforts  and  thus  to  restore  normal 
function. 


TKANSFUSION"  OF  BLOOD  823 


IIL    Beneficial   Effects  of  Transfusion 

Whatever  the  purpose  for  which  transfusion  may  l>e  clone,  there  are 
various  beneficial  results  to  be  obtained  by  the  proceihire  which  may  be 
enumerated  before  a  discussion  of  them  is  undertaken.  They  are  as 
follows:  1.  The  effect  upon  the  oxygen  capacity  of  the  blood.  2.  The 
effect  upon  the  blood  volume.  3.  The  effect  uj)on  the  factors  of  coagula- 
tion. 4.  The  effect  upon  blood  regeneration.  5.  The  effect  upon  immune 
bodies.  6.  The  effect  upon  the  basal  and  nitrogen  metabolism.  7.  The 
effect  upon  the  more  immediate  symptomatology. 

1.  The  Effect  upon  the  Oxygen  Capacity  of  the  Blood. — One  of  the 
chief  objects  of  transfusion  is  to  increase  the  power  of  the  recipient's  blood 
to  carrv'  oxygen.  In  normal  blood  the  total  oxygen  capacity  w^hich  depends 
upon  the  hemoglobin  content  of  the  corpuscles  is  about  18.5  volumes  per 
cent.  After  acute  hemorrhage  or  in  severe  anemia  this  figure  may  be 
reduced  to  one-fouith  or  one-fifth  of  the  normal,  and  in  such  conditions 
it  is  obvious  that  more  hemoglobin  must  be  introduced  into  the  circulation 
in  order  to  avoid  oxvo^en  starvation  of  the  tissues.  This  can  he  done  onlv 
by  giving  red  corpuscles  for  which  there  is  no  known  substitute. 

In  the  resting  normal  individual  the  venous  blood  returns  to  the  heaii: 
with  a  reserve  oxygen  supply  of  12  to  14  volumes  per  cent.  In  a  state  of 
gi-ave  anemia,  however,  as  Lundsgaard(e)  has  pointed  out,  the  tissues  may 
demand  the  last  residuum  of  available  oxygen  from  the  blood,  just  as 
readily  as  the  first  part,  and  the  blood  may  return  to  the  heart  in  a 
nearly  completely  asphyxiated  state.  At  the  present  time  there  are  no 
figures  showing  complete  asphyxiation  of  venous  blood  in  man,  but  the 
blood  of  many  cases  of  severe  anemia  closely  approximates  this  conditioUc 
Pfliiger  and  Voit  also  showed  that  the  demand  of  the  tissues  for  oxygen 
was  independent  of  the  supply.  The  reduction  of  the  oxygen  combining 
power  of  the  blood  may  be  so  great  in  extent  that  the  ordinary  compensa- 
tory factors  may  not  be  sufficient  to  maintain  the  internal  respiration 
of  the  body  even  in  a  completely  resting  individual.  A  condition  of  this 
nature  is  perhaps  most  often  seen  in  pernicious  anemia  in  which  the 
occurrence  of  gi-eat  prostration  and  tissue  changes  of  serious  extent  form  a 
familiar  clinical  picture.  What  may  be  immediately  accomplished  in 
such  a  patient  is  illustrated  in  Table  I,  in  which  is  presented  the  data 
cf  a  case  before  and  after  transfusion  of  600  c.c.  of  blood,  together  with 
the  oxygen  figures  for  the  blood  of  a  normal  ijidividual  for  compari- 
son. 

In  contrast  to  a  normal  ox^^gen  reseiTe  of  12  to  14  volumes  per  cent, 
this  patient  had  less  than  two  volumes  per  cent  which  accounts  for  his 
complete  physical  disability.  The  longer  an  individual  remains  in  such  a 
condition  the  gi-eater  the  irreparable  damage  to  body  structure.     Thus  if 


824 


GEORGE  E.  MI]SrOT  AND  ARLIE  V.  BOCK 


Table  I 


Red 
Count 

in 
Mil- 
lions 

Pulse 
Rate 
per 
Min- 
ute 

Blood 

Press. 

in  mm. 

Hg 

Arterial  Blood 

Venous  Blood 

Diagnosis 

Oxygen 
Cap.  in 

Vol.  % 

Oxy- 
gen 
Cont.  in 
Vol.  % 

Oxy- 
gen 
Cap. 
.  in 
Vol. 
% 

Oxy- 
gen 
Cont.  in 
Vol.  % 

Hemo- 
globin 
% 

Pernicious  Anemia 

After  Transfusion ..... 
A   normal    man 

0.82 

1.5 

4.5 

112 

100 

72 

100/50 
110/50 

128/80 

4.42 
19.6 

4.20 
18.5* 

4.42 
6.67 
19.6 

1.9.3   ;     2.3.8 
2.45  1     36. 
11.96  j  106. 

transfusion  is  decided  upon  in  cases  of  chronic  anemia  the  procetlurc 
should  not  he  po3tix)ued  for  weeks  to  see  first  if  the  patient  will  not  regen- 
erate some  of  his  own  hlood.  After  this  case  had  received  600  c.c.  of  blood 
the  increase  in  hemoglobin  was  equal  to  50  per  cent  of  the  amount  in  the 
circulation  before  transfusion.  Even  so,  the  total  hemoglobin  remains 
only  one-third  of  the  normal.  Though  this  amount  of  hemoglobin  is  in- 
sufficient to  enable  the  organs  of  the  body  to  function  well,  it  permits  them 
to  act  distinctly  better  than  with  the  amount  of  hemoglobin  present  before 
transfusion.  In  fact,  it  is  rather  striking  that  a  slight  elevation  of  the 
hemoglobin  level  will  often  largely  remove  the  symptoms  of  anemia. 

The  actual  inci-ease  per  c.c.  of  blood  in  the  number  of  red  corpuscles 
after  transfusion  depends  upon  such  factors  as  the  amount  of  blood  trans- 
fused, the  amount  of  plasma  in  the  recipient's  circulation,  the  degi-ee  of 
anemia  present  and  certain  unknown  factors  among  which  may  be  a 
possible  redistribution  of  blood,  as  Iluck  has  suggested.  When  about 
600  c.c.  of  blood  is  given,  the  usual  increase  in  the  number  of  coi*puscles 
is  from  200,000  to  700,000  per  c.mm.,  and  the  hemoglobin  is  increased 
within  a  range  of  5  to  20  per  cent.  There  may  not  be  a  very  close  rela- 
tionship between  the  increase  in  the  number  of  corpuscles  and  the  per- 
centage increase  in  hemoglobin.  Rarely,  after  transfusion,  no  increase  in 
red  corpuscles  can  be  demonstrated  by  counts. 

The  beneficial  eft'ect  of  the  transfused  red  cells  in  increasing  the  oxygen 
carrying  capacity  of  the  blood  must  be  regarded  as  only  temporary.  This 
is  because  they  do  not  remain  indefinitely  in  the  circulation  of  the  re- 
cipient. According  to  the  work  of  Ashby  the  life  of  transfused  corpuscles 
may  be  as  long  as  thirty  days  aiid  under  certain  conditions  even  much 
longer.  Previous  work  has  suggested  that  10  per  cent  of  the  red 
corpuscles  are  destroyed  daily.  Though  the  transfused  red  cells  them- 
selves increase  temporarily  the  oxygen  carrying  capacity,  transfusion  will 
often  tide  the  patient  over  a  period  of  time  until  he  can  fui-nish  enough 
cells  to  serve  satisfactorily  the  functions  of  the  body. 

In  considering  the  necessity  for  transfusion,  emphasis  usually  is  to  bo 
placed  ui>on  the  hemoglobin  content  of  the  blood.     Fluid  substitutes  for 


tka:^sfusioit  of  blood  825 

blood  have  their  uses  but  they  cannot  take  the  place  of  blood  if  increased 
oxygen  carrying  power  is  needed. 

2.  The  Efifect  upon  the  Blood  Volume. — In  most  conditions  for 
which  transfusion  is  indicated,  a  diminished  volume  of  circulatino-  blood 
usually  exists,  either  by  reason  of  a  mechanical  reduction  in  the  whole 
blood,  as  after  acute  hemorrhage,  or  on  account  of  a  diminished  content 
of  red  corpuscles  which  is  associated  with  most  types  of  anemia.  Reduc- 
tion of  the  plasma  volume  may  occur  following  blood  loss,  and  in  other 
anemias  when  the  hemoglobin  is  below  30  per  cent.  Transfusion  of  blood 
after  a  severe  hemorrhage  may  help  to  restore  the  plasma  volume  to  about 
its  normal  figure  but  the  total  blood  volume  may  not  be  regained  except 
through  regeneration  of  corpuscles  unless  it  is  made  up  by  repeated  trans- 
fusions. Hypertransfusion  should  be  avoided  because  of  the  possibility  of 
bone  marrow  depression,  as  demonstrated  experimentally  by  Robertson (c). 

In  chronic  anemia,  in  contrast  to  acute  anemia  due  to  blood  loss  the 
volume  of  the  plasma  is  usually  not  abnonnal  if  the  patient  has  a  normal 
fluid  intake.  When  transfusion  is  undertaken  for  such  a  condition,  the 
only  gain  in  total  blood  volume  is  due  to  the  addition  of  corpuscles. 
Under  such  a  circumstance  the  plasma  of  the  transfused  blood  rapidly 
leaves  the  circulation  for  the  tissues.  This  consideration  is  an  important 
one,  since  it  shows  that  alterations  in  the  blood  volume  in  anemia  are 
almost  wholly  dependent  upon  variations  in  the  total  mass  of  corpuscles, 
as  discussed  by  Bock.  There  is  no  method  of  increasing  the  total  blood 
volume  in  chronic  anemia  except  by  the  addition  of  corpuscles. 

3.  The  Effect  upon  the  Factors  of  Coagulation. — In  the  various 
forms  of  purpura  hemorrhagica  there  occurs  a  deficiency  in  the  number 
of  blood  platelets  which  is  associated  with  the  pathologic  hemorrhage 
frequently  encountered  in  these  cases.  In  hemophilia,  as  Minot  and 
Lee(a)  haveshown,  there  occurs  a  qualitative  deficioicy  of  the  blood  plate- 
lets. In  other  conditions  in  which  pathologic  hemorrhage  occurs,. there  are 
often  unknown  alterations  in  the  physical  chemistry  of  the  blood  "which  in- 
terfere with  normal  clot  formation.  This  may  be  due  to  an  upsetting  of  the 
balance  of  prothrombin  and  antithrombin  as,  for  example,  by  a  decrease 
of  the  former  or  increase  of  the  latter  substance,  or  thei-e  may  be  a  de- 
ficiency of  fibrinogen  or  some  other  not  well  recognized  alteration.  The 
only  truly  efficient  w^ay  of  remedying  a  defect  in  one  or  more  of  the 
factors  that  promote  clotting,  is  by  transfusion  of  noi*mal  blood  which 
contains  all  of  the  factors.  It  is  to  be  recognized  that  serious  bleeding 
associated  with  a  deficiency  in  the  numbers  of  platelets,  does  not  occur 
until  these  elements  have  been  reduced  from  their  normal  number  of  about 
300,000  to  60,000  per  cmni.  oi*  below.  If  a  litci*  of  noi*mal  blood  is  trans- 
fused the  platelets  will  be  increased  in  the  recipient's  blood  by  about 
70,000  per  c.mm.  Thus,  when  transfusion  is  necessary  to  stop  bleeding 
due  to  a  deficiency  of  platelets,  a  large  amount  of  blood  should  be  given 


826     GEOEGE  E.  MINOT  AND  AELIE  V.  BOCK 

in  order  to  restore  a  sufficient  number  of  platelets  to  prevent  spontaneous 
bleeding.  It  is,  however,  probable  that  other  elements  in  the  blood  assist 
to  check  a  hemorrhage  particularly  associated  with  a  deficiency  or  a  defect 
in  the  platelets. 

The  duration  of  the  life  of  the  platelets  is  but  a  few  days  in  contrast 
to  the  longer  life  of  the  red  corpuscles.  Thus  if  a  patient  does  not  make 
up  some  of  his  platelet  deficiency  within  3  to  5  days  following  a  trans- 
fusion for  such  a  defect,  one  must  anticipate  a  recurrence  of  the  spon- 
taneous hemorrhage.  Hence  further  transfusion  will  be  necessary  if  it  is 
desired  to  continue  to  check  the  bleeding.  In  hemophilia,  in  contrast  to 
the  various  forms  of  purpura  hemorrhag?ca,  hemorrhage  is  not  spontaneous 
but  follows  as  a  result  of  trauma,  though  this  may  be  exceedingly  slight. 
In  order  to  check  a  severe  hemorrhage  in  hemophilia,  enough  blood  should 
be  given  to  reduce  the  clotting  time  of  the  patient's  blood  to  approximately 
normal.  By  means  cf  such  a  procedure,  hemorrhage  is  checked  and  thus 
the  bleeding  point  allowed  to  close.  Later,  as  the  transfused  platelets 
disappear  from  the  circulation,  the  clotting  time  of  the  hemophiliac's  blood 
again  becomes  abnormally  prolonged.  Hemorrhage  does  not  recur  unless 
the  external  or  internal  w^ound  has  not  healed  sufficiently.  Hemon-hage 
will  of  course  recur  when  there  is  sufficient  further  trauma.  Transfusion 
may  also  be  undertaken  in  hemophilia  to  prevent  bleeding  when  operation 
has  to  be  performed.  Under  such  conditions  it  may  be  desirable  to  remove 
some  blood  before  the  normal  blood  is  injected. 

In  Table  II  is  shown  the  effect  of  transfusion  on  the  blood  of  a  hemo- 
philiac in  w^hom  rather  severe  bleeding  was  to  be  anticipated  from  the 
extraction  of  teeth,  if  no  normal  blood  had  been  given. 

The  foreign  blood,  with  its  normal  platelets,  held  the  clotting  time  of 
the  patient's  blood,  with  its  qualitatively  defective  platelets,  close  to 
normal  for  enough  time  to  permit  primary  healing  of  the  w^ound. 

In  hemorrhagic  disease  of  the  newborn,  the  effect  of  transfusion  is, 
in  a  very  high  percentage  of  the  cases,  very  striking,  for  hei-e  it  seems 
that  normal  blood  is  capable  of  doing  more  than  tiding  a  patient  over  a 
critical  j>eriod.  Following  adequate  transfusion  in  such  cases  there  nearly 
always  occurs  a  permanent  correction  of  the  blood  defect  which  is  associ- 
ated with  a  prolonged  coagulation  time  and  prothrombin  time.  To  ac- 
complish this  result  it  may  be  necessary  to  give  several  doses  of  blood, 
but  frequently  40  c.c.  suffices. 

In  other  conditions  in  which  pathologic  hemorrhage  occurs  due  to 
recognized  or  unrecognized  blood  defect,  the  principle  outlined  above 
applies,  namely,  that  if  transfusion  is  to  be  used,  enough  blood,  which  will 
furnish  all  the  factors  for  coagulatiouj  must  be  given  to  accomplish  the 
desired  result. 

4.  The  Effect  upon  Blood  Regeneration. — When  the  bone  marrow 
is  functioning  deficiently,  an  increase  in  its  regenerative  activity  often 


TRAJSrSFUSIO]^  OF  BLOOD 


827 


Table  II 


Date 

Coagulation 
Time  in 

Minutes  * 

1 

Transfusion 

Remarks 

May  1 
10  A.M. 

1          .... 
60 

Slight  bleeding  from  about  carious  teeth 

10.30  A.M. 

.. 

1000  c.c. 

11.30  A.M. 

10 

Teeth  removed — no  abnormal  bleeding 

]VIay  2 

15 

No  bleeding 

IVIay  3 
10  A.M. 

20 

Slight  bleeding 

11  A.M. 

.• 

500  c.c. 

11.30  A.M. 

8 

No  bleeding 

May  4 

15 

No  bleeding 

May  5 

20 



No  bleeding 

May  6 

30 

No  bleeding 

May  7 

50 

No  bleeding 

May  8 

65 

No  bleeding 

*Tirae  required  for  1.5  c.c.  of  venous  blood  to  clot  in  &  test  tube  8  mm.  in  diameter. 
Upper  limits  of  normal  15  min. 


occurs  following  transfusion.  This  may  be  due  to  a  direct  or  indirect 
effect  of  the  transfused  blood.  Increased  bone  marrow  activity  may  be 
manifested  not  only  by  increases  of  young  red  cells  but  increases  also  of 
platelets  and  marrow  white  cells  above  a  level  due  to  the  transfused  blood. 
In  other  instances,  when  the  regeneration  is  not  so  rapid,  significant  in- 
creases of  young  red  cells  do  not  occur,  but  the  platelets  and  marrow  white 
cells  remain  at  a  higher  level  than  before  transfusion.  If  a  suitable  for- 
mation occurs  the  count  of  the  red  cells  remains  elevated  and  increases 
while  the  transfused  cells  gradually  cease  to  exist  in  the  circulation.  Such 
a  picture  indicates  that  the  bone  marrow  elements  are  being  delivered  into 
the  circulation  at  a  desirable  rate. 

Alteration  in  the  white  count  following  transfusion  may  be  associated 
with  a  mechanical  redistribution  of  the  blood  in  the  same  manner  as  the 
red  cells.  Thus,  elevation  of  the  white  count  does  not  necessarily  indi- 
cate a  general  increase  of  bone  marrow  activity.  A  sharp  leukocytosis 
following  transfusion  may  be  only  a  fui'ther  manifestation  of  a  reaction 
due  to  the  foreign  blood,  as  described  on  page  S40,  rather  than  a  sign 
of  general  marrow  activity.  Still  the  degree  of  leukocytosis  indicates 
roughly  the  ability  of  the  marrow  to  produce  blood  even  though  the 
transfusion  may  not  be  followed  by  an  increase  of  blood  production.  Al- 
terations in  the  platelets  may  occur  after  transfusion  in  a  similar  manner. 


828  GEOEGE  K.  jMIXOT  AND  ARLIE  Y.  BOCK 

However,  if  both  the  platelets  and  marrow  white  cells  increase  in  number 
and  remain  elevated  after  transfusion,  these  rises  should  be  interpreted 
as  evidence  of  increased  marrow  activity.  With  increased  regeneration 
the  platelets  usually  begin  to  increase  in  number  slightly  later  than  the 
white  cells.  With  an  orderly  increased  acti^-ity  of  the  marrow  such  as 
may  occur  in  pernicious  anemia,  the  reticulated  red  cells  (young  cells) 
begin  to  increase  still  later — that  is,  in  about  three  to  five  days. 

The  response  of  normal  bone  marrow  to  the  stimulus  of  hemorrhage 
is  more  rapid  and  proceeds  more  uniformly  with  respect  to  all  of  the  blood 
elements  than  may  be  seen  after  transfusion  in  cases  having  pathological 
bone  marrow.  There  may  occur  with  regeneration  of  blood,  with  or  with- 
out transfusion,  a  distinct  qualitative  change  in  the  process  of  regeneration 
such  as  a  disproportionate  output  of  platelets,  or  of  young  red  corpuscles, 
in  relation  to  the  other  elements  produced  by  the  bone  marrow.  If  the 
marrow  is  aplastic  the  response  to  transfusion  may  be  very  feeble  or  more 
often  does  not  occur.  Distinct  inactivity  or  depression  of  the  bone  marrow 
following  transfusion  is  a  bad  prognostic  sign.  Likewise  the  presence 
in  the  peripheral  blood  of  veiy  large  numbers  of  immature  man'ow  cells 
of  the  red  and  white  series  is  unfavorable  and  indicates  what  may  be 
termed  a  dissolution  of  the  marrow.  For  a  further  discussion  .of  the 
question  of  bone  marrow  activity,  reference  may  be  made  to  the  work  of 
Drinker,  Vogel  and  McCurdy,  and  Minot  and  Lee. 

5.  The  Effect  upon  Immune  Bodies. — Theoretical  considerations 
have  led  to  the  use  of  transfusion  for  the  transfer  from  one  individual 
to  another  of  immune  bodies,  particularly  for  the  treatment  of  disease. 
Experience  up  to  the  present  is  variable  in  character  and,  for  the  most 
part,  disappointing. 

In  sepsis  the  supportive  effect  of  fresh  blood  has  long  been  thought  to 
be  beneficial,  but  in  practice  little  good  has  been  accomplished  by  such 
therapy,  probably  because  normal  blood  has  less  bactericidal  power  than 
the  blood  of  the  patient.  Wright  and  Colebrook  have  recently  sug- 
gested a  method  of  ^'immuno-transfusion'^  for  cases  of  sepsis,  in  which  the 
blood  to  be  transfused  may  be  rendered  bactericidal  in  vitro,  and  then 
injected  into  the  circulation  of  the  patient.  The  vaccine,  used  for  this 
purpose  need  not  be  specific.  The  blood  transfused  in  a  case  reported 
by  Wright  and  Colebrook  was  thus  immunized  against  the  patient's  strep- 
tococcus ;  the  protective  action  of  the  senim  against  the  patient's  organism 
was  previously  demonstrated  by  a  simple  laboratory  study.  A  cure  re- 
sulted in  this  case  in  which  operative  and  other  therapeutic  measures 
had  failed. 

6.  The  Effect  upon  the  Basal  and  Nitrogen  Metabolism. — Trans- 
fusion of  blood  in  cases  of  anemia,  according  to  Tompkins,  Brittingham 
and  Drinker  reduces  the  basal  metabolism  to  a  normal  or  diminished  level. 
They  suggest  that  the  basal  metabolism  may  serve  as  a  guide  in  knowing 


TEANSFUSIOISr  OF  BLOOD  829 

when  to  push  transfusion  in  the  treatment  of  anemia,  and  when  little  may 
be  expected  from  the  procedure.  For  example,  if  the  metabolism  is 
minus  10,  only  temporary  comfort  to  the  patient  is  to  be  expected.  If 
the  result  is  phis  10  more  will  be  accomplished  by  transfusion.  Transr- 
fusion  provides  relief  for  certain  compensatory  phenomena  such  as  in- 
creased pulse  rate  and  increased  ventilation  of  the  lungs,  but  the  demand 
of  the  tissues  for  increased  oxygen  may  continue  for  days  after  the  trans- 
fusion. Transfusion  is  regarded  by  these  authors  as  a  measure  by  which 
early  cases  of  pernicious  anemia  may  be  assisted  toward  a  remission. 
Studies  at  the  ^fassachusetts  General  Hospital,  yet  incomplete,  tend  to 
show  that  the  basal  metabolism  is  not  always  indicative  of  what  trans- 
fusion will  accomplish  in  anemia. 

Little  is  known  as  to  the  effect  of  transfusion  upon  nitrogen  metab- 
olism. Mosenthal(c7)  found  a  lowered  nitrogen  balance  after  transfusion, 
owing  to  the  output  in  the  urine  of  the  nitrogen  contained  in  the  trans- 
fused blood.  In  dogs,  Haskins(<z.)  found  that  transfusion  after  hem- 
orrhage does  not  prevent  the  destruction  of  protein  which  occurs  as  a  i^esult 
of  hemorrhage. 

7.  The  Effect  upon  the  More  Immediate  Symptomatology. — Symp- 
tomatic improvement  following  transfusion  depends  not  only  upon  tLe 
cause  of  the  anemia  but  also  upon  the  state  of  the  patient.  The  greatest 
clinical  change  is  seen  in  patients  transfused  after  sudden  loss  of  much 
blood.  The  usual  signs  of  restlessness,  rapid  pulse,  increased  respiration 
and  sweating,  are  improved  at  once  or  entirely  relieved.  A  general  sense 
of  well  being  is  substituted  for  a  state  of  anxiety,  and  a  condition  of 
doubtful  outcome  may  be  changed  at  once  to  one  having  a  favorable  prog- 
nosis. The  improvement  is  duo  to  a  number  of  complex  factors,  chief 
among  which  is  the  increased  efficiency  of  the  circulation  as  manifested 
by  higher  blood  pressure  in  certain  cases,  slower  pulse  rate,  and  increased 
oxygen  carrying  power  of  the  blood. 

The  more  immediate  symptomatic  improvement  in  chronic  anemia  is 
not  so  pronounced,  owing  to  structural  changes  in  the  lx)dy  and  to  the 
probable  persistence  of  the  cause  of  the  anemia,  toxic  or  othenvise. 

Weakness,  palpitation,  dyspnea,  and  visual  and  auditory  disturbances 
are  often  relieved.  If  fever  is  present  due  to  the  blood  condition,  the 
temperature  may  subside  after  transfusion.  Improvement  of  appetite  and 
diminution  of  gastrointestinal  spnptoms  frequently  occur  shortly  after 
transfusion,  especially  in  states  of  chronic  anemia.  Although  achylia 
may  persist  in  pernicious  anemia  the  stomach  distress  present  before 
transfusion  may  entirely  disappear  afterward.  Troublesome  diarrhea 
occasionally  met  with  in  pernicious  anemia  may  also  be  controlled.  It  has 
been  shown  that  the  kidney  function  is  deficient  in  chronic  anemia,  and, 
among  other  benefits  that  result  from  transfusion  is  improvement  in  the 
functional  state  of  the  kidneys. 


830  GEOEGE  R  MINOT  ANI>  AKLIE  V.  BOCK 


IV.    Indications  for  Transfusion 

1^0  detailed  account  of  all  of  the  conditions  for  which  transfusion  is 
indicated  will  be  undertaken  here.  In  a  general  wav  they  belong  to  two 
groups,  namely,  conditions  in  which  transfusion  is  an  absolute  necessity 
in  order  to  save  life  and  conditions  in  which  the  procedure  may  he  desir- 
able either  for  the  comfoi-t  of  the  patient  or  to  shorten  convalescence. 

1.  Conditions  in  Which  Transfasion  is  a  Necessity. — The  usual 
conditions  in  which  transfusion  may  be  obligatory  in  order  to  save  life 
are  hemorrhage  and  shock.  Since  moderate  or  severe  hemorrhage  is  always 
accompanied  by  a  state  of  shock,  these  two  conditions  may  present  the 
same  indications  for  treatment.  They  have  in  common  diminished  blood 
volume  and  low  blood  pressure,  both  of  which  may  be  corrected,  at  least  in 
part,  by  transfusion.  In  the  case  of  hemorrhage,  danger  to  life  lies  not  so 
much  in  the  extent  of  hemorrhage  as  in  sudden  loss  of  blood.  The  latter 
may  result  in  a  rapid  fall  of  blood  pressure  to  a  dangerous  level,  a  state  in 
which  the  tissues  of  the  body  are  deprived  of  oxygen  owing  to  the  failure 
of  the  circulation.  Keith  has  shown  that  the  blood  volume  in  shock,  not 
complicated  by  hemorrhage,  may  be  diminished  to  the  same  extent  as  in 
hemorrhage.  In  such  a  condition  the  body  may  not  survive  for  more 
than  a  brief  period  unless  energetic  measures  are  taken  to  increase  the 
volume  of  the  circulating  blood,  which  in  turn  reacts  favorably  upon  the 
blood  pressure.  Fluid  substitutes  for  blood,  such  as  gum-saline,  may 
serv^e  to  restore  the  circulation  and  may  be  used  instead  of  blood  when 
the  blood  loss  has  not  been  too  great.  In  shock  gum-saline  is  highly  useful 
if  it  is  used  soon  after  the  advent  of  the  condition.  However,  if  such  a 
fluid  is  not  available,  normal  salt  solution  may  temporarily  tide  a  patient 
over  a  brief  period  of  time  until  transfusion  can  be  carried  out. 

The  criteria  upon  which  to  judge  the  condition  of  the  patient  are  blood 
pressure  readings,  hemoglobin  determinations  and  pulse  rate,  as  has 
been  discussed  by  Robertson  and  Bock.  A  very  low  systolic  blood  pressure, 
TO  mm.  of  mercuiy  for  example,  after  acute  hemorrhage,  or  in  shook, 
usually  means  a  great  diminution  in  blood  volume.  Subsequent  blood 
pressure  determinations  are  important  to  note  w*hether  the  reaction  of 
the  patient  is  favorable  or  not.  For  example,  a  rising  blood  pressure  is  a 
good  prog-nostic  sign.  A  single  hemoglobin  estiraation,  especially  if  made 
soon  after  hemorrhage  has  occurred,  is  of  little  significance.  It  is  im- 
portant to  know  whether  subsequent  hemoglobin  readings  at  hour  inter- 
vals are  the  same  or  steadily  becoming  lower.  A  flow  of  fluids  from  the 
tissues  to  the  circulation,  or  internal  transfusion,  as  Gesell  has  called  it, 
wdll  dilute  the  hemoglobin,  and  if  this  does  not  fall  below  30  per  cent, 
transfusion  is  not  urgent  though  it  may  be  advised.  Cases  of  hemorrhage 
and  shock  in  which  the  hemoglobin  remains  at  a  stationary  figure  for  se\'- 


TKANSFUSIOiT  OF  BLOOD  ^  831 

eral  hours  are  almost  always  fatal,  even  with  repeated  transfusions. 
Large  amounts  of  fluids  administered  by  the  alimentary  tract  may  often 
accomplish  the  purpose  for  which  transfusion  or  infusion  seems  indicated. 

Xo  absolute  indication  for  transfusion  exists  so  far  as  oxygen  need  is 
concerned,  as  long  as  the  hemoglobin  remains  above  30  per  cent.  There  is 
abundant  evidence  to  show  that  animals,  after  bleeding  to  as  low  as  25 
per  cent  of  hemoglobin,  will  sui-vive  providing  the  fluid  volume  of  the 
blood  is  maintained  by  intravenous  injection  of  fluid  substitutes  for 
blood.  In  case  the  hemoglobin  is  below  30  per  cent  transfusion  should 
be  looked  upon  as  a  necessity  and  not  as  a  matter  of  choice.  Life  itself 
may  be  immediately  endangered,  other  things  being  equal,  only  when  the 
blood  contains  less  than  about  30  per  cent  of  hemoglobin. 

As  has  been  mentioned,  transfusion  may  be  necessary  to  control  hemor- 
rhage due  to  pathological  blood  defects  such  as  occur  in  hemophilia,  hem- 
orrhagic disease  of  the  new  born,  and  other  hemoiThagic  conditions.  It  is 
reiterated  here  that  it  may  be  necessaiy  to  ti*ansfuse  more  than  once  to 
control  hemorrhage  of  this  type.  Often  in  hemorrhagic  conditions,  trans- 
fusions also  must  be  used  in  a  preventive  manner  when  operation  becomes 
necessary. 

2.  Conditions  in  Which  Transfusion  is  Often  Desirable, — ^In  the 
group  of  conditions  now  to  be  discussed  transfusion  of  blood  may  be  done 
to  improve  the  general  state  of  the  patient  though  the  procedure  may  not 
be  a  life-saving  one.  The  articles  by  Pemberton,  Garbat,  McClure  and 
Dunn,  Lewisohn,  Lindeman,  Ottenberg  and  Libman,  Bernheim,  and 
Minot,  among  many  others,  consider  this  aspect  of  transfusion. 

Transfusion  in  pernicious  anemia  has  been  discussed  by  Anders, 
Minot  and  Lee  (6),  and  many  others.  It  is  generally  agreed  that  trans- 
fusion in  this  disease  helps  to  bring  about  remissions  which  probably  would 
not  otherwise  occur.  It  appears  to  make  remissions  about  10  per  cent  and 
perhaps  20  per  cent  more  frequent.  It  undoubtedly  often  adds  greatly  to 
the  comfort  of  the  patient.  While  remissions  may  be  favored  by  trans- 
fusion, the  natural  course  of  the  disease  is  not  altered  by  such  treatment. 

Transfusion  probably  should  be  employed  before  the  stage  of  gi-eat 
anemia  and  prostration  has  developed.  The  gradual  failure  of  an  adequate 
oxygen  supply  to  the  tissues  is  always  critical  because  of  the  transforma- 
tion of  normal  tissue  to  fat  and  water.  Good  results  cannot  be  expected 
from  any  measure  of  therapy  after  such  changes  have  occurred  in  the 
body.  The  value  of  transfusion  in  pernicious  anemia  at  present  is  based 
for  the  most  part  upon  its  use  in  the  treatment  of  cases  in  the  stage  of 
prostration  due  to  such  tissue  changes.  It  is  important  that  the  diagnosis 
of  pernicious  anemia  should  be  made  early,  and  the  cases  transfused 
while  the  hemoglobin  is  still  at  a  relatively  high  level  in  order  to  attempt 
to  forestall  the  inevitable  results  of  anemia.  A  detailed  discussion  of 
transfusion  in  this  disease  cannot  be  entered  into  here,  as  it  is  not  our 


832  GEORGE  R  M^OT  AIND  ARLIE  V.  BOCK 

purpose  to  discuss  the  treatment  of  pernicious  anemia.  One  must  consider 
the  probability  of  remission  as  told  by  tlie  history  of  the  case,  the  character 
of  the  blood,  etc,  as  well  as  the  desires  of  the  patient  and  his  family  when 
considering  transfusion  in  this  disease. 

In  other  forms  of  chronic  hemolytic  anemia  transfusion  may  be  used 
similarly  as  in  pernicious  anemia.  However,  it  is  possible  that  in  a  case 
with  increased  blood  destruction  transfused  corpuscles  may  perhaps  re- 
main in  the  circulation  a  shorter  time  than  w^hen  a  noraial  amount  of 
hemolysis  is  occurring.  For  this  reason,  among  others,  in  some  forms 
of  hemolytic  anemia,  such  as  chronic  hemolytic  jaundice,  splenectomy  is 
the  best  treatment  and  transfusion  then  may  be  used  to  improve  the  con- 
dition of  the  patient  for  operation. 

In  anemia  from  blood  loss  both  acute  and,  particularly  from  chronic 
types,  in  which  no  emergency  exists  for  transfusion,  remarkable  results 
may  follow  the  use  of  this  therapy.  In  addition  to  an  increased  output 
of  corpuscles  from  the  marrow,  a  definite  permanent  alteration  of  the  color 
index  of  the  corpuscles  has  been  noted,  in  that  the  hemoglobin  content  per 
corpuscle  seems  definitely  increased.  In  such  cases  transfusion  restoi'es  the 
patient  to  health  considerably  sooner  than  with  any  other  method  of  ther- 
apy. In  cases  of  chronic  anemia  due  to  blood  loss,  when  the  bleeding  has 
been  stopped,  the  marrow  may  regenerate  very  sluggishly.  Transfusion 
enables  such  patients,  who  may  be  chronic  invalids,  to  regenerate  blood 
and  regain  health  often  months  earlier  than  without  such  treatment. 

Single  and  often  repeated  transfusion  is  also  of  value  in  aiding  a 
return  to  normal  in  other  forms  of  chronic  anemia,  particularly  if  the 
cause  has  been  removed,  or  if  it  is  anticipated  that  transfusion  will 
diminish  the  activity  of  the  cause.  A  striking  example  of  the  effect  of 
many  transfusions,  when  the  cause  of  anemia  has  been  removed,  is  seen 
in  severe  benzol  poisoning.  This  poison  tends  to  produce  aplasia  of  the 
marrow  and  the  resulting  clinical  and  blood  picture  is  that  of  aplastic 
anemia  w^ith  secondary  purpura  hemorrhagica.  When  the  influence  of  the 
poison  is'  removed  the  blood  may  return  to  normal.  However,  in  the  severe 
cases  the  trap  seems  to  be  sprimg  so  far  that  the  maiTow  is  unable  to  re- 
generate at  the  moment  enough  blood  to  maintain  life.  In  some  such 
cases  repeated  transfusion  performed  about  as  often  as  bleeding  recurs, 
permits  the  patient  to  live  during  the  time  the  marrow  regenerates  to  a 
point  at  which  it  can  supply  sufficient  blood  elements  to  maintain  satis- 
factorily the  needs  of  the  body. 

In  idiopathic  aplastic  anemia  transfusion  appears  to  result  in  only 
temporary  benefit,  for,  unlike  the  cases  of  benzol  poisoning,  the  unknown 
cause  is  not  removed. 

Besides  the  use  of  transfusion  to  stop  hemorrhage  and  to  prevent  its 
occurrence  at  operation  in  a  patient  having  a  hemorrhagic  disease,  repeated 
transfusions  may  be  used  in  certain  conditions  to  accomplish  the  same 


TKA^SrSFUSION  OF  BLOOD  833 

results  as  in  benzol  poisoning.  Cases  of  acute  idiopntluc  purpura  hemor- 
rhagica best  illustrate  this.  Hero  repeated  transfusion  checks  hemorrhages 
and  supplies  red  corpuscles,  and  in  so  doing  the  transfused  corpuscles  may 
keep  the  individual  alive  until  the  unknown  cause  diminishes  so  that  the 
platelets  can  return  to  normal  as  sometimes  occurs.  In  cases  of  secondary 
purpura  hemorrhagica,  and  other  hemon-hagic  states,  where  the  cause  can- 
not be  removed,  no  real  benefit  can  bo  anticipated  from  repeated 
transfusion. 

Transfusion  also  finds  valuable  use  in  improving  the  condition  of  the 
patient  with  anemia  before  operation  is  undertaken,  even  though  the 
anemia  is  not  gi-eat.  Ottenberg  arid  Libman,  among  others,  have  com- 
mented on  the  value  of  transfusion  preparatory  to  operative  procedures. 

Transfusion  has  been  used  to  combat  sepsis  and  toxemias  such  as 
eclampsia,  but  no  definite  beneficial  results  have  been  obtained. 

From  time  to  time  transfusions  have  been  reported  for  the  cure  of 
carbon  monoxid  poisoning,  but  there  is  almost  no  evidence  forthcoming 
to  show  that  transfusion  is  beneficial  in  this  condition.  Crile  and  Lenhart 
found  that  transfusion  was  the  most  efiicient  therapy  in  the  restoration 
of  dogs  overcome  by  carbon  monoxid  gas,  but  clinical  results  have  not  met 
with  the  same  success.  Henderson  has  summarized  our  present  knowledge 
concerning  the  effects  of  carlx)n  monoxid  as  follows:  It  is  a  ph3'sio- 
logically  harmless  gas  except  in  its  affinity  for  hemoglobin,  and  its  toxic 
effects  are  entirely  due  to  the  inability'  of  the  blood  combined  with  carbon 
monoxid  to  transport  oxygen.  Hemoglobin  has  a  very  great  affinity  for 
carbon  monoxid,  but  the  combination  is  not  a  permanent  one  and  is  rapidly 
broken  up  in  the  presence  of  oxygen  or  pure  air.  Injury  resulting  from 
this  gas  o'ccui's  during  the  time  in  which  the  patient  breathed  carbon 
monoxid.  When  placed  in  an  atmosphere  of  pure  air  almost  all  of  the 
carbon  monoxid  is  eliminated  from  the  body  within  a  period  of  one  to 
three  hours,  if  recovery  is  to  occur.  Transfusion  cannot  repair  the  injui-y 
caused  by  this  gas.  The  treatment  consists  mainly  in  fi-esh  air  and  s;^anp- 
tomatic  measures.  However,  in  some  instances  transfusion  may  be  very 
beneficial,  as  suggested  by  Lindeman's  case. 

In  other  conditions,  such  as  nitrobenzene  poisoning,  there  occur  other 
forms  of  altered  hemoglobin  than  CO-hemoglobin,  namely,  methemoglobin 
and  KO-hemoglobin,  which  prevent  oxygen  from  being  transported.  The 
amoimt  of  these  abnormal  forms  of  hemoglobin  may  be  so  great  that  ex- 
treme cyanosis  is  present  and  less  than  30  per  cent  of  oxyhemoglobin  re- 
mains. Under  such  conditions  transfusion  may  be  required.  Usually 
Avith  the  formation  of  altered  hemoglobin  the  patient's  condition  is  not 
severe  enough  to  require  transfusion.  Cases  of  nitrobenzene  poisoning 
show  a  surprising  tendency  toward  spontaneous  recovery  when  the  source 
of  the  poisoning  is  removed,  as  is  the  case  in  CO  poisoning.  However, 
we  have  seen  death  occur  from  the  effects  of  this  substance  and  others, 


834  GEORGE  R.  UINOT  AND  ARLIE  V.  BOCK 

as  Donavon,  have  reported  the  same  result.  Two  cases  of  nitrobenzene 
poisoning  that  we  have  personally  observed  had  their  oxyhemoglobin  re- 
duced to  30  per  cent  and  35  per  cent,  respectively.  Both  recovered  with 
transfusion. 

V,    The  Amount  of  Blood   to  be  Transfused 

It  is  generally  agreed  that  a  donor  may  give  blood  up  to  one  quarter 
of  his  blood  volume  without  serious  discomfort.  A  man  weighing  70 
kilograms  has  a  blood  volume  of  about  5,500  cc,  hence  blood  may  be  taken 
from  him  for  purposes  of  transfusion  up  to  about  1,300  cc.  It  is  seldom 
necessary  to  use  such  a  mass  of  blood  for  transfusion,  but  it  may  be  helpful 
to  have  in  mind  the  limit  of  safety  for  the  donor.  This  limit  varies 
directly  with  the  body  weight. 

What  constitutes  a  proper  amount  of  blood  to  be  given  for  the  different 
conditions  in  which  transfusion  is  indicated  has  been  suggested  by  various 
authors  as  a  result  of  clinical  experience.  It  has  not  been  possible  to 
make  definite  quantitative  measurements  of  the  various  factors  involved, 
and  therefore  only  a  general  statement  can  be  made  with  reference  to  this 
important  subject.  In  every  instance  the  weight  of  the  patient  to  be 
transfused  should  be  considered  in  order  to  avoid  hypertransfusion.  A 
normal  individual  has  a  volume  of  blood  equal  to  80  to  85  cc.  per  kilo- 
gi*am  of  weight.  A  patient  weighing  70  kilograms,  with  severe  anemia, 
may  have  his  blood  volume  reduced  to  50  cc  per  kilogram,  representing  a 
reduction  in  blood  volume  of  approximately  40  per  cent.  It  would  be 
futile  to  attempt  to  restore  the  normal  blood  volume  by  means  of  trans- 
fusion in  such  a  case  and  fortunately  this  is  never  necessary.  On  the 
other  hand,  if  repeated  transfusions  are  done  at  intervals  of  a  few  days  to 
control  hemorrhage,  as  in  hemophilia,  hypertransfusion  causing  polycy- 
themia should  be  avoided. 

In  the  routine  use  of  transfusion,  owing  to  the  gi-eat  elasticity  of 
the  vascular  bed,  hypertransfusion  seldom  occurs.  It  is  manifested  chiefly 
by  cough,  by  pain  in  the  back,  and,  in  rare  instances,  pulmonary  edema 
may  develop,  as  Unger  has  recently  described.  These  symptoms  may 
occur  regardless  of  the  rate  at  which  blood  is  transfused.  It  is  probable 
that  the  same  symptoms  might  be  produced  by  a  relative  hypertransfusion, 
that  is,  by  the  introduction  of  a  large  amount  of  blood  into  the  circulation 
of  a  patient  having  a  gTeatly  reduced  blood  volume,  such  symptoms  being 
due  to  temporary  embarrassment  of  the  circulation. 

When  transfusion  is  indicated  for  loss  of  hemoglobin  after  hemorrhage, 
a  large  transfusion,  1,000  cc,  may  be  necessary.  In  chronic  anemic  con- 
ditions smaller  amounts  of  blood,  300  to  750  cc,  may  serve  as  well  as 
larger  amounts.  In  chronic  anemia  there  is  some  evidence  to  show  that  a 
small  quantity  of  blood,  repeated  within  a  few  days,  may  be  more  bene- 


TKA:N'SFUSIOiT  OF  BLOOD  835 

ficial  than  a  single  transfusion  of  a  large  amount.  As  an  explanation  for 
the  fact,  it  has  been  suggested  that  the  bone  marrow  reacts  better  follow- 
incr  a  small  than  a  large  transfusion.  When  transfusion  is  indicated  in 
hemorrhagic  conditions  enough  blood  should  be  given  to  stop  the  hemor- 
rhage.    This  is  usually  a  large  amount  rather  than  a  small  one. 


VI.    The  Choice  of  a  Donor 

The  donor  must  be  in  good  health.  He  should  have  a  negative  Wasser- 
mann  reaction,  and  should  be  able  to  provide  the  requisite  amount  of 
blood  desired  for  the  particular  case.  It  must  be  realized  that  the  amount 
the  donor  can  spare  and  the  amount  the  patient  may  receive  should  be 
considered  in  relation  to  the  body  weight  of  each.  A  donation  of  500  c.c. 
of  blood  from  a  donor  weighing  50  kilogi'ams  is  equivalent  to  a  donation 
of  SCO  c.c.  from  a  man  weighing  80  kilogi*ams. 

The  blood  of  the  donor  should  be  compatible  with  the  blood  of  the 
patient,  that  is,  the  red  corpuscles  of  the  donor's  blood  should  not  be 
agglutinated  by  the  serum  of  the  patient.  It  is  also  desirable,  but  not  as 
important,  as  explained  below,  that  the  serum  of  the  donor  should  not 
agglutinate  the  patient's  red  cells.  The  test  for  compatibility  is  a  simple 
one  and  no  transfusion  should  be  done,  except  in  an  emergency  of  an 
extreme  nature,  unless  the  donor's  blood  is  shown  to  be  suitable  for  the 
patient.  It  is  important  not  only  to  avoid  iso-agglutination,  but  also  iso- 
hemolysis,  which  is  a  greater  danger  than  iso-agglutination.  Iso-hemo- 
lysius  are  found  in  many  but  not  all  adults  in  whom  iso-agglutinins  are 
present,  but  they  are  not  present  if  iso-agglutinins  are  absent.  This  is 
convenient,  because  by  tests  for  agglutination,  one  may  rule  out  the  possi- 
bility of  iso-hemolysis  occurring  as  well  as  iso-agglutination.  The  results 
of  iso-agglutination  tests  obtained  in  vitro,  if  carefully  perforaied,  are  a 
reliable  index  as  to  what  will  occur  in  vivo,  so  far  as  iso-agglutination  and 
iso-hemolysis  are  concerned. 

Through  the  work  of  Moss  and  Jansky,  it  is  now  known  that  the  blood 
of  each  adult  falls  into  one  of  four  definite  groups,  as  shown  by  the 
agdutination  reactions  of  the  red  corpuscles  and  serum. 

These  groups  are  sho\\'n  in  Table  III. 

The  blood  of  each  group  is  absolutely  compatible  within  the  gi'oup; 
that  is,  no  iso-agglutination  or  iso-hemolysis  will  occur  when  two  bloods 
of  the  same  group  are  mixed  in  vivo  or  vitro.  The  group  character stic 
may  not  be  fully  established  at  birth.  If  it  is  not,  in  most  cases  it  is 
established  during  the  first  year  of  life.  Once  established,  the  gi*oup  of 
each  human  being  appears  never  to  alter  in  health  or  disease.  Studies 
on  the  iso-hemolysins  and  iso-agglutinins  of  infants  are  reported  in  the 
recent  papers  of  Happ  and  Basil  B.  Jones, 


836 


GEORGE  R.  MINOT  AND  ARLIE  V;  BOCK 


Table  III 


Red  Corpuscles  of  Group* 


1 

2 

3 

4 

Group  1 

0 

0 

0 

0 

Serum  of - 

«       2 

+ 

p 

+ 

0 

"       3 

+ 

+ 

0 

0 

L     "       4 

+ 

+ 

+ 

0 

Per  cent  of  frequency 

5 

40 

10 

45 

0  =  no  agglutination  +  =  agglutination 

*The  classification  given  here  and  referred  to  in  the  text  is  that  giv^n  by  ^Moss. 
Since  this  paper  was  originally  sent  to  the  press,  it  has  been  officially  recommended 
(Jour.  A.  M.  A.,  1921,  76,  130.)  that  on  the  basis  of  priority  the  Janaky  classilica- 
tion  be  adopted,  in  spite  of  the  fact  that  the  Moss  classification  has  been  in  wide 
use  in  America  and  Europe.  The  Jansky  classification  is  considered  identical  to 
Moss*  except  that  groups  1  and  4  are  interchanged.  However,  it  is  not  known  that 
Moss'  groups  2  and  3  are  actually  identical  to  Jansky's.  This  is  because  there  is 
no  evidence  that  anyone  has  compared  the  blood  of  an  individual  belonging  to  group 
2  or  3  as  determined  by  known  sera  or  cells  originating  from  Moss  against  the 
blood  of  individuals  classed  by  Jansky  as  group  2  or  3. 

When  a  donor  is  to  be  tested  for  the  compatibility  of  his  blood  \vitli 
that  of  a  patient,  it  can  be  accomplished  in  two  ways.  The  first  one 
involves  testing  directly  the  donor^s  cells  and  the  patient's  serum  for 
agglutination,  and  the  patient's  cells  and  the  donor's  serum.  If  no  agglu- 
tination occurs  with  both  of  these  combinations  of  cells  and  semm,  it 
indicates  that  the  two  individuals  belong  to  the  same  group,  thus  their 
bloods  are  compatible.  If  either  of  the  tests  is  positive  it  indicates 
that  the  individuals  belong  to  different  gi'oups.  These  tests  do  not  tell 
us  to  what  gi'oup  the  individual  belongs.  This  is  of  no  real  consequence, 
for  our  object  is  only  to  transfer  blood  which  is  compatible.  The  second 
way  in  which  one  may  determine  whether  a  donoi-'s  blood  is  compatible 
with  that  of  a  patient  is  to  determine  the  blood  group  of  each.  This  may 
be  done  by  testing  the  blood  of  each  (either  cells  or  serum)  against 
bloods  (either  serum  or  cells)  whose  gTOups  are  known.  If  both  belong 
to  the  same  gi'oup,  their  blood  is  compatible.  The  blood  of  individuals 
of  a  certain  gi-oup  may  be  given  to  those  of  another  gToup,  as  is  referred 
to  later,  even  when  the  subjects  belong  to  different  gTOups  and  their 
bloods  are  not  strictly  compatible. 

The  detei-mination  of  the  blood  group  of  a  patient  and  prospective 
donor  frequently  simplifies  the  selection  of  a  donor  in  that  the  blood  tests 
may  be  carried  out  at  different  times  and  in  different  places.  Further- 
more, blood  only  need  be  taken  once  from  the  patient.  However,  in  order 
to  control  all  possible  errors,  it  is  distinctly  advisable  just  before  each  and 
every  transfusion  to  test  the  recipient's  serum  against  the  cells  of  thq 
selected  dopor. 


TEANSFUSIO:fT  OF  BLOOD  837 

The  simplest  way  to  determine  to  what  group  a  given  blood  belongs 
is  to  test  its  cells  against  the  sera  of  groups  2  and  3.  The  reason  why 
one  may  determine  the  group  by  these  two  agglutination  tests  is  because, 
as  will  bo  seen  by  reference  to  Table  Til,  thvre  are  but  four  possible  com- 
binations of  positive  and  negative  reactions  of  unknown  cells  with  known 
sera  of  gi-oups  2  and  3.  These  four  different  combinations,  one  for  each 
of  the  four  groups,  allow  identification  of  unknown  cells  by  the  presence 
or  absence  of  their  agglutination  by  groups  2  and  3  sera.  It  serves  as  au 
excellent  control  if  when  the  group  is  determined  a  test  is  made  between 
the  unknown  cells  and  gi*oup  4  serum,  in  addition  to  gioups  2  and  3  sera. 

While  it  is  always  advisable  to  choose  a  donor  who  belongs  to  the 
same  blood  gi^oup  as  that  of  the  patient,  this  is  by  no  means  always  neces- 
sary. This  is  because,  owing  to  certain  protective  mechanisms  associated 
with  a  preponderating  blood  whose  cells  can  be  agglutinated  by  other 
sera,  it  is  possible  to  give  plasma  which  can  in  vitro  agglutinate  and 
hemolyze  the  cells  of  such  blood.  However,  in  the  body,  the  blood  of 
the  recipient  will  pi-event  agglutination  or  hemolysis  of  its  cells  by  the 
donor's  plasma  if  the  transfusion  is  given  under  suitable  conditions  and  in 
at  least  the  usual  amounts.  One  can  never  give,  without  serious  risks, 
red  cells  that  can  be  agglutinated  by  the  patient's  plasma,  which  is  under 
usual  conditions  the  preponderating  plasma  following  transfusion.  Con- 
sequently, a  group  4  donor  may  be  regarded  as  a  universal  donor,  since 
his  cells  cannot  be  agglutinated  by  any  plasma,  and  a  member  of  group  1 
can  be  regarded  as  a  universal  recipient  since  his  plasma  can  agglutinate 
the  cells  of  no  other  group.  It  is,  as  stated,  desirable  to  transfuse  blood 
within  the  same  group,  yet  as  a  practical  measure  it  has  been  demonstrated 
repeatedly  that  blood  of  group  4  can  be  utilized  for  transfusion  in  any 
one  of  the  four  groups. 

The  practical  advantage  of  regarding  a  member  of  gi'oup  4  as  a  uni- 
versal donor  is,  of  course,  obvious.  It  mei'ely  requires  the  testing  of  a 
donor  and  does  not  require  the  testing  of  a  patient  This  enables  one  to 
have  a  supply  of  group  4  donors  on  hand  for  possible  emergency  trans- 
fusions. With  the  presence  of  a  combination  of  a  gi-eat  reduction  of 
blood  volume,  a  majked  reduction  of  red  cell>.  an  anticipated  transfusion 
of  a  large  amount  of  blood,  and  a  strong  iso-hemolysin  in  the  donor's 
blood,  it  is  unwise  to  transfuse  from  a  group  4  donor  into  a  recipient  of 
another  group.  Clinical  experience  justifies  this  exception  to  the  rule  of 
the  use  of  group  4  individuals  as  universal  donors,  when  it  is  difficult  to 
obtain  a  donor  of  the  same  group  as  that  of  the  patient.  It  is,  however, 
more  desirable  under  any  circumstances  to  use  a  group  4  donor  for  an 
individual  of  another  gTOup  than  one  thought  to  belong  to  the  same 
group  as  the  patient,  but  whose  gi'oup  designation  is  not  clear  cut.  This 
is  particularly  true  when  dealing  with  grouj)?  1  and  3  patients  whose  iso- 
agglutinins  and  red  cell  receptors  are  apt  to  be  of  a  weaker  nature  than 


838  GEORGE  R.  MmOT  AND  ARLIE  V.  BOCK 

those  of  groups  2  and  4.  For  a  more  detailed  discussion  regarding  the  iso- 
agglutinins,  iso-hemolysins  and  the  selection  of  donors,  the  reader  is  re- 
ferred to  the  references  cited  above  and  to  those  by  Brem,  Minot(&),  Coca, 
Vincent(Z)),  Sanford,  Rous  and  Turner,  Karsner(6),  Karsner  and  Koeck- 
ert,  Clough  and  Richter. 

It  is  not  the  purpose  of  this  article  to  discuss  technic,  but  it  seems 
desirable  briefly  to  summarize  a  suitable  method  for  performing  these 
agglutination  tests.  This  summary  is  essentially  the  same  as  that  previ- 
ously given  by  Minot  and  Lee. 

In  order  to  make  a  test  between  serum  (fresh  or  stock)  and  the  red 
cells,  the  following  simple  procedure  with  chemically  clean  glassware 
will  usually  suffice.  A  suspension  of  cells  (about  5  per  cent)  is  obtained 
by  the  addition  of  3  to  5  drops  of  blood  to  about  2  c.c.  of  1  per  cent  solu- 
tion of  sodium  citrate  in  0.0  per  cent  sodium  chlorid  solution.  These 
cells  need  not  be  washed.  A  drop  of  the  red  cell  suspension  is  mixed 
with  a  drop  of  serum.  It  is  important  to  make  the  mixture  complete. 
This  may  be  done  upon  a  glass  slide  with  a  cover  glass  put  over  the 
mixture.  The  cover  glass  should  always  be  raised  and  the  cells  and  seinim 
remixed  several  times  before  a  negative  reading  is  made.  A  hanging  drop 
preparation  peniiits  neater  technic  and  avoids  drying.  The  test  often 
may  be  read  macroscopically,  but  should  always  be  read  microscopically, 
in  order  to  avoid  any  possible  errors  except  when  it  is  rapidly  and  un- 
doubtedly positive.  In  order  to  guard  against  possible  errors,  it  is  always 
wise  to  allow  the  mixture  of  cells  and  serum  to  remain  for  at  least  30 
minutes,  preferable  in  the  incubator.  While  there  are  few  opportunities 
for  confusion  in  this  simple  test,  nevertheless  the  penalty  of  transfusion 
of  incompatible  blood  may  be  so  great  that  every  reasonable  care  should 
be  given  to  the  performance  of  the  test.  Confusion  may  be  caused  by 
weak  agglutination.  It  is  always  possible  by  employing  different  amount  s 
of  cells  and  serum,  by  incubating  the  mixture  for  some  hours  and  by 
thoroughly  washing  the  red  cells,  to  decide  the  problem  of  doubtful  reac- 
tions. However,  if  by  the  method  described  the  reaction  is  not  clear 
and  perfectly  definite,  the  test  must  be  repeated  and  perhaps  amplified. 
A  safe  rule  is  never  to  regard  a  reaction  in  w^hich  there  is  any  doubt  as 
negative.  Rouleaux  formation  may  be  easily  demonstrated  as  quite 
different  from  agglutination.  Confusion  may  be  caused  by  atypical  agglu- 
tinations, that  are  very  rarely  intense,  due  to  auto-agglutination  and  allied 
phenomena  which  are  little  understood.  Stock  sera  for  determining  to 
what  group  a  human  being  belongs  will  keep  many  months  and  even  years 
if  sterile,  carefully  sealed  and  in  the  ice-box.  Stock  sera  liave  an  ad- 
vantage over  fresh  sera  in  that  they  are  less  liable  than  fiesh  sera  to 
produce  reactions  with  red  cells,  which  may  be  confused  with  iso-agglu- 
tination.  It  may  be  again  emphasized  that  when  carefully  done  the  re- 
action of  agglutination  is  in  a  very  large  proportion  of  cases  clear  and 


TRANSFUSIOi^  OF  BLOOD  839 

definite.  In  practice  it  is  always  expedient  to  discard  as  a  donor  one 
whose  blood  causes  any  doubt  about  his  group  or  about  the  reaction  of  his 
cells  with  the  patient's  serum. 


VII.     Reactions  from  Transfusion 

Previously,  the  beneficial  elTects  of  transfusion  have  been  discussed. 
It  is  now  necessary  to  point  out  the  harmful  eifects  which  may  result  from 
this  procedure.  If  a  donor  is  used  who  is  not  healthy,  syphilis,  malaria 
and  other  diseases  may  be  transferred  to  the  patient.  Hypertransfusion 
has  been  previously  referred  to  and  can  always  be  avoided.  Reactions 
due  to  incompatibility  of  blood,  as  shown  in  vitro,  may  occur  if  improper 
tests  are  made.  The  deleterious  effects  of  transfusions  done  with  com- 
pletely proper  technic  are  those  in  the  nature  of  a  reaction  from  some  un- 
known alteration  in  the  transfused  blood,  and,  in  some  instances,  depen- 
dent upon  the  state  of  the  patient.    Such  I'eact ions  are  ver\-  rarely  serious. 

1.  Reactions  Due  to  Recognized  Incompatibility. — Reactions  re- 
sulting from  the  transfer  of  blood  incompatible  with  that  of  the  patient's, 
in  that  iso-agglutination  or  iso-hemolysis  occurs,  may  vary  from  a  state  of 
temporary  discomfort  to  a  grave  disturbance  which  may  be  fatal.  The 
reasons  for  variations  in  the  degree  is  due,  at  least  in  part,  to  quantitative 
variations  in  the  amounts  of  the  factors  involved  in  iso-agglutination  and 
iso-hemolysis.  The  selection  of  donors  by  means  of  proper  agglutination 
tests  eliminates  reactions  of  this  type.  Very  rarely,  as  is  referred  to  below, 
similar  hemolytic  reactions  may  occur  w^hen  bloods  apparently  have  been 
properly  tested. 

When  blood  is  given  to  an  individual  whose  serum  can  agglutinate 
the  donor's  red  cells,  the  symptoms  due  to  this  incompatibility  may  develop 
after  a  very  small  amount  of  blood  has  been  injected.  Typically  this 
reaction  may  be  described  as  follow^s:  The  patient  becomes  restless,  com- 
plains of  pain  in  the  back,  develops  an  increased  respiratory  and  pulse 
rate  and  may  soon  vomit  and  have  a  chill  followed  by  a  sharp  rise  of 
temperature.  With  hemolysis,  jaundice  may  develop  rapidly  and  become 
severe,  and  the  urine  may  be  scanty  and  filled  with  hemoglobin.  The 
patient  may  become  iinconscious  and  appear  as  in  shock.  Death  may 
follow  rapidly  or  wnthin  a  few  days,  though  the  severity  of  the  reaction  is 
usually  over  within  twenty-four  hours  and  the  patient  much  more  usually 
recovers  than  dies.  The  temperature  often  remains  elevated  for  several 
days  and  the  jaundice  may  persist  for  a  similar  length  of  time.  The 
degree  of  anemia  following  severe  reactions  is  usually  more  pronounced 
than  before  transfusion.  Occasionally,  such  a  reaction  is  followed  by  in- 
tense activity  of  the  bone  marroAV  and  a  surprisingly  rapid  improvement 
in  the  anemia  occurs. 


840  GEORGE  R.  MI^^OT  AKD  A.RLIE  V.  BOCK 

The  severity  of  the  reaction  may  vary  greatly  not  only  in  different 
patients,  but  also  in  the  same  patient,  even  when  the  same  donor  is  used 
for  a  subsequent  transfusion.  A  mild  reaction  following  a  first  trans- 
fusion may  consist  of  but  a  very  temporary  rise  of  temperature  and  a 
chill.  On  the  contrary,  a  second  transfusion  from  the  same  donor  may 
induce  a  severe  hemolytic  reaction.  A  presumptive  explanation  for  this 
change  in  reaction  is  the  development  in  the  interim  between  the  trans- 
fusions of  an  increase  in  strength  of  the  agglutinins  and  the  development 
of  hemoh'sins  in  the  patient^s  blood. 

2.  Reactions  Not  Due  to  Recognized  Incompatibility. — These  are 
of  two  types.  First,  those  that  are  distinctly  rare  and  that  resemble  an  iso- 
liemolytic  reaction.  Second,  those  that  are  the  commonest  and  mildest  re- 
actions that  follow  transfusion,  and  that  are  associated  with  the  instability 
of  blood  when  removed  from  the  body. 

(a)  Reactions  Thai  Eesemhle  Those  Due  to  Recognized  Iso-hem- 
olysis. — In  some  diseased  conditions,  particularly  sepsis  and  blood  dis- 
eases, the  blood  sometimes  seems  to  be  altered  with  a  production  of 
hemolysins  and  agglutinins  not  normally  present.  To  these  abnormal 
hemolysins  and  agglutinins  are  attributed  some  of  the  rare  reactions  of  a 
hemolytic  nature  which  may  be  fatal  following  transfusion  perfonned 
with  donors  selected  by  the  usual  tests.  Such  reactions  appear  to  be 
delayed  usually  some  hours  in  their  onset  in  contrast  to  the  classical  iso- 
heraolytic  reactions  that  develop  at  least  shortly  after  transfusion.  (See 
Eowcock,  and  Robei-tson  and  Rous.) 

Sydenstricker,  Mason  and  Rivers  have  observed  serious  hemolytic  re- 
actions following  repeated  transfusion  in  pernicious  anemia,  wdienthe 
donors  were  properly  chosen.  The  cause  of  these  reactions  is  Unknown. 
These  hemolytic  reactions  a^isociated  with  properly  tested  donors  are  not 
to  be  confused  with  true  iso-hemolytic  reactions  dependent  upon  improper 
agglutination  tests.  Some  hemolytic  reactions  that  have  been  reported 
when  the  donor's  and  patient's  blood  w^as  tested,  undoubtedly  have  been 
due  to  improper  laboratory  tests.  The  tests  were  probably  incorrectly 
read  owing  to  the  presence  of  weak  agglutination  reactions  in  vitro. 

(b)  Reactions  Associated  with  Instahility  of  Blood  \Vhen  Removed 
from  the  Body. — The  commonest  reactions  seen  after  transfusion  cannot 
be  foretold  and  they  are  not  definitely  associated  with  agglutination  or 
hemolysis.  These  reactions  are  of  a  milder  nature  than  those  previously 
described  though  they  rarely  may  be  distinctly  severe.  The  onset  of 
symptoms  is  usually  about  an  hour  after  transfusion.  In  the  majority  of 
cases  they  subside  w- ithin  tw^enty-four  hours.  The  s^inptoms  usually  begin 
with  a  sharp  rise  of  temperature  of  a  degree  to  four  or  five  degrees,  and 
even  more.  With  the  symptoms  of  fever,  nausea,  vomiting  and  diarrhea 
may  occur.  Chills  may  be  associated  wath  temperature  rise.  Urticaria, 
and  other  lesions  of  the  erythema  group,  and  rarely  edema  and  purpura, 


TRANSFUSION  OF  BLOOD  841 

may  occur.  Herpetiform  vesicles  may  develop  about  the  mouth.  The 
symptoms  are  rarely  alannlng  and  usually  the  reaction  consists  of  only  a 
simple  rise  in  temperature. 

These  reactions  follow  the  giving  of  blood  by  any  method.  They  are 
apparently  much  more  common  when  blood  is  altered  by  an  anticoagulant 
than  when  blood  is  given  without  addition  of  such  a  substance.  The  fre- 
quency of  such  reactions  varies  gi-eatly  according  to  different  observers. 
It  seems  that  in  round  numbers  outspoken  definite  reactions  occur  fol- 
lowing transfusion  of  blood,  as  such,  in  about  1 5  per  cent  of  the  instances 
and  with  citrated  blood  in  about  35  per  cent  of  the  instances. 

Reactions  of  this  type  are  generally  considered  as  dependent  upon  some 
not  clearly  demonstrated  alterations  of  blood,  associated  with  its  removal 
from  the  body.  In  some  cases,  alteration  of  the  patient^s  blood  seems  to 
play  a  part.  This  is  thought  to  be  the  case  because  these  reactions  appear 
to  be  commoner  in  patients  with  extensive  pathology  of  their  hematopoietic 
organs,  such  as  occurs  in  pernicious  anemia,  than  in  those  whose  hemato- 
]X)ietic  system  is  of  a  noiinal  type,  such  as  is  found  in  cases  with  anemia 
due  to  acute  blood  loss. 

Satterlee  and  Hooker,  in  a  review  of  the  known  facts  concerning  such 
reactions,  suggest  three  possible  mechanisms  by  which  they  may  be  pro- 
duced. One  is  that  the  trypsin-antitrypsin  balance  in  the  circulating 
blood  of  the  recipient  is  so  disturbed  as  to  result  in  the  immediate  forma- 
tion of  serotoxin  from  cleavage  products.  A  second  theory  is  that  the 
action  of  the  protective  colloids  in  the  body  cells  of  the  recipient  may  be 
upset  so  that  these  cells  are  exposed  to  a  reaction  of  the  antigen  and 
antibody  present  in  the  circulation  of  the  recipient,  but  harmless  to  the 
protected  cells.  The  third  theory,  one  which  is  substantiated  by  many 
facts,  concerns  the  possibility  of  a  toxic  disturbance  in  the  circulation  of 
the  recipient  by  the  introduction  of  blood  which,  though  perfectly  fluid, 
may  be  undergoing  incipient  coagulation  changes  dtte  to  the  physical 
influences  to  which  it  is  subjected  in  the  process  of  transfer.  The  experi- 
mental work  of  Drinker  and  Brittingham  and  Wright  and  ^linot,  as  well 
as  the  clinical  results  of  workers  experienced  in  the  technic  of  trans- 
fusion, suggests  that  the  coagulation  changes  may  account  for  most  of 
these  reactions. 

Novy  and  DeKruif  attribute  the  toxicity  of  blood  in  the  precoagula- 
tion  stage  to  the  presence  of  poison,  anaphylatoxin,  which  is  also  present 
in  greater  or  less  concentration  in  normal  serum.  The  mechanism  of  the 
production  of  this  substance  is  the  subject  of  an  interesting  theory  pro- 
posed by  these  authors,  and  it  may  explain  certain  post-transfusion  reac- 
tions. Novy  and  DeKruif  believe  that  the  matrix  of  the  i>oison  is  always 
present  in  the  circuhitiiig  blood  and  is  a  substance  as  labile  as  fibrinogen, 
and  that  just  as  fibrinogen  is  changed  by  thrombin  to  fibrin,  so  the  matrix 
is  converted  through  the  action  of  a  great  variety  of  substances  into 


842  GEORGE  R.  MmOT  AKD  ARLIE  V.  BOCK  "^ 

anaphjlatoxin.  A  foreign  blood  plasma  could  thus  easily  act  as  an  accel- 
erator of  this  action  and  suddenly  convert  the  circulating  blood  into  a 
toxic  substance. 

Another  factor  to  be  considered  is  the  influence  of  an  anticoagulaut 
such  as  sodium  citrate.  Experience  with  citrated  blood,  as  statefl  before, 
has  resulted  in  a  much  larger  percentage  of  reactions  of  mild  type  than 
when  blood  is  used  to  which  no  substance  has  been  added.  Drinker  and 
Brittingham  have  suggested  that  this  may  in  part  be  due  to  the  action 
on  the  red  cells  of  sodium  citrate  which  promotes  hemolysis. 

It  is  certainly  true  that  the  less  blood  is  altered  the  less  chance  there 
is  that  these  reactions  will  occur.  Such  alterations  are  often  beyond  con- 
trol, for  at  least  a  small  number  of  these  reactions  will  develop  despite 
scrupulous  technic  in  transfusion.  Even  so,  neat  technic  with  rapid 
transfer  of  blood  will  permit  the  fewest  possible  reactions. 

By  no  manner  of  means  is  it  to  be  thought  that  transfusions  with 
citrated  blood  should  not  be  done,  because  these  reactions  are  usually 
slight  and  rarely  alarming,  and  fatality,  if  it  occurs,  must  be  very  rare. 
However,  reactions  appear  to  be  less  frequent  when  blood  without  an  anti- 
coagulant is  used,  so  that  in  certain  instances  it  may  be  preferable  not 
to  give  citrated  blood. 


VIII.    Methods  of  Transfusion 

Indirect  methods  of  transfusion  have  entirely  replaced  the  original 
direct  methods.  The  simplicity  of  the  indirect  methods,  together  with  the 
ease  with  which  hemolysis  may  be  avoided,  has  led  to  the  general  use  of 
blood  transfusion.  Such  methods  are  designed  to  transfer  blood  either 
as  unaltered  whole  blood  or  blood  mixed  with  an  anti-coagulant,  especially 
sodium  citrate. 

The  chief  advantage  of  transfusion  of  blood  to  which  no  substance  has 
been  added  is  that  it  produces  fewer  reactions,  not  due  to  recognized 
incompatibility,  than  citrated  blood.  In  view  of  the  reactions  associated 
with  transfusion,  it  is  theoretically  desirable  to  transfuse  blood  in  its 
natural  state  as  far  as  it  lies  within  technical  means  to  do  so.  The  dis- 
advantages encountered  in  the  transfer  of  blood  to  which  no  substance  has 
been  added  consist  in  difficulties  with  a  more  cumbersome  technic  for 
transfusion,  usually  requiring  two  or  more  persons,  and  more  experience 
than  is  necessary  with  the  citrate  method.  There  is  also  a  more  frequent 
necessity  for  cutting  down  on  veins  when  certain  methods  for  transfusing 
blood  without  anticoagulant  are  employed.  In  the  hands  of  experts,  these 
difficulties  are  not  troublesome,  and  in  such  cases  transfusion  of  unaltered 
whole  blood  is  the  method  of  choice. 

Descriptions  of  methods  for  the  transfusion  of  blood  to  which  no 


TRA:N"SFUSIOiNr  OF  BLOOD  '     843 

substance  has  been  added  may  be  found  in  the  papers  of  Kimpton  and 
Brown,  Vincent(rt),  Lindeman,  and  linger  (a)  (?>). 

The  reasons  for  the  use  of  an  anticoagulant  for  transfusions  are  sim- 
plication  of  teclinic;  the  necessity  for  haste  becomes  a  secondary  considera- 
tion and  it  is  often  more  convenient  since  the  donor  and  recipient  need 
not  be  in  the  same  room.  One  person  can  perform  a  transfusion  with  the 
citrate  method,  and  it  is  usually  possible  to  avoid  exposure  of  veins  hy 
skin  incision. 

There  is  theoretical  ground  for  objection  to  the  use  of  sodium  citrate 
on  the  grounds  of  toxicity,  but  the  experience  of  Weil,  Le\visohn(a)(6), 
and  many  others,  shows  that  in  doses  up  to  5  grams  the  drug  has  no  dem- 
onstrable ill  effects.  Investigation  of  the  effect  of  citrate  upon  the  coagula- 
tion time  of  the  blood  in  vivo  has  demonstrated  that  in  animals  the 
coagulation  time  is  greatly  shoi-tened.  In  man,  there  has  been  observed 
no  important  change  in  the  coagulation  time  after  the  injection  of  citrated 
blood,  when  the  coagulation  time  was  not  abnormal.  However,  transfusion 
of  citrated  blood  appears  to  be  able  to  shorten  a  patient's  abnormally  long 
coagulation  time  in  the  same  manner  as  blood  to  which  no  substance 
has  been  added.  The  effect  of  citrate  upon  hemolysis  of  red  cells  has 
been  referred  to. 

For  details  of  the  methods  for  the  use  of  citrated  blood,  the  reader 
may  consult  articles  by  Robertson,  Drinker  and  Brittingham,  and 
Lewisohn. 


Mineral  Waters ..........  e Henry  A.  Mattiii 

Saline  Waters — Alkaline  Waters,  Including  Carbonated — Bitter  Waters — Sul- 
phur Waters — Iron  Waters — Arsenic  Waters — Radioactive  Waters. 


Mineral  Waters 

HEXRY  A.  MATTILL 

ROCHESTER,   N.   Y. 

On  no  subject  in  medical  literature  probably  has  there  appeared  so 
much  worthless  writing  as  on  that  of  mineral  waters.  Our  own  country 
is  not  guiltless  but  by  far  the  largest  mass  of  advertising  under  the  guise 
of  science  has  appeared  in  Europe  particularly  in  Germany,  France  and 
Austria.  While  there  may  be  virtue  in  many  of  the  "drinking  cures'' 
the  careful  dieting  and  well  ordered  living  which  are  a  part  of  the 
'^cure''  are  in  themselves  of  great  therapeutic  value,  and  the  ingestion 
of  water  without  any  mineral  has  very  definite  effects  on  metabolism, 
effects  which  indeed  may  outweigh  any  others  attendant  upon  the  pres- 
ence of  a  small  amount  of  mineral  salts.  While  the  combined  action  of 
mineral  substances  as  they  are  found  in  natural  mineral  waters  is  un- 
doubtedly different  from  that  of  the  individual  substances,  it  is  not  to  be 
supposed  that  the  action  would  be  different  if  the  natural  mineral  water 
were  exactly  reproduced.  In  considering  the  relation  of  mineral  water 
to  metabolism  only  such  investigations  as  have  been  made  with  natural 
mineral  waters  themselves  will  in  general  be  reviewed,  since  the  metab- 
olism of  mineral  matter  is  considered  elsewhere.  Until  the  laws  govern- 
ing mineral  metabolism  are  more  clearly  understood  than  they  are  to-day 
the  therapeutic  value  of  mineral  water  administration  must  remain  in  the 
realm  of  the  empirical. 

A  clear  cut  classification  of  mineral  waters  is  not  easily  made  since 
a  water  may  contain  several  ingredients;  according  to  their  predominating 
characteristics,  they  may  be  divided  into  the  following  classes :  saline,  alka- 
line (including  carbonated),  sulphate  or  bitter  water,  sulphur,  iron  or 
chalybeate,  arsenic  and  radioactive  waters.^ 

*  From  a  geochemical  standpoint  the  fundamental  cliaraeter  of  a  mineral  water  is 
best  expressed  in  terms  of  tl.e  "properties  of  reaction"  a?!  suggested  by  Palmer.  Pri- 
mary salinity  is  caused  by  strong  acid  salts  of  tlie  alkalies  (as  NaCl,  KjSO^,  etc. ); 
secondary  salinity  by  strong  acid  salts  of  the  alkaline  earths  (as  CaS04,  MgClj,  etc.)  ; 
primary  alkalinity  is  caused  by  weak  acid  salts  of  the  alkalies  (as  XaHCOaKHS,  etc.)  ; 
secondary  alkalinity  by  weak  acid  salts  of  the  alkaline  earths  (as  CaHC03)3,  etc.)  and 
tertiary  alkalinity  by  colloidal  oxids  of  iron  and  aluminum  and  free  weak  acids,  as 
SiOz  and  CO2.  These  "properties  of  reaction"  ca,n  easily  be  calculated  from  a  water 
analysis  in  which  the  values  are  given  in  terms  of  the  ionic  substance  and  the  quality 
or  character  of  the  water  though  not  its  actual  content  of  minerals,  is  then  expressed. 

845 


846  HENRY  A.  MATTILL 

Saline  Waters. — The  first  important  work  on  the  effects  of  saline 
waters  on  gastric  secretion  was  done  by  Dappor(Z?)  on  persons  suffering 
from  gastric  disordei*s;  when  the  usual  amount  of  saline  water  was  given 
before  breakfast  he  was  able  to  note  nonnal  amounts  of  hydrochloric  acid 
in  cases  of  hypoacidity  due  to  catarrh.  Hypoacidity  of  nei-vous  origin 
was  not  affected,  while  in  a  number  of  patients  hyperacidity  of  nerxous 
origin  was  considerably  reduced  by  the  same  treatment,  thus  indicating  that 
the  result  was  not  merely  a  stimulation  or  inhibition  of  acid  secretion, 
but  a  modification  of  the  processes  in  the  epithelium.  Later  work  on 
patients  (Meinel)  and  experiments  on  a  dog  with  accessory  stomach  re- 
ported by  Bickel(a),  also  showed  that  saline  water  given  before  a  test  meal 
caused  a  slight  increase  in  acidity,  a  slightly  more  rapid  appearance  of 
the  hydrochloric  acid  and  emptying  of  the  stomach. 

Similar  experiments  on  the  Homburg  Springs  (Baumstark)  (saline, 
CO2)  showed  that  these  waters  brought  about  a  very  noticeable  increase 
in  the  amount  of  gastric  secretion  (av.  74  per  cent)  as  compared  with  ordi- 
nary water,  and  also  an  increase  in  acid  content.  The  opposite  result  ap- 
peared when  milk  was  given  with  the  water,  from  which  it  was  concluded 
that  the  digestion  period  must  not  be  identical  with  that  in  which  mineral 
waters  are  ingested.  The  presence  of  CO2  may  explain  the  gi'eater  stimu- 
lating effect  of  the  water  alone  (see  below). 

Sasaki,  who  obtained  like  results,  claimed  that  the  per  cent  of  hydro- 
chloric acid  in  gastric  juice  was  not  changed  but  that  the  larger  amount  of 
secretion  was  the  fundamental  thing.  Casciani(a)  and  Coleschi(a)  em- 
phasized the  fact  that  the  hypotonic  hydrochloric  acid  waters  especially 
have  a  stimulating  effect,  while  hypertonic  waters  act  as  depressants, 
isotonic  having  no  effect.  Whether  the  tonicity  of  the  gastric  contents  as 
such  is  an  important  factor  has  been  the  subject  of  considerable  experiment 
and  discussion.  The  existence  of  a  "diluting  secretion'^  was  affirmed  by 
Strauss  and  Roth  such  that  the  higher  the  molecular  concentration  of  a 
water,  the  longer  it  remains  in  the  stomach  and  the  gi'eater  the  retardation 
in  the  appearance  of  hydrochloric  acid  (Strauss,  h).  Other  investigators 
(Bonniger;  Sommerfeld  and  Boeder;  Otto)  have  not  confirmed  the  ex- 
istence of  a  diluting  secretion  and  the  behavior  of  mineral  water  in  the 
stomach  bears  no  simple  relation  to  its  molecular  concentration  (Tauss). 
However,  the  delay  of  gastric  function  by  concentrated  waters  is,  accord- 
ing to  V.  Xoorden,  a  matter  of  therapeutic  importance.  Hypotonic  solu- 
tions (Wiesbaden*  Kochbrunnen)  rapidly  become  less  so  in  the  stomach 

Since  these  chemical  qualities  are  not  likewise  "physiologicar'  qualities,  it  seemed 
best  to  retain  the  older  and  more  familiar  classification.  As  Albu  and  Neubcrg  suggest, 
balneotherapy  may  become  more  useful  when  the  ionic  composition  of  a  mineral  water 
is  properly  considered.  \Miile  they  express  great  hope  for  the  future  of  mineral 
water  therapy  along  the  lines  of  Koeppe's  investigation  on  the  osmotic  pressure  and 
dissociation  constants  of  mineral  waters,  no  such  development  seems  as  yet  to  have 
taken  place. 


MIiYERAL  WATERS  847 

( Bickel(«) )  and  the  stimulating  effect  of  water  alone  (King  and  Ilanford ; 
Sutherland;  Hawk(e))  first  shown  by  L'awlovv  probably  play.s  an  impor- 
tant rule.  In  this  connection  may  also  be  mentioned  v.  Xoorden's  opinion 
that  experimental  results  of  value  in  tlierapeutics  cannot  be  obtained  in  the 
normal  organism  but  must  be  secured  in  one  that  is  deranged  by  disease. 

On  pancreatic  secretion  saline  waters  have  a  stimulating  effect 
(Bickel(r  ) )  as  shown  in  experiment  on  dogs  with  pancreatic  fistuhi.  The 
question  as  to  the  influence  of  these  waters  on  the  utilization  of  food  has 
long  been  of  interest  and  the  monograph  of  v.  Xoorden  summarizes  his 
own  results  and  those  of  others  on  persons  in  health  and  in  disease.  Fats 
especially  had  customarily  been  contra-indicated  during  the  cures  because 
of  their  supposedly  defective  absorption  and  this  idea  is  completely  refuted, 
for  the  changes  in  fat  excretion  were  within  normal  limits,  during  the 
mineral  water  periods  sometimes  above  and  sometimes  below  the  original 
values.  This  was  found  true  even  when  unusual  amounts  of  fat  were  in- 
gested; no  marked  decrease  in  its  assimilation  occurred  despite  the  simul- 
taneous administration  of  maximum  quantities  of  fat  and  mineral  water 
together.  Even  small  supplements  of  (Kissingen)  bitter  waters  (SO4) 
did  not  always  increase  the  fecal  content  of  fat  and  of  nitrogen  though 
their  laxative  action  was  noted. 

In  their  long  series  of  cases  the  stimulation  of  protein  metabolism,  a 
phrase  which  appears  ad  nauseam  in  so  much  of  the  balneological  litera- 
ture, was  not  observed.  The  excretion  of  uric  acid  was  generally  increased 
by  drinking  weak  saline  waters,  especially  in  gouty  patients  (v.  ISToorden 
and  Dapper  (a)  ;  Leber)  a  statement  for  which  v.  Xoorden  has  no  explana- 
tion, but  which  must  be  accepted  on  the  basis  of  the  figures  given  ;  opposite 
findings  on  well  persons  are  reported  by  Bain  and  Edgecombe  and  v. 
Xoorden  also  observed  the  opposite  in  nephrolithiasis. 

A  diuretic  property  has  also  been  the  marvelous  possession  of  all  min- 
eral waters.  Water  is  the  best  diuretic,  said  Osier,  and  mineral  waters  are 
seldom  properly  compared  with  ordinary  water  nor  are  the  relations  of 
diet,  muscular  activity  and  external  temperature  and  humidity  ever  con- 
sidered. A  transient  diuresis  (15-30  min.)  is  indeed  often  observed  after 
drinking  mineral  water  and  the  increased  rapidity  with  which  some  min- 
eral w^aters  leave  the  stomach  as  compared  with  ordinary  water  may  in 
part  account  for  this;  some  of  the  salts  they  contain  do  also  act  as  stimu- 
lants to  the  renal  epithelium  but  no  one  has  addressed  himself  pi-operly  to 
the  task  of  determining  the  behavior  of  the  kidney  under  the  prolonged  and 
immediate  influence  of  mineral  waters,  and  to  the  temporary  and  perma- 
nent effects  on  the  body  of  such  behavior.  The  ingestion  of  larger  amounts 
of  water  (1200  c.c.  in  1  hr.)  with  consequent  enormous  diuresis  has  very 
little  effect  on  the  blood  according  to  Haldane  and  Priestley.  Its  conduc- 
tance is  slightly  diminished  whereas  when  salt  solution  is  ingested  its 
conductance  is  increased  but  hemoglobin  percentage  is  lowered.     It  has 


848  he:n'Ry  a.  mattill 

been  stated  that  the  mineral  content  of  the  blood  usually  increases,  always 
within  physiological  limits  after  drinking  various  mineral  waters,  with 
proportionate  clianges  in  A  (v.  Szabohy;  Grube),  but  most  observations 
are  to  the  effect  that  the  molecular  concentration  of  the  blood  is  maintained 
with  gi-eat  tenacity  (Grossmann;  Strauss(c))  though  here  again  the  be- 
havior of  normal  cases  may  not  properly  indicate  that  of  pathological  ones. 
The  tissues  rather  than  the  blood  are  the  regidating  factors  in  this  con- 
nection (Bogert,  Underbill  and  ^Nlendel). 

Alkaline  Waters,  Including  Carbonated. — Earlier  work  on  the  im- 
mediate effect  of  alkaline  waters  taken  \vith  a  meal  on  gastric  secretion  was 
inconclusive  because  the  variations  found  were  within  nomial  limits. 
Later  work  indicates  that  such  waters  taken  with  food  have  very  little  in- 
fluence (v.  Xoorden  and  Dapper(rt)  ;  Xing  and  Hanford).  When  given 
before  meals  in  the  usual  spa  fashion  sodium  carbonate  according  to  some 
earlier  investigations  has  very  little  if  any  effect  on  the  secretion  of 
hydrochloric  acid  (Reichmann),  according  to  others  a  stimulation  up  to 
the  point  of  neutralization  and  perhaps  beyond  (Linossier  and  Lemoine)  to 
an  abnormally  high  amount.  The  earlier  work  on  Carlsbad  water  (alka- 
line-saline, containing  also  small  amounts  of  Glauber's  salts)  which  iX)inted 
to  a  slightly  stimulating  effect  on  hydrochloric  acid  secretion  for  the  gen- 
eral digestion  period  has  been  supplanted  by  results  secured  on  dogs  with 
accessory  stomach  or  human  cases  with  esophageal  fistula.  According  to 
Bickel(&)  such  water  has  no  influence  on  gastric  secretion,  although  clin- 
ically favorable  results  are  reported  both  in  hyperacidity  and  hypoacidity. 
However,  it  cannot  be  claimed  that  these  effects  are  other  than  temporary 
and  transient.  Dieting,  according  to  v.  Xoorden,  is  a  much  more  satis- 
factory and  efficient  remedy.  According  to  Sasaki  these  waters  are 
generally  slightly  inhibitory,  a  statement  with  which  most  later  investi- 
gators are  in  agi'eement  (Bickel(<:Z) ;  Casciani(?^)  ;  Heinsheimer ;  Pime^ 
now;  Rozenblatt). 

The  results  obtained  with  alkaline-saline  waters  from  certain  Rou- 
manian springs  suggest  that  chlorid  and  bicarbonate  are  to  an  extent  an- 
tagonistic in  their  influence  on  gastric  secretion  and  that  the  resultant 
effect  is  dependent  on  the  proportions  present  (Teohari  and  Babes). 

Carbonated  waters  are  generally  found  to  be  stimulating  in  their  ef- 
fect on  the  gastric  mucosa  (Penzoklt(?>) ;  Casciani(a)(&)  ;  Coleschi(a)) 
and  also  on  pancreatic  secretion  (Becker)  (perhaps  as  a  result).  The 
stimulating  action  of  alkaline  waters  containing  CO2  is  therefore  to  be 
credited  to  the  influence  of  CO2  as  neutralizing  the  inhibitory  tendency  of 
the  alkali.  Gaseous  CO2  in  the  stomach  stimulates  secretion  and  acidity 
in  the  accessory  stomach  (Pincussohn)  and  such  stimulation  of  alkali  as 
has  been  observed  is  credited  to  COo  formation  (Pimenow)  since  about  the 
same  results  are  obtained  when  using  water  saturated  with  COg.  The  ef- 
fect of  calcium  carbonate  in  producing  a  '"stormy'^  (Heinsheimer)  increase 


MINEEAL  WATP:RS  840 

in  secretion  is  likewise  probably  to  be  credited  to  the  carbon  dioxid  evolved, 
peihaps  also  to  calcium  (Polimanti).  The  effect  of  lithium  salts  and 
water  is  to  be  explained  in  the  same  way  (Mayeda). 

Purely  alkaline  waters  also  depress  pancreatic  secretion,  while  car- 
bonated waters,  like  the  saline  waters  stimulate  it;  these  also  increase 
biliary  secretion  (Jappelli),  all  of  which  effects  can  probably  be  traced 
back  to  a  gastric  origin. 

Information  as  to  their  influence  on  the  utilization  of  food  is  scanty. 
Early  experiments  indicate  little  if  any  change  in  the  utilization  of  pro- 
tein and  fat  as  a  result  of  drinking  1  liter  of  alkaline  water,  and  ethereal 
sulphates  were  also  unchanged.  The  influence  of  alkalies  themselves  on 
ethereal  sulphates  is  variable  and  there  is  need  of  data  on  the  efl^ect  of 
mineral  waters  in  cases  of  high  ethereal  sulphates  and  indican.  By  the 
ingestion  of  alkaline  water  the  ammonia  content  of  the  urine  is  decreased, 
and  the  normally  acid  reaction  of  the  urine  may  be  changed  to  an  alkaline 
reaction  with  sufficient  alkaline  Avater,  but  with  wide  variations  in  indi- 
vidual cases.  Such  results  are  also  reported  in  the  case  of  infants  (Ylppo). 
More  recently  in  an  experiment  on  four  men  lasting  18  days  the  effect  of 
an  alkaline  mineral  water  (Manitou)  on  dig-estion  and  utilization  was  de- 
termined (llattill).  This  w^ater  contains  a  large  amoimt  of  lime  (secon- 
dary alkalinity),  some  chlorids  and  sulphates  and  a  considerable  amount  of 
free  carbon  dioxid.  During  the  mineral  water  ingestion  a  true  alkalinity 
of  the  urine  w^as  observed  together  with  marked  reduction  in  urinary  am- 
monia. There  was  a  -slight  retention  of  nitrogen  in  all  four  subjects. 
Uric  acid  and  indican  excretion  were  very  slightly  reduced,  the  latter, 
however,  not  because  of  a  better  utilization  of  tho  food.  Fecal  moisture 
and  fat  in  particular  were  somewhat  increased,  nitrogen  only  very  slightly. 
The  larger  proportion  of  the  added  lime  was  excreted  by  the  intestine; 
during  the  mineral  water  periods  all  subjects  showed  a  marked  retention 
of  lime  and  the  positive  balance  continued  wdth  a  gradual  decrease  in 
the  post-w^ater  control  period.  Earthy  phosphates  in  the  urine  were 
slightly  increased  but  total  urinary  phosphate  was  reduced,  presumably 
through  a  deviation  into  the  intestine  by  lime. 

Alkalinization  of  tho  urine  has  been  of  interest  because  of  the  greater 
solvent  power  of  such  urine  for  uric  acid.  For  such  alkalinization  the 
carbonates  and  citrates  of  the  alkaline  earths  (especially  calcium)  ofi'er 
some  advantage  over  those  of  the  alkalies  because  Ca  is  excreted  for  the 
most  part  by  way  of  the  large  intestine  and  because,  since  it  tends  to 
divert  phosphate  from  the  urine  to  the  feces  (Rose)  a  relative  as  well  as  an 
absolute  decrease  in  primary  phosphates  occurs  (Strauss (a)).  In  his 
short  experiment  on  alkaline  earth  waters  Heini  found  no  decrease  in 
monosodium  phosphate  but  the  diet  was  not  kept  constant.  But  although 
alkalinized  urines  possess  greater  solubility  for  uric  acid,  the  ingestion  of 
alkaline  mineral  ^vaters  to  provide  such  a  condition  has  little  or  no  effect 


850  HENKY  A.  MATTILL 

on  the  excretion  of  uric  acid  (Liidwig;  Lai|ueur(a);  Klemperer;  Gilar- 
doni;  Bradeiibiir^S  Leva  (a)  ;  Croce  (b));  if  the  amount  excreted  is 
changed  at  all  it  is  just  as  apt  to  be  increased  as  decreased  by  alkaline 
waters.  The  same  may  be  said  of  various  alkalines  administered  as  such 
(Herrmann;  Strauss(a)  ;  Salko\vski(&)  ;  Gorsky).  v.  Xoorden  remarks 
npon  the  two  centuries  of  treatment  of  gout  with  alkalies  in  the  absence  of 
any  findings  even  npon  gouty  patients,  to  justify  the  supposed  ability  of 
alkalies  and  alkaline  mineral  waters  to  remove  uric  acid.  In  nephrolithia-^ 
sis  on  the  other  hand  alkalies  often  seem  to  increase  the  uric  acid  output 
considerably. 

A  decreased  urinary  acidity  is  also  often  desirable  in  glycosuria  and 
can  be  secured  by  the  ingestion  of  large  amounts  of  alkali  (10-40  gr. 
XallCOo,  even  100  gr.  daily)  amounts  which  are  not  supplied  by  the  drink- 
ing of  large  amounts  of  mineral  waters.  In  milder  foi-ms  of  sucli  acidosis 
the  amount  of  alkali  in  some  mineral  waters  may  be  adequate  to  render 
the  nrine  alkaline.  The  transitory  nature  of  this  reduction  in  acid  is  ob- 
vious as  is  also  the  fact  that  the  reduction  in  acid  excretion  is  not  the  real 
object.  Any  reported  improvement  in  diabetic  conditions  resulting  from 
mineral  water  cure  can  not  be  credited  to  the  water  but  must  be  explained 
by  the  many  other  contributing  factors. 

The  acidosis  of  nephritis  particularly  as  it  is  related  to  retention  of 
phosphates  in  the  blood  (Marriott  and  Rowland  (a))  requires  further 
investigation  as  to  the  therapeutic  value  particularly  of  calcium  and  of 
the  alkaline  mineral  waters  containing  it. 

The  fate  of  alkalies  and  their  influence  on  the  blood  and  tissues  are 
questions  that  have  not  been  answered  for  the  isolated  elements  and  tlieir 
salts,  much  less  for  their  wide  variety  of  combination  as  they  occur  in 
mineral  waters.  Too  little  is  known  of  the  role  of  mineral  substances  in 
the  processes  of  metabolism  profitably  to  employ  the  information  in  a 
consideration  of  mineral  waters. 

Bitter  Waters.— Bitter  waters  depress  the  secretion  of  gastric  juice 
and  may  cause  a  secretion  of  water  into  the  stomach,  similar  to  their  be- 
havior in  the  intestine.  In  experiments  on  Pawlow  dogs  the  inliibitory 
effect  was  not  observed  if  saline  and  carbonated  waters  were  added 
(Odaira).  Acidity  is  said  not  to  be  markedly  changed  by  the  administra- 
tion of  30  pel-  cent  sodium  or  magiiesium  sulphate  solutions  though  pepsin 
is  decreased  (Ileinsheimer).  Pancreatic  secretion  is  also  interfered  with 
(Pewsner),  even  by  relatively  small  doses  when  food  is  given  an  lioiir 
afterward  (Bickel(r)).  These  waters  are  laxative  in  their  action  and 
a  less  complete  utilization  of  all  the  food  constituents  is  to  be  expected  as 
a  residt  of  their  use.  Such  findings  have  been  reported  for  niti'ogen  and 
fat  utilization  by  many  investigators  (Leva(«)  ;  Vahlen ;  Katz(a)  ;  Dapper 
(«)  ;  Jacoby).  In  a  metabolism  experiment  on  eight  persons  Kolb  found 
fecal  carbohydrate  also  increased  as  well  as  ash.     Such  waters  have  been 


*  MIlSrERAL  WATEKS  851 

found  to  increase  urinary  ethereal  sulphates  (Rosin)  though  not  in- 
variably (Porges).  On  the  basis  of  urea  fleterniinations  in  a  dog  in 
nitrogen  balance,  and  in  patients,  it  was  eoncliuled  that  absoi*ption  of 
nitrogenous  substances  during  a  drinking  cure  was  not  interfered  with 
since  the  urea  values  were  not  changed  (Zorkendorfer).  This  type  of 
water  has  usually  been  employed  in  oljesity  cures. 

Sulphur  Waters.— A  diminished  gastric  acidity  as  the  result  of  drink- 
ing sulphur  waters  has  been  repoiled  from  observations  on  a  few  hypei'- 
acidity  cases  and  is  recommended  by  Heubner(6)  for  the  treatment  of 
chronic  alimentary  catarrh  in  children.  It  is  probable  that  the  alkalinity 
of  the  w^ater  is  the  determining  factor  and  such  waters  if  they  contain 
carbon  dioxid  may  have  the  contrary  effect  (Coleschi(&)). 

Several  metabolism  experiments  with  sulphur  water  are  reported  by 
Brown  in  which  during  the  sulphur  water  periods  the  amount  of  urinary 
nitrogen  was  increased,  as  well  as  the  excretion  of  creatinin  and  endog- 
(jnous  uric  acid.  The  laxative  action  of  the  water  caused  a  considerable 
increase  in  the  amount  of  feces  of  which  no  account  is  taken  in  the  nitro- 
gen calculations.  Indican  w^as  almost  doubled  during  sulphur  water  in- 
gestion.   The  value  of  sulphur  water  as  a  therapeutic  agent  is  doubtful. 

Iron  Waters. — Iron  waters  have  long  been  used  with  some  success  in 
anemia  but  only  one  investigation  deals  with  their  actual  influence  on 
metabolism.  From  this  investigation  by  Vandeweyer  and  Wybauw  on 
two  normal  persons  it  appears  that  protein  and  carbohydrate  in  the  feces 
decreased  during  the  iron  water  periods,  fat  on  the  other  hand  was  in- 
creased. Since  the  nitrogen  intake  was  not  entirely  uniform  in  all  the 
periods,  conclusions  as  to  the  effect  on  nitrogen  metabolism  are  not  easily 
drawn.  In  one  case  there  was  a  considerable  minus  balance  during  the 
iron  water  periods  as  compared  witli  the  final  ordinary  water  period; 
in  the  other  case  there  was  a  plus  balance,  but  nevertheless  they  conclude 
that  during  the  iron  water  periods  nitrogen  catabolism  is  stimulated.  Uric 
acid  was  relatively  decreased. 

The  therapeutic  value  of  iron  in  chlorosis  is  discussed  elsewhere  and 
while  improvement  in  hyperacidity  and  increased  hemoglobin  and  erythro- 
cytes are  show^i  to  follow  uj^on  several  weeks  of  iron  water  cure  other 
factors  such  as  rest,  out  of  door  life  and  proper  food  nuist  be  considered. 
The  amount  of  iron  ingested  through  drinking  iron  waters  is  less  than 
is  usually  administered  in  medicinal  preparations  but  the  former  are  often 
more  effective,  perhaps  for  the  reason  just  given,  perhaps  because  of  the 
manner  of  administration.  Iron  carbonate  waters  deteriorate  when  bot- 
tled and  on  standing  due  to  precipitation  of  iron  oxid. 

Arsenic  Waters. — Arsenic  waters  usually  also  contain  iron,  and  for 
certain  types  of  anemia  it  would  seem  that  administration  of  iron  alone 
is  useless  but  that  with  arsenic  good  results  are  sometimes  obtained.  Aside 
from  such  infonnation  (Henius(6)  ;  Brenner)  no  reliable  metabolism  data 


852  HENKY  A.  MATTILL 

on  arsenic  waters  are  at  liand.  Uric  acid  elimination  during  the  arsenic 
water  period  is  said  to  be  decreased  with  an  increase  in  the  after  period 
(Croce(6 ) ),  but  the  presence  of  other  salts  is  probably  responsible  for  such 
results  as  have  been  noted.  The  excretion  of  arsenic  in  the  arsenic  water 
cures  is  subject  to  considerable  iudivi(hial  variation  (iNTishi).  A  more 
rapid  increase  in  weight  in  animals  receiving  ai*senic  water  as  compared 
with  those  receiving  ordinary  water  has  been  reported  for  rabbits  (Lar- 
delli;  Bachem)  and  for  rats  (Croce(a))  which  is  only  partially  explained 
by  an  effect  on  the  appetite. 

Eadioactive  Waters. — The  literature  on  radioactive  waters  is  exten- 
sive and  much  of  its  content  is  entirely  characteristic  of  the  bulk  of  min- 
eral water  literature.  Radium  is  undoubtedly  not  Avithout  influence  ou 
metabolism  but  a  great  many  statements  about  it  are  quite  without  experi- 
mental foundation.  As  ordinarily  used  in  ''cures"  radium  emanation  13 
taken  into  the  body  by  drinking  radioactive  water.  When  so  taken  it  has 
no  influence  on  gastric  secretion  (Olszewski).  In  a  bath  in  radioactive 
water  radium  emanation  enters  not  by  tbe  skin  but  through  respiration 
(Loewenthal),  but  that  any  considerable  amount  gets  into  the  blood  by  this 
means  is  improbable  (Gudzent(/))  since  the  amount  in  the  blood  was 
found  always  to  be  about  one-fifth  of  that  in  the  expired  air  (Kemen). 
After  injection  into  the  duodenum  of  animals  (rabbits)  Strasburger(6) 
found  it  in  three-fourth  hours  in  the  blood;  after  two  hours  only 
a  trace  was  left,  and  the  time  curve  of  emanation  content  of  the  blood 
and  of  the  expired  air  were  the  same ;  by  divided  doses  the  content  could 
be  maintained,  but  only  about  a  third  of  the  ingested  radium  emanation 
gets  into  the  systemic  circulation  at  all,  and  only  a  Yerj  small  fraction 
is  found  there  at  any  one  time.  Similar  results  were  found  after  drink- 
ing radium  emanation  water.  In  seemingly  careful  experiments  by  Pieper 
the  results  of  Strasburger  were  verified  and  it  was  estimated  that  two- 
thirds  of  the  ingested  radium  emanation  was  lost  by  way  of  the  lungs. 
A  small  fractitm  (1/4000)  of  the  ingested  radium  emanation  w^as  also 
demonstrated  in  the  iirine  from  which  it  had  disappeared  after  three 
hours  (Laqueur(i)).  In  longer  periods  of  radium  cmanalion  ingestion 
the  amount  found  in  the  urine  gradually  fell  (Kalmann).  Eadium  is 
also  excreted  by  the  feces  and  in  greater  amounts  than  in  the  urine,  and 
in  whatever  manner  given  it  may  be  foiuid  in  the  tissues  (Meyer). 
Thorium  X  seems  to  behave  similarly  and  the  bone  marrow  is  said  to  be 
most  rich  in  it  after  administration  (Brill).  Aleasurements  of  radium 
emanation  in  expired  air  are  a  good  measure  of  the  blood  content  (Spartz). 

Radium  emanation  is  reported  as  having  been  used  successfully  for 
the  reduction  of  blood  pressure,  in  the  relief  of  anemia  (Th.  X),  and  for 
the  cure  of  gout !  and  the  literature  on  the  latter  is  particularly  extensive 
and  vacuous.  The  supposed  transformation,  solution  and  destruction 
of   uric   acid    by   radium    emanation    (Gudzent(«)  (r)  (cZ)  ;  Engelmann; 


MI^^ERAL  WATERS  853 

'Mesermtzky(a)(c)(d)  ;  Sarvonat)  cither  could  not  be  verified  (Knaffl- 
Lonz  and  Wiecliowski)  or  was  found  (in  vitro)  to  be  the  result  of  bacteria 
and  molds  (Kerb  and  Lazarus)  or  took  place  just  as  rapidly  in  the  body 
without  radium  emanation  as  with  it  (Jlockendorif),  and  the  cases  of 
true  g'out  which  improved  under  the  influence  of  radium  emanation  did 
not  show  any  change  in  the  uric  acid  curve  (Afandel).  Radium-contain- 
ing waters  may  not  even  owe  their  value  to  their  content  of  radiiun  emana- 
tion (Lazarus (a)).  Trustworthy  information  on  the  effect  of  radium  or 
radium  emanation  on  metabolism  is  meager.  AVhen  given  with  meals 
certain  radioactive  saline  waters  were  found  to  have  an  inhibitory  effect 
on  the  action  of  pepsin,  but  only  after  the  water  had  lost  its  radioactivity 
through  storage  (Bergell  and  Bickel)  w^hich  the  authors  consider  an  evi- 
dence of  activation  of  pepsin  by  radium  emanation  and  a  removal  of  the 
inhibitory  effect  of  the  water  on  gastric  activity.  After  feeding  radium 
bromide  to  dogs  Berg  and  Welker  were  unable  to  show  any  change  in 
protein  metabolism ;  the  total  sulphur  of  the  urine  was  increased.  Accord- 
ing to  Skorczewski  radium  therapy  causes  an  increased  output  of  nitrogen 
and  uric  acid,  as  well  as  of  neutral  and  oxidized  sulphur.  Using  the 
respiration  chamber  Kikkoji  demonstrated  increased  gaseous  exchange  and 
increased  nitrogen  and  uric  acid  elimination  which  was  not  invariable. 
After  intravenous  injection  of  radium  Rosenbloom  found  increased  nitro- 
gen elimination,  but  nitrogen  partition  showed  no  constant  behavior.  He 
verified  the  previous  findings  on  sulphur  excretion  and  found  that  the 
effects  lasted  about  three  days  aftei'  the  injection.  Intravenous  doses  of 
an  active  deposit  of  radium  emanation  produced  a  decided  increase  in 
urinary  nitrogen  excreted  by  dogs  (Bagg(&)).  The  destruction  of  cellu- 
lar material  as  indicated  l)y  the  fall  in  number  of  blood  cells  probably 
accounts  for  this  as  well  as  for  the  rise  in  body  temperatui-e.  In  a  five 
and  one-half  w-eeks^  continuous  metabolism  experiment  on  a  gouty  subject 
(Kaplan)  the  ingestion  of  radium  emanation  and  alkaline  mineral  water 
decreased  the  excretion  of  uric  acid  as  compared  with  the  alkaline  water 
alone,  purin  bases  show^ed  a  slight  absolute  but  a  high  relative  increase. 
On  the  other  hand,  Chace  and  Fine  found  it  impossible  to  change  the  uric 
acid  concentration  of  the  blood  in  gout  and  arthritis  by  emanatorium, 
drinking  water  or  injections,  a  conclusion  confirmed  by  others  (McCiiidden 
and  Sargent(&)).  An^increased  elimination  of  uric  acid  in  arthritis 
after  treating  wdth  large  doses  of  radium  emanation  is  considered  by  v. 
Xoorden  and  Falta  as  definitely  shown.  This  is  possibly  connected  with 
cell  destruction.  An  influence  on  respiratoiy  metabolism  has  not  been 
established  except  that  after  large  doses  a  slight  increase  was  observed 
(Benczur  and  Fuchs).  A  transient  decrease  in  blood  pressure  has  been 
noted  (Loewy  and  Plesch).  Despite  the  claims  which  are  made  for 
radium  and  radium  emanation  therapy  in  metabolic  disorders  (v.  Xoorden 
(e))  it  can  hardly  be  considered  well  established  on  an  experimental  basis. 


Hydrotherapy .  Henry  A.  Mattill 

Cold  Baths — Hot  Baths — The  Influence  of  Mechanical  and  Chemical  Stimu- 
lation Accompanying  Baths — Effervescent  Baths — Baths  and  Sweat  Se- 
cretion. 


Hydrotherapy 

IIEXPtY  A.  IIATTILL 

ROCHESTER,    N.    Y. 


The  external  use  of  water  as  a  therapeutic  measure  was  first  advocated 
in  England  bv  Sir  John  Floyer  in  1697.  A  hundred  years  later  Dr. 
James  Currie  of  Liverpool,  inspired  by  Dr.  William  Wright^  published 
his  reports  on  the  effect  of  cohl  and  warm  water  as  a  remedy  in  fever  and 
other  diseases.  The  works  of  these  men  bore  tlieir  first  fruit  in  Germany 
and  Austria,  where  some  of  the  claims  put  forth  by  the  advocates  of  hydro- 
therapy were  put  to  experimental  test.  Among  the  investigators  Winter- 
nitz  occupies  the  foremost  place  as  his  many  monographs  and  his  larger 
works  testify.  His  efforts  and  those  of  similarly  minded  men  that  followed 
him  have  done  much  to  illuminate  the  really  valuable  contributions  of 
hydrotherapy  shrouded  as  they  often  are  under  a  cloud  of  pseudo-scientific 
effusions.  Recent  books  in  this  country  are  by  Baruch,  Hinsdale  and 
Kellogg.  Among  the  recent  English  authors  may  be  mentioned  Fox  and 
among  the  German,  Matthes  whose  valuable  chapters  on  baths  and  bathing 
in  V.  I^oorden's  Metabolism  and  Practical  Medicine  cites  the  older  litera- 
ture, and  Schiitz. 

The  skin  is  the  organ  through  which  baths  produce  their  effects  on  the 
body.  The  foundation  of  hydrotherapy  must  therefore  rest  on  the  func- 
tions and  activity  of  the  skin  as  they  may  be  modified  by  extenial  treat>- 
ment,  and  may  in  turn  thereby  modify  the  functions  of  the  internal  organs. 
Probably  the  most  important  function  of  the  skin  is  that  of  regulating 
the  body  temperature,  the  mechanism  of  which  is  described  elsewhere. 
By  virtue  of  its  activity  in  temperature  regulation  the  skin  is  both  a 
vascular  organ  and  an  organ  of  excretion.  To  the  cutaneous  sensations 
of  heat  and  cold  involved  in  temperature  regnlation  must  be  added  those 
of  touch,  pressure  and  pain,  and  the  skin  is  thus  a  sense  organ  of  first 
importance.  The  influences  of  hydrotlierapeutic  measures  may  therefore 
be  sought  in  the  effect  of  tem|>eraturc  changes  and  other  cutaneous  sensa- 
tions on  the  processes  of  metabolism,  including  the  activity  of  organs 
other  than  those  of  digestion  and  absorption  merely,  and  in  the  effect  of 
these  stimuli  on  the  excretory  Fuiictious  of  the  skin. 

It  may  be  recalled  that  the  temperature  of  the  wann-blooded  animals  is 
regulated  by  physical  and  chemical  means,  both  mechanisms  being  under 

855 


856  HEJSTRY  A.  MATTILL 

the  control  of  the  autonomic  nervous  system.  The  physical  regulation 
governs  heat  losses  by  a  variable  cutaneous  circulation  and  the  activity 
of  the  sweat  glands.  The  chemical  regulation  controls  heat  production 
through  increased  muscular  activity.  By  means  of  the  protection  of 
clothing,  man  aids  these  methods  of  regulation  through  surrounding  him- 
self with  an  atmosphere  but  little  cooler  than  the  body.  While  the  internal 
temperature  of  the  body  is  about  37.5°C.  the  temperature  of  the  skin  is 
usually  only  a  few  degTces  below  this,  such  that  a  bath  at  about  34°  C. 
neither  adds  to  nor  subtracts  from  the  body  supply  of  heat.  Such  a  bath 
is  called  an  indifferent  bath.  This  indifferent  point  may  vary  with  differ- 
ent individuals  and  in  different  conditions  and  has  been  given  variously 
from  34.2°  to  37°. 

There  is  fairly  general  agreement  that  exactly  indifferent  baths  have  no 
demonstrable  influence  on  metabolism,  whatever  their  duration,  but  while 
the  effect  of  such  baths  or  of  those  slightly  above  or  below  can  not  be  meas- 
ured in  terms  of  metabolism,  their  importance  in  the  treatment  of  many 
forms  of  insanity  and  in  psychoses  must  be  mentioned  (Beyer).  Tlie  con- 
tinuous flow  bath  at  indifferent  temperature  produces  relief  from  nervous 
symptoms  and  frequently  exercises  a  more  powerful  and  effective  sedative 
action  than  any  drug.  Such  effects  are  secondary  to  those  p'dduced  on 
metabolism  itself  but  they  far  outweigh -the  latter  in  importance. 


Gold  Baths 

The  immediate  effect  of  a  cool  or  cold  bath  is  a  contraction  of  the 
cutaneous  blood  vessels,  more  or  less  proportional  to  the  degree  of  cold, 
whereby  loss  of  heat  by  radiation,  conduction  and  evaporation  is  dimin- 
ished. Depending  on  the  extent  of  the  cold,  respiration  also  becomes  more 
deep  and  rapid  and  muscular  activity  is  excited  reflexly.  These  responses, 
especially  the  muscular  contractions  known  as  shivering,  are  an  attempt 
to  produce  more  heat,  loss  of  which  from  the  body  has  been  compensated 
to  a  slight  degree  only  by  physical  regidation  (Loewy).  If  cold  application 
is  prolonged,  heat  production  fails  to  keep  pace  with  loss,  anemia  gives 
place  to  hyperemia  which  unless  it  is  only  local  (as  from  an  ice  bag) 
produces  a  rapid  fall  in  body  temperature  and  the  circulation  begins  to 
fail.  If,  however,  the  cold  is  withdrawn  before  this  time  a  secondary 
hyperemia,  the  "reaction"  in  hydrotherapy,  is  secured  and  by  thus  prem- 
aturely breaking  oft'  the  physical- regulation,  the  stimulus  due  to  the  tem- 
perature change  is  artificially  enhanced.  In  the  opinion  of  Matthes  the 
stimulus  due  to  a  short  exposure  to  cold  is  probably  of  small  importance 
compared  with  the  effect  of  the  "reaction."  According  to  Fox  the  whole 
effect  of  baths  of, every  description  is  founded  on  the  power  of  reaction 
possessed  by  the  organism.     The  extent  of  the  reaction  is  diminished 


HYDROTHERAPY 


857 


when  the  abstraction  of  heat  is  gradual  or  prolonged  or  when  the  individual 
is  already  cool  or  remains  quiescent  during  and  after  the  bath;  it  is  in- 
creased when  the  application  of  cold  is  rapid  and  wlien  a  mechanical  stimu- 
lus is  added. 

A  transient  fall  in  body  temperature,  even  several  degi*ees,  may  follow 
a  cold  bath  and  the  effectiveness  of  a  bath  only  slightly  below  body  tem- 
perature in  reducing  fever  temjxirature  has  long  been  known  (Palmer). 
The  contrary  findings  of  different  investigators  (Liebermeister(&) ;  Le 
Fevre(c) ;  Durig  and  Lode)  often  of  ti  single  investigator  on  the  same 
subject,  are  evidence  that  body  temperature  is  not  a  simple  resultant  or 
that  physical  regulation  does  not  behave  unifoiTnly,  a  possibility  su^ested 
by  the  ability  of  adaptation  to  repeated  cold.  Jiirgenson  found  the  gi-eat- 
est  lowering  of  temperature  by  a  cold  bath  not  during  but  after  the  bath, 
a  "primary  after  effect'^  that  has  been  found  by  others  (Mattill(a.)) 
and  may  be  due  in  paii;  to  evaporation  of  water  retained  on  ,and  in  the 
epidemiis,  in  part  to  the  failure  of  physical  r^ulation  during  the  active 
hyperemia  and  its  increase  of  heat  loss.  After  the  cooling  period  (5-8 
hrs.)  the  temperature  may  rise  higher  than  the  corresponding  daily  tem- 
perature and  remain  there  some  hours  as  a  result  of  the  "after-effect." 
The  duration  ^and  extent  of  these  variations  in  body  temperature  are  ex- 
tremely variable  (Loewy,  Miiller,  et  aL;  Hoffman).  Local  applications 
of  cold  may  markedly  lower  the  temperature  of  the  part  treated  as  well  as 
of  the  underlying  tissues  and  organs  (Riehl). 

The  effect  of  cold  baths  on  heat  production  is  marked  and  the  small 
magnitude  of  body  temperature  changes  is  in  fact  ver^'  good  evidence  of 
the  efficiency  of  the  thermoregulating  mechanism.  Widely  quoted  figures 
(Matthes(6))  for  the  effect  of  bathing  on  heat  production  appear  in 
Table  L 

TABLE  I 

Effect  of  Bathing  on  Heat  PitODtrcTion" 


Heat  production  in  calories 

Heat — 18    calories    for    heat    loss   in 

resp 

Pleat — 91    calories   which   a   man   of 

CO  kg.  normally  produces    

Metabolism  reduced  to  grams  of  fat. 
After-effect  of  bath  reduced  to  grams 

of  fat 

Total  effect  and  after-effect  reduced 

to  grams  of  fat 


Temp,  of  Bath 

. 

15**  C. 

20*' C. 

25°  C. 

30*  C. 

Z5'*C. 

480 

370 

240 

150 

80 

498 

388 

258 

168 

98 

407 
43 

297 
31 

167 
18 

77 
8 

7 
0.7 

9 

6 

4 

1 

0.0 

52 

37 

22 

9 

0.7 

Similar  results  were  obtained  by  Ignatowski  who,  in  a  bath  at  17°  C. 
lasting  2.5  minutes  found  heat  production  14  times  normal.     Of  the  65 


858 


HENRY  A.  MATTILL 


Cal.  thus  expended,  44  were  given  out  during  the  first  minute,  21  in  the 
subsequent  one  and  one-half  minutes,  and  the  subject  was  0.3°  warmer  at 
the  end.  In  a  bath  at  20.75°  C.  for  fifteen  minutes  the  heat  loss  in  the 
three  successive  five-minute  periods  was  43,  17,  and  17  calories.  An  ab- 
normal loss  of  heat  therefore  takes  place  before  physical  regulation  be- 
comes entirely  efficient  and  the  cooling  of  the  skin  itself  tends  to  reduce 
heat  loss.  This  investigator  also  found  that  when  his  patients  were  really 
cooled  down,  if  no  "reaction"  occurred  heat  loss  after  the  bath  continued 
to  decrease  and  heat  production  also.  With  a  prompt  "reaction"  a  diminu- 
tion in  heat  loss  could  not  be  observed. 


TABLE  II 


Form  of  Bath 

Duration 

Temp. 

Increase  in 

Respired 

Air  % 

Increased 
CO,  Output 

Increased 
0,  Intake 

Resp. 
Quotient 

Douch    

Tub  bath 

3-5  min. 
3-5  min. 

54.5 
22.9 

149.4 
64.8 

110.1 
.    46.8 

0.87-1.02 
0.88-1.0 

Rubner^s(^*)  experiments  on  the  effects  of  baths  and  douches  given  in 
Table  II  show  the  marked  effect  of  douches  as  compared  with  baths 
at  the  same  temperature  (compare  mechanical  stimulation  below)  and  the 
respiratory  quotient  indicates  that  carbohydrates  were  the  source  of  the 
extra  energy  expended.  The  experiments  of  Lusk  in  which  men  in  a  post- 
absorptive  condition  bathed  in  water  at  10-16°  C.  are  summarized  in 
Table  III.  The  shivering  induced  caused  a  fall  in  the  respiratory  quo- 
tient to  the  fasting  level  indicating  complete  exhaustion  of  the  stores  of 
glycogen ;  in  one  muscular  individual  this  did  not  obtain.  Severe  shiver- 
ing in  one  case  produced  a  respiratory  quotient  of  0.G7,  indicating  the 
foiTnation  of  glycogen  from  protein,  but  there  are  no  data  on  nitrogen 
elimination. 

TABLE  III 


Form  of  Bath 

Duration 

Temp. 

Increased 
Cal.  per  Kg. 

per  Hr.  C'c 

Increased 
COi  Output 

Increased 
0^ Intake 

Resp. 
Quotient 

Subject   I,  Tub 

bath   

Subject  I,  Tub 

bath   

Subject  IT,  Tub 

bath   

Subject  II,  Tub 

bath   

6  rain. 

8  min. 

9  min. 
10  min. 

10** 
12° 
10° 
10° 

29. 

3.3. 
181. 
116. 

11. 
22. 

160. 
158. 

34. 

.40. 
188. 
106. 

.99-.82 
.88-.75 
.95-.85 
.67-.84 

Obsei-v-ers  agree  that  the  extra  energy  called  out  by  ordinary  cold  baths 
comes  from  non-nitrogenous  material  only.  When  body  temperature  falls 
and  wami-blooded  animals,  obeying  the  laws  to  which  cold-blooded  ani- 


nYDROTIIERAPY  859 

raals  are  always  subject,  decrease  their  metabolism,  protein  disintegration 
rises  above  normal,  as  shown  on  dogs  (Lepine  and  Fhivard;  Dommer) 
and  also  on  men  whose  temperatures  were  reduced  to  32°  (Formanok(&)). 
On  nitrogen  distribution  following  cold  fresh-water  baths,  the  data  of 
Schilling  are  considered  reliable;  he  found  a  marked  increase  in  ammonia 
excretion  not  associated  with  a  simultaneous  increase  in  nitrogen  elimina- 
tion. The  findings  of  Krauss  showed  an  increased  acidity  after  cold  baths 
and  temporary  ali)uminuria  may  often  appear  after  prolonged  cold  baths 
(Araki(6)  ;  Itcm-Picci).  Under  normal  bathing  conditions  as  employed 
in  hydrotherapy,  short  cold  baths  cause  an  increase  in  metabolism  of  non- 
nitrogenous  materials  only,  the  energy  derived  therefrom  being  used 
for  heat  production  and  for  the  increased  muscular  work  which  this  neces- 
sitates. Any  energy  changes  due  to  the  cooling  itself  are  obscured  by  the 
energy  expended  in  muscular  activity  and  it  is  probable  that  both  of  these 
are  influenced  somewhat  by  the  adaptive  power  of  individuals  to  repeated 
heat  deprivation,  as  well  as  by  their  physical  characteristics  and  state 
of  nutrition.  Whether  the  additional  heat  production  necessitated  by  cold, 
baths  takes  place  in  the  absence  of  muscular  activity  iieetl  not  Ik?  discussed 
at  this  time  since  imder  ordinary  conditions  there  is  no  restraint  npon 
movement.  In  experiments  on  men  it  was  shown  that  tlie  cooling  of  the 
body  in  cold  baths  was  accompanied  by  a  rise  in  respiratory  metabolism 
only  where  involuntary  shivering  occurred  (Silber).  It  must  be  expected 
that  even  in  the  absence  of  such  movement  the  additional  work  performed 
by  the  respiratory  muscles,  the  heart  and  the  vasomotor  system  provides 
some  heat  as  a  by-product. 

The  redistribution  of  blood  under  local  or  general  application  of  cold 
is  considerable  (Hewlett,  van  Z.  and  M.)  and  organ  activity  and  local 
metabolism  are  thereby  modified  in  so  far  as  they  are  dependent  on  blood 
supply.  Also,  since  cold  can  penetrate  more  deeply  than  heat,  it  is  possi- 
ble to  limit  its  effect  on  individual  organs  more  accurately  than  is  the 
case  with  heat.  The  general  effects  of  cold  baths  on  the  circulatory 
system  involve  the  many  hydrostatic  as  well  as  reflex  vascular  factors 
affecting  the  bulk  and  the  flow  of  the  blood,  and  are  therefore  very  com- 
plex. After  a  cold  bath  the  pulse  is  slowed  (Beck  and  Dohan),  the  volume 
pulse  and  minute  volume  are  increased  (Schapals),  arterial  blood  pressure 
is  often  increased  and  venous  pressure  decreased  (Winternitz(e)  ;  Edge- 
combe and  Bain),  the  extent  probably  depending  in  part  on  internal  com- 
pensations and  antagonisms  (Miiller(a)).  According  to  Strassburger 
systolic  blood  pressure  during  a  cold  bath  may  show  two  or  three  phases,  a 
rapid  rise,  the  more  rapid  as  the  bath  is  colder,  a  decrease  (corresponding 
to  the  ''reaction")  and  a  final  increase,  depending  on  the  balance  between 
the  heart  action  and  the  condition  of  the  capillaries.  After  the  bath  there 
is  a  fall  in  blood  pressure,  usually  under  the  original  level.  The  transient 
increase  in  blood  pressure  has  been  given  as  the  cause  of  the  diuresis  tern- 


860  HEJSTRY  A.  MATTILL 

porarily  occasioned  by  cold  baths  (Lambert),  but  the  vasomotor  changes  in 
the  skin,  perhaps  also  in  the  kidney  (Delezenne;  Werthheimer),  probably 
influence  urine  secretion  somewhat.  An  increase  in  the  number  of 
erythrocytes  takes  place  during  a  cold  bath  and  is  maintained  for  as  long 
as  two  hours  according  to  Winternitz  but  this  is  not  confirmed  by  Tuttle^ 
An  increased  elimination  of  urobilin  after  cold  baths  has  been  reported 
(Siccardi)  and  leucocytosis  has  also  been  observed  (Rovighi;  Thayer). 
The  occurrence  of  paroxysmal  hemoglobinuria  after  cold  baths  is 
common ;  a  fairly  complete  review  of  this  condition  is  given  by  Donath  who 
concludes  that  a  hemolytic  property  is  imparted  to  the  plasma  by  cold. 

Ccld  baths  usually  have  a  refreshing  effect ;  whether  this  comes  as 
a  result  of  modifications  in  the  cutaneous  sensations  (Santlus)  or  in  muscle 
sense  (Vinaj)  or  as  the  result  of  changes  in  muscular  efticicncy  (Uhlich)  is 
imcertain.    That  baths  produce  these  changes  is  also  questioned  (Tuttle). 

Hot  Baths 

The  body  possesses  no  chemical  regulation  for  lessened  heat  production 
and  when,  in  surroundings  warmer  than  the  body,  the  utmost  heat  loss  by 
radiation  and  evaporation  has  been  secured,  the  body  temperature  must 
rise.  Kise  of  temperature  means  increased  metabolism,  as  was  first  shown 
by  Pfliiger  on  animals  and  later  by  Winternitz  and  others  (Ignatowski; 
Linser  and  Schmid)  on  man.  Even  moderate  heating  without  any  change 
in  respiration  causes  an  increase  in  oxygen  consumption  in  excess  of  that 
due  to  fever  ( Winternitz  (&)).  Some  of  this  increased  heat  production 
can  be  accounted  for  by  increased  work  of  the  heart,  of  the  muscles  of 
respiration  and  of  the  sweat  glands,  but  Winteniitz's  calculation  still 
leaves  30-75  per  cent  unaccounted  for,  and  it  is  probable  that  under  these 
conditions  wami-blooded  animals,  having  overstepped  the  limits  set  by 
the  heat-regulating  mc^chanism,  are  subject  to  the  etfects  of  the  general 
law  applying  to  all  chemical  reactions. 

The  after-effects  of  a  hot  bath  are  less'  uniform  than  those  of  a  cold 
bath.  A  continuation  in  tlie  rise  of  body  temperature  after  a  hot  or  vapor 
bath  is  explained  (Speck)  as  a  natural  result  of  the  higher  temperature  of 
the  skin  and  subcutaneous  tissues  as  compared  with  that  of  the  muscles  and 
internal  organs  (Ilirsch  and  Miiller),  a  reversal  of  the  ordinary-  condition. 
A  compensating  abnormal  fall  in  temperature  is  seldom  obsei*ved  but  in 
the  two  hours  after  a  hot  bath  during  which  normal  temperature  is  i-e- 
gained  (Wick)  there  is  a  continued  loss  of  heat  in  the  various  ways  at 
double  or  three  times  the  normal  rate  (Ignatowski).  Winternitz (2>) 
found  oxygen  consumption  still  29  per  cent  above  normal,  75  minutes 
after  a  hot  bath.  Even  in  hot  baths  of  short  duration  without  appre- 
ciable heat  disturbance  the  volume  of  inspired  air,  the  oxygen  in- 
take and  the  CO2  output  are  increased  but  to  a  much  smaller  extent 


HYDROTIIEEAPY  8C1 

than  in  cold  baths.  In  br.th  cases  Rubner  found  the  respiratory  quotient 
rising  from  O.SO  to  1,  as  if  the  organism  were  called  upon  to  do  increased 
work  alike  by  cold  and  hot  baths.  Ridjuer  also  found  that  an  hour  after 
a  sliort  hot  bath  or  douche  the  volume  of  respired  air  and  the  metabolism 
decreased  considerably,  and  there  is  thus  a  considerable  difference  in  the 
after-effects  of  hot  baths  according  to  their  duration.  The  absolute  rf-la- 
ti<ni  between  the  amount  of  heat  applied  and  the  increased  heat  production 
varies  according  to  difrerent  investigators  (Linser  and  Schmid;  Salomon), 
and  the  differing  activity  of  the  sweat  glands  in  physical  regulation  mav 
be  an  adequate  explanation.  Marked  increases  in  oxygen  constmip- 
tion,  40-111  per  cent,  are  usually  not  accompanied  by  a  proportional 
increase  in  COy  output,  with  the  result  that  the  respiratory  quotient 
assumes  low  values.  Similar  low  values  are  common  in  fever  and 
after  violent  exercise,  suggesting,  as  in  Lusk's  ice  bath  experiment,  the 
complete  exhaustion  of  glycogen  and  the  breakdown  of  protein  for  its 
formation.  An  increase  in  protein  metaljolism  after  hot  baths  was  long 
ago  found  in  animals  (Itichter,  Koch)  and  later  in  men  (Formanek(a)  ; 
Topp).  However,  Tuttlo  (with  Folin)  in  careful  experiments  was  unable 
to  show  any  changes  iji  metabolism  as  a  result  of  hot  baths.  Since  these 
were  usually  hot  air  baths  at  100°  F.  or  below  for  5  minutes  followed  by 
indifferent  and  cold  douches  lasting  one  minute,  or  indifferent  douches 
followed  by  cold  douches  lasting  between  one  and  two  minutes,  it  is  possible 
that  the  total  heat  effect  was  inadeqtiate  to  produce  changes  in  nitrogen 
metabolism.  They  made  no  determination  of  gaseous  metabolism.  An 
increase  in  protein  metabolism  according  to  Voit  is  not  a  primar}'  result 
of  increased  body  temperature  but  follows  upon  the  exhaustion  of  readily 
available  non-nitrogenous  material  since  he  found  only  a  very  small  amount 
of  glycogen  in  the  liver  after  artificial  overheating  and  since  the  admin- 
istration of  o0-40  gm.  of  sugar  prevented  an  increased  nitrogen  excre- 
tion. This  relation  of  rise  in  temperature  to  glycogen  stores  was  not 
confirmed  (Senator  and  Richter).  It  is  probable  that  hyperthermia 
does  not  always  cause  increased  nitrogen  metabolism,  according  to 
Winternitz  in  only  about  one-third  of  the  cases,  and  Linser  and  Schmid 
found  that  in  fever,  carbohydrate  administration  limited  nitrogen 
elimination  to  a  less  extent  than  when  the  temperature  w^as  noi-mal.  Ac- 
cording to  these  investigators  the  application  of  external  heat  even  for 
maiiy  days  does  not  increase  nitrogen  output  if  the  body  temperature 
remains  at  39°  C.  or  below,  though  when  40°  C.  is  reached  it  usually 
does,  particularh'  if  the  heating  process  is  abrupt.  They  do  not  agree  with 
Voit  that  it  is  a  question  mei'cly  of  inadequate  oxidizable  material  of  a 
non-nitrogenovis  nature,  and  consider  that  in  fevers  the  toxemia  plays  a 
part.  The  nitrogen  loss  as  a  result  of  hot  baths  is,  according  to  Reilingh 
de  Vries,  only  momentary  since  he  finds  that  during  a  considerable  period 
in  which  not  excessively  hot  air  baths  were  taken  a  compensatory  nitrogen 


862  HENRY  A.  l^IATTILL 

letentioii  took  place,  but  with  great  individual  variation,  depending  also 
on  the  bathing  procedure  and  on  the  amount  of  liquid  ingested.  As  to 
the  nitrogen  distribution  in  the  urine,  ammonia  runs  parallel  with  total 
nitrogen  though  slightly  below  proportionate  amounts  (Linser  and 
Schmid;  Schilling;  Formanek(a)).  Phosphoric  acid  also  parallels 
nitrogen.  There  may  be  a  very  slight  though  not  marked  increase  in 
purin  bodies.  The  hydrogen  ion  concentration  of  the  urine  is  increased  by 
15-20  minutes  of  heating  in  a  sweat  cabinet  (Talbert(6)).  Urinary  de- 
terminations alone  are  not  sufficient  since  in  conditions  of  overheating  the 
amount  of  sweat  and  its  solid  content  are  greatly  increased. 

The  effects  of  very  hot  baths  (105-110°  F.)  on  pulse  and  blood  pres- 
sure were  investigated  by  Hill  and  Flack.  After  15-20  minutes  in  such  a 
bath  body  temi>erature  rose  4-6°  F.,  pulse  increased  to  IGO  and  blood 
pressure  fell  60,  thus  confii-ming  earlier  observations  (Bain,  Edgecombe 
and  Frankling).  They  also  verify  previous  findings  as  to  increased 
respiratory  frequency  and  volume  (Edgecombe  and  Bain)  accompanied 
by  a  notable  fall  in  carbon  dioxid  tension  with  corresponding  rise  in 
oxygen  tension.  An  increased  systolic  pressure  during  a  hot  bath  was 
obtained  by  Strassburger(a),  the  hotter  the  bath  the  greater  the  final  rise, 
which  he  considered  due  to  increased  work  of  the  heart.  The  pulse  vol- 
ume (Schapals)  and  the  heart  volume  (Beck  and  Dohan)  are  decreased. 
The  viscosity  of  the  blood  is  said  to  be  decreased  (Hess,  W.)  and  certain 
of  the  antil)odies  have  showed  slight  increase  after  various  foims  of  heat 
treatment  (Laqueur),  but  these  changes  are  probably  as  transient  as  are 
the  more  readily  determined  variations.  The  non-protein  nitrogen  content 
of  the  blood  in  nephritis  is  not  reduced  by  sweat  baths  (Austin 
and  Miller).  The  oxidation  of  benzol  to  phenol  in  the  organism  is,  ac- 
cording to  Siegel,  greatly  accelerated  by  sweating  processes,  also  by  cold 
baths  and  by  salt  water  baths  more  than  by  ordinary  baths  at  the  same 
temperature.  The  effect  extended  beyond  the  period  of  treatment,  but 
there  was  great  individual  variation.  It  is  stated  that  hot  baths  increase 
the  secretion  of  bile  (Kowalski)  and  that  hot  poultices  or  packs  induce  a 
secretion  of  gastric  hydrochloric  acid  (Penzoldt(a)).  It  has  long  been 
known  that  the  hy|xu'emia  produced  by  local  application  of  heat  accelerates 
absorption  (Sassezky). 

The  Influence  of  Mechanical  and  Chemical  Siimulation 
Accompanying  Baths 

Under  this  heading  will  be  considered  the  effect  of  mechanical 
factors  in  the  application  of  baths  in  ordinary  water,  and  the  mechanical 
and  chemical  stimuli  arising  from  the  presence  of  gases,  salts  and  other 
substances  in  the  bathing  water. 


HYDROTHERAPY  863 

The  markedly  increased  stimulation  to  heat  prodiiction  (more  than 
(kmhle)  from  a  cold  douche  as  compared  with  a  cold  tnh  hath  at  the  same 
temperature  is  evident  from  the  table  given  above.  Wintemitz(a)  showed 
that  the  application  of  friction  in  a  cold  bath  caused  an  earlier  fall  in 
temperature  and  a  greater  increase  in  oxygen  intake  and  COj  production 
than  a  similar  bath  without  friction.  He  also  observed  a  very  marked 
increase  in  heat  production  in  a  hot  sand  bath  as  compared  with  the  re- 
sults of  hot  air  baths.  Two  factors,  a  premature  breakdown  of  physical 
regulation  and  a  direct  stimulation  probably  come  info  play.  Brush- 
ing the  skin  causes  rise  in  temperature  in  man  (Paalzow)  ;  so  also  the 
application  of  mustard  paste.  Mustard  added  to  a  bath  at  indifferent  tem- 
perature increased  Oo  consumption  and  COo  output  by  25  per  cent  though 
without  affecting  the  respiratory  cpiotient.  By  far  the  gi'eatest  interest 
naturally  attaches  to  sea  baths  and  to  the  various  other  natural  and  artifi- 
cial baths  containing  salts.  That  it  is  not  a  question  of  absorption  through 
the  skin  is  pretty  w^ell  agTced  upon,  since  the  sebaceous  secretions  forms  a 
barrier  to  w^ater  and  all  water  soluble  substances  unless  they  act  chemically 
on  the  skin.  Fats  and  their  solvents  on  the  other  hand  may  be  imbibed 
by  the  cells  or  make  their  w^ay  through  the  capillary  spaces  and  it  has  been 
reported  ^  that  water  soluble  substances  may  be  taken  up  by  ether-cleansed 
skin.  Most  of  the  investigations  on  sea  and  brine  baths  seem  to  show  that 
their  effect  on  energy  metabolism  is  no  different  from  that  of  baths  in  ordi- 
nary water  at  the  same  temperature  (Jacob(a)(&) ;  Leichtenstem)  al- 
though as  early  as  1871  Rohrig  and  Zunz  showed  a  gi'eater  gaseous  exchange 
in  rabbits  in  a  sea  salt  bath  than  in  a  fresh  water  bath.  Winternitz(e) 
concluded  that  such  baths  produce  very  little  change  in  the  metabolism  of 
healthy  adults,  not  more  than  15  per  cent  after  baths  lasting  one  hour.  The 
careful  work  of  Loewy  and  Mliller  on  sea  air  and  sea  baths  showed  an  in- 
creased metabolism  as  evidenced  by  greater  oxygen  consumption  and  a 
decreased  respiratory  quotient  extending  beyond  the  duration  of  the  bath, 
but  there  are  no  comparative  data  for  fresh  water  bathing  with  similar 
climatic  influence.  The  influence  of  salt  w^ater  baths  on  nitrogen  and  in- 
organic especially  salt  metabolism  has  been  the  subject  of  more  extended 
work  and  discussion.  Some  early  results  (Dommer)  tending  to  show  that 
4  per  cent  XaCl  baths  caused  a  marked  increase  in  nitrogen  output  (in  a 
dog)  have  generally  not  been  corroborated.  The  one  investigator  who  does 
uphold  this  idea  (Eobin)  probably  had  too  short  a  preliminary  period  to 
observe  nitrogen  metabolism  properly.  Koestlin  found  a  decrease  in 
nitrogen  excretion  after  wann  sool  baths  (Stassfurt  salt)  while  fresh  water 
baths  had  no  influence  nor  did  sodium  chlorid  or  magnesium  chlorid  baths, 
but  potassium  chlorid  baths  gave  the  same  results  as  Stassfurt  salts  from 
which  he  concluded  that  potassium  chlorid  was  the  active  factor.  How- 
ever, he  did  not  account  for  fecal  nitrogen  or  for  the  nitrogen  given  out  in 

*Kahlenl>er^',  private  comnuinicatidn  to  the  author. 


m 


864  HENRY  A.  MATTILL 

the  sweat  and  his  results  are  questioned  by  Bahrmann  and  Kochmann  who 
conclude  that  even  sool  baths  have  effects  no  different  from  those  of  baths 
in  ordinary  water  at  the  same  temperature,  nor  do  they  trust  the  various 
reports  on  the  usually  increased  chlorid  excretion  as  a  result  of  bathing 
(Keller;  Eobin)  because  of  too  brief  preliminary  periods  and  because  the 
laws  of  sodium  chlorid  metabolism  are  not  yet  well  enough  imderstood. 
In  the  careful  work  on  sea  bathing  above  referred  to  an  increased  excre- 
tion of  sodium  chlorid  was  recorded  during  the  bathing  periods,  an  amount 
that  would  have  required  an  intake  of  100  c.c.  of  sea  water,  and  the 
accidental  gidping  of  water  was  avoided. 

In  experiments  on  the  metabolic  effects  of  bathing  in  the  Great  Salt 
Lake  (20  per  cent  solids,  mostly  sodium  chlorid)  it  appeared  (Mattill(a) 
(b)  )  that  the  excretion  of  urinary  nitrogen  and  salt  increased  progressively 
during  the  progress  of  the  bathing  periods.  Most  of  the  extra  elimination 
appeared  during  the  three  hours  following  the  bath  and  in  amounts  of  from 
15  to  50  per  cent  above  the  excretion  during  the  same  period  on  non-bathing 
days  (Fig.  1).  There  was  no  evident  compensatory  decrease  during  the 
other  periods  of  the  day  and  the  accidental  swallowing  of  salt  water  was 
studiously  avoided.  The  fairly  uniform  parallelism  between  nitrogen  and 
chlorid  excretion  has  no  obvious  explanation;  it  is  similar  to  the  find- 
ings obtained  by  various  investigators  in  experiments  on  the  influence  of 
water  ingestion.  Other  urinary  constituents,  ammonia,  uric  acid  and  crea- 
tinin  were  uninfluenced  by  the  bathing.  The  mechanical  effect  of  the 
pressure  of  water  was  much  greater  in  this  case  because  of  the  high  concen- 
tration of  solids,  and  the  residual  effect  of  the  salts  on  the  skin  was  cor- 
respondingly higher.  This,  according  to  Ililler  may  be  as  great  as  tliat 
of  the  bath  itself.  Such  salts  may  be  demonstrated  spectroscopically  on 
the  skin  as  long  as  a  week  after  a  bath  and  various  physical  as  well  as 
chemical  eft'ects  have  been  ascribed  to  them  (Lehmann;  Frankenhauser; 
Schwenkenbecher).  The  amounts  remaining  after  a  salt  bath  vary  with 
different  individuals  perhaps  as  a  result  of  varying  amount  of  body  hair 
(Loewy  and  Midler ). 

The  clinical  investigations  as  to  the  influence  of  salt  baths  on  metabo- 
lism seem  to  show  more  significant  results  than  the  purely  experimental. 
The  experiments  of  Heubner  on  two  strumous  children  and  those  of 
Schkarin  and  Kufajeff  on  rachitic  infants  show  that  these  baths  have  a 
vei-y  definite  influence  on  the  child's  organism,  perhaps  because  of  the 
relatively  greater  surface  area.  The  former  investigator  used  gi\adually 
increasing  salt  concentrations  and  found  no  increase  in  body  weight  in 
spite  of  liberal  feeding.  Nitrogen  elimination  increased  as  the  bathing 
period  progressed  with  highest  values  in  the  final  period  leading  to  a  nega- 
tive balance  in  one  case  in  which  there  was  poorer  utilization  of  food. 
In  this  case  there  was  chlorid  retention,  in  the  foraier  sodium  chlorid 
excretion  remained  practically  unifonn.    Heubner  considered  that  metab- 


HYDROTnERAPY 


8G5 


olism  was  affected  (1)  by  the  tide  of  tlio  blood  between  tbe  surface  and  tbe 
interior  of  the  hody,  aii<l  (2)  by  th(;  stiniidation  of  the  peripheral  vaso- 
motor and  sensory  iiciTes.  The  Russian  investigators  in  their  five  cases 
observ'Ml  a  considerable  decrease  in  nitrogen  retention  during  the  bathing 
periods,  which  was  not  a  result  of  poorer  utilization  of  the  food.  In  three 
cases  in  which  a  final  period  was  also  possible  nitrogen  retention  was  seen 


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Fig.  1,  Total  nitrogen  and  sodinni  clilorid  in  tenths  of  gi-aras,  ereatinin  in 
liiindredths  of  grams.  B  =  Bath.  (Reproduced  by  permission  of  the  American  Jour- 
nal of  Physiology.) 


to  increase  toward  the  values  found  in  the  preliminary  periods  and  the 
possibility  that  all  children  may  not  react  to  the  ^'cure"  in  this  way  indi- 
cates that  the  use  of  sool  baths  in  pediatrics  must  rest  on  a  scientific  founda- 
tion. 

Blood  pressure  measurements  made  by  Loewy  and  others  in  the  sea- 
bathing experiments  mentioned  above  showed  a  pronounced  rise  in  systolic 
pressure,  scarcely  any  change  in  the  diastolic,  with  the  result  that  pulse 
pressure  reached  high  levels.  There  was  usually  also  an  increase  in  pulse 
late.     Wirhin  five  minutes  after  the  bath  these  phenomena  had  practically 


866  HENRY  A.  MATTILL 

disappeared.  The  comparative  findings  in  a  cold  tub  bath  during  which 
both  systolic  and  diastolic  pressures  are  raised  and  pulse  is  slowed  show 
the  great  diiference  in  the  eft'ects  of  the  two  kinds  «»£  baths  on  the  circula- 
tion, and  they  consider  that  a  sea  bath  involves,  in  addition  to  the  effect  of 
a  cold  bath,  three  factors,  the  salt  content  of  the  water,  the  mechanical 
eifect  of  the  waves  on  the  skin  and  the  muscular  work  involved  in  buffeting 
the  waves.  Similar  data  from  fresh  water  seem  not  to  be  at  hand.  Blood 
pressure  values  following  bathing  in  Great  Salt  Lake,  although  obtained 
during  the  bath,  were  normal  perhaps  because  the  factor  of  exercise  in 
resistance  to  waves  was  absent. 

It  is  a  common  experience  that  the  skin  feels  "smoother"  after  a  salt 
water  bath  than  after  a  fresh  water  bath.  This  may  be  associated  with 
modifications  in  skin  sensitivity  (Santlus). 


Effervescent  Baths 

The  presence  of  a  dissolved  gas  in  water  lowers  the  indifferent  tem- 
perature of  the  water,  that  is,  the  temperature  at  which  heat  is  neither 
added  to  nor  taken  from  the  body.  Water  at  25°  C.  feels  cool ;  COg  or  Oo 
at  that  temperature  feels  warmer  (Senator  and  Frankenhauser).  In  a 
cold  effervescent  bath  when  the  body  becomes  covered  wdth  bubbles  the 
points  of  the  skin  in  contact  with  gas  feel  warmer  than  those  in  contact 
with  water  and  the  former  also  give  off  heat  less  rapidly  since  gas  is  a 
poorer  conductor  than  water,  CO2  only  one-half  that  of  air.  However, 
the  tactile  end-organs  of  the  skin  as  well  as  the  warm  and  cold  spots  are 
stimulated  (Goldscheider)  and  the  tendency  to  heat  loss  and  to  secondary 
heat  production  is  greater  in  an  effervescent  bath  because  physical  regula- 
tion is  prematurely  broken  down  by  the  mechanical  stimulus.  Hyper- 
emia of  the  skin,  the  "reaction"  appears  more  quickly  and  with 
less  feeling  of  cold  than  in  an  ordinary  bath  at  the  same  temperature. 
After  due  allowance  has  been  made  for  these  different  and  variable  factors, 
it  may  be  questioned  whether  an  effen*escent  bath  introduces  into  hydro- 
therapy any  new  features  beyond  the  possibility  of  further  combinations 
of  the  effects  secured  by  ordinary  procedures.  The  resultant  temperature 
effect  is  the  determining  factor. 

The  original  experiments  of  Winternitz  showed  that  OO2  baths  caused 
an  increase  in  the  total  volume  of  respired  air  and  a  remarkable  rise  in 
CO2  output  without  corresponding  increase  in  oxygen  intake  \  he  explained 
the  increased  COv,  output  by  assuming  an  absorption  of  COo  by  the  skin. 
During  the  last  two  decades  a  very  considerable  body  of  literature  has 
appeared  on  the  effects  of  COo  and  Oo  containing  baths  particularly  on 
blood  pressure  (Groedel),  much  of  it  contradictory  and  propagandist  in 
nature.     According  to  Swan  the  influence  of  carbonated  baths  on  blood 


HYDKOTTIERxVPY  867 

pressure  is  variable  and  any  favorable  results  secured  in  cardiac  cases  are 
independent  of  the  effect  on  blood  pressure. 

Peat  and  mud  baths  have  a  j)oint  of  thermal  indifference  considerably 
above  that  of  water,  as  high  as  *Jt^°  C. ;  in  the  absence  of  convection  cur- 
rents and  l)ecau<e  of  the  non-conducting  layer  next  the  skin  the  effects  of 
heat  are  equalized  and  the  skin  temperature  remains  more  constant.  Pos- 
sibly the  chemical  action  of  the  acids  and  salts  found  in  peat  and  mud 
and  the  physical  efl'ects  of  friction  and  pressure  may  affect  metabolisTu; 
but  there  are  no  entirely  trustworthy  data  as  to  the  effects  of  such  baths 
and  such  as  are  at  hand  (Tuszkai;  Silber)  do  not  show  results  that  are 
not  attributable  to  temperature  effects  on  metabolism.  Sulphur  baths 
seem  to  have  no  specific  influence  on  metabolism  (Bain,  Edgecombe  and 
Frankling;  AVintemitz  and  Popischil). 

Kadioactive  baths  and  springs  have  given  the  opportunity  for  the 
publication  of  a  number  of  papers  dealing  with  the  supposed  benefits  at- 
tending their  extensive  use.  ]^adium  emanation  does  not  enter  the  body 
by  the  skin  (Xagelschmidt  and  Kohlrausch)  and  when  it  was  added  to  a 
fresh  water  bath  no  influence  on  gaseous  metabolism  was  observed  (Silbcr- 
gleit(a.)). 

Baths  and  Sweat  Secretion 

The  influence  of  baths  on  the  rate  of  secretion  and  on  the  composi- 
tion of  the  sw^eat  is  of  special  interest  because  of  a  possible  vicarious  skin 
excretion  under  the  influence  of  heat  treatment,  especially  in  diseases  of 
the  kidney.  The  data  on  the  composition  of  human  sweat  are  fragmentary 
and  conflicting  partly  because  of  the  wide  variety  of  conditions  under 
which  sweat  has  been  collected,  because  the  composition  changes  with 
changing  rate  of  secretion  (Kittsteiner(a)  (&)),  varies  with  the  diflPerent 
parts  of  the  body  from  which  it  comes,  and  may  vary  with  the  diet  (Kitt- 
steiner(f)  ;  Berry).  It  is  thus  not  possible  to  tabulate  the  results  that 
have  been  obtained  (Argutinsky;  Benedict(a) ;  Schwenkenbecher  and 
Spitta ;  Tayloru/).  Talbertf^)  ).  The  values  for  nitrogen  elimination 
under  different  conditions  vary  from  0.07  to  0.75  gr.  per  day  (or  part 
of  a  day),  half  of  which  is  in  the  foriu  of  urea  (Plaggemeyer  and  Mar- 
shall). Salt  excretion  is  said  to  vary  from  0.33  gr.  to  1  gram  in  profuse 
perspiration.  Whether  nephritics  eliminate  more  solids  in  the  sweat  than 
noiTnal  persons  seems  undecided  (Kohler;  Tachau;  Riggs;  Loofs;  Strauss 
(a))  and  figures  on  the  A  of  the  blood  in  nephritis  as  influenced  by  sweat- 
ing  procedures  (Bendix;  Ocorgopulos)  are  not  extensive  enough  to  he 
convincing.  Even  if  perspiration  leads  to  a  decrease  in  the  urea  of  the 
urine,  which  it  does  not,  always  (Leube;  Dapper(«)  ;  v.  ^oorden(c)) 
the  amounts  of  nitrogenous  material  and  salts  which  can  be  eliminated 
by  the  skin  are  a  very  small  fraction  of  those  eliminated  by  the  kidney, 


;S-^ 


S68  HENRY  A.  MATTILL 

or  of  those  present  in  the  blood  and  tissues  in  renal  disease,  and  in 
V.  Xoorden's  opinion  there  is  no  evidence  of  a  ''vicarious'^  excretion  on  the 
part  of  the  sweat  glands.  A  reported  suppression  of  alimentary  glyco- 
suria by  rapid  perspiration  and  appearance  of  sugar  in  the  sweat  (Bendix) 
requires  confirmation.  While  hot  baths  may  be  of  value  in  nephritis 
(Strasser  and  Bhunenkranz)  the  excessive  water  lost  in  perspiration  must 
be  restored  and  in  the  light  of  the  information  on  the  influence  of  hot  baths 
on  nitrogen  metabolism,  the  heat  application  should  not  be  so  powerful  or 
rapid  as  to  cause  a  rise  in  body  temperature. 


'■*■'■- 1 


The  Influence  of  Roentgen  Rays,  Radioactive  Substances, 

Li^ht  and  Electricity  upon  Metabolism 

Thomas  Ordway,  Arthur  Knudson 

Roentgen  Rays  and  Radioactive  Substances — Introduction — Measurement 
(Standardization)  of  Radioactive  Substances  and  of  Roentgen  Rays — 
Distribution  and  Elimination — Effect  on  the  Blood  and  Blood  Forming 
Organs — Effect  on  Immunity — Effect  on  Normal  Metabolism — Effect  on 
Metabolism  in  Disease — Constitutional  Effects — Theories  of  Action — 
Light — Electricity. 


The   Influence   of   Roentgen   Rays^ 
Radioactive    Substances,    Light 
and  Electricity  upon  Metabolism 


THOMAS  ORDWAY 

AX  J) 

ARTHUR  KIs^UDSOi^ 

ALBANY 

I.     Roentgen  Rays  and  Radioactive  SubwStances 

Introduction. — This  discussion  of  the  effect  of  Roentgen  raA's  and 
riidioactive  substances  npon  metabolism  will  be  limited  almost  exclusively 
to  the  more  recent  investigations  npon  man  and  other  mammals.  Ko  at- 
tempt will  be  made  to  duplicate  the  comprehensive  sui^eys  of  previous  au- 
thors, nor  can  any  detailed  description  of  the  physical  nature  of  these  fonns 
of  energy  be  considered  here.  In  studying  the  effects  of  radiations  both  ra- 
dium and  x-rays  have  been  used  as  a  means  of  experiment  and  the  litera- 
ture of  both  may  be  considered  together.  As  a  working  basis  for  experiment 
the  effects  of  Iwth  are  comparable  especially  in  the  case  of  the  gamma  rays 
of  radium.  The  effect  of  the  other  rays  is  not  however  to  be  considered 
negligible  but  seems  to  differ  in  degree  rather  than  in  the  kind  of  their 
action  so  that  the  results  do  not  conflict  with  our  working  hypothesis. 

In  a  sur\-ey  of  the  subject  of  radiotherapy  Ordway(a)(&)  has  briefly 
described  the  methods  of  use  of  radioactive  substances  and  Roentgen  rajs 
for  external  or  so-called  surgical,  and  internal  or  medical  conditions.  He 
has  shown  that  our  knowledge  of  the  former  is  far  greater  than  that  of  the 
latter,  which  is  to  be  advanced  almost  exclusively  by  a  careful  study  of 
the  effect  of  these  physical  agents  upon  metabolism. 

IMuch  of  the  earlier  work  has  been  rendered  very  uncertain  because 
of  the  faulty  physical  or  biological  methods.  It  is  also  unfortunate  tbat 
the  application  of  the  results  has  been  in  certain  instances  prema- 
turely made  to  clinical  therapeutic  work  on  the  assumption  that  any 
changes  in  the  metabolism  were  necessarily  beneficial. 

Great  caution  should  be  used  in  estimating  the  therapeutic  effect  of 
physical  agents  Ix'cause  of  the  marked  fluctuations  which  occur  in  the 

871 


872 


Tno:MAS  OHDWAY  AXD  AJlTIIlTIl  KlS^UBSO^S- 


course  of  clironlc  diseases,  iiulopenflent  of  treatment.  The  importance 
of  the  psychical  effect  of  any  treatment  must  also  be  considered  in  thera- 
peutic work.  Encouragement  from  tiie  fact  that  something  (frequently 
the  more  unusual  the  greater  the  effect)  is  being  done  is  often,  at  least 
temporarily,  very  beneficial  to  patients  suffering  from  a  chronic  disease. 
It  is  important  to  establish  definitely  in  an  objective  manner  how  metab- 
olism is  affected  by  these  physical  agents  and  then  to  proceed  very  care- 
fully to  their  therapeutic  application. 

Measurement  (Standaj-dization)  of  Radioactive  Substances  and  of 
Roentgen  Rays. — It  is  extremely  important  that  detailed  information  of 
the  exact  technique  be  included  in  reports,  so  that  the  work  may  be  dupli- 
cated by  others.  In  the  past  the  difficulty  of  standardizing  the  energy  of 
x-rays  has  led  to  varying  results  and  the  measurement  of  the  activity  of  the 
x-rays  by  their  effect  upon  chemical  pastilles  or  photographic  films  have  not 
proven  satisfactory.  The  development  of  the  Coolidge  tube  has  made  it 
possible  to  secure  the  desired  milliamperage  as  distinct  from  the  voltage 
and  the  recently  devised  stabilizer  prevents  fluctuations  in  the  current. 

The  relation  of  the  methods  of  measurement  of  x-rays  as  expressed 
in  erythema  dose  is  indicated  in  the  following  table : 

TABLE  I 
TABLE  OF  COMPARATIVE  X-RAY  DOSAGE' 


Erythema  Dose 


Designation 
Tint  B 

E  16 

6  H 

1-H  H 

10  X 
4  Ha 

16  Ha 


Author 
Sabouraiul 

Kimura 

Holzkneclit 


Kienboeck 
Hampson 


Position 

^2  target  skin  dis- 
tance 

^^  target  skin  dis- 
tance 

%  target  skin  dis- 
tance 

Pastille  on  the 
skin 

Strip  on  the  skin 

Pastille  on  the 
skin 

Pastille  at  V2  dis- 
tance 


Cooli(l*:e  tube — 40  milliaiiipore  minutes  at  a  distance  of 
10  inches,  CO  kilovolts  and  without  any  filtration;  60  mil- 
liampore  minutes  with  filtration  of  1  mm.  of  alununum. 


Special  ionization  chambers  have  been  devised  to  measure  the  in- 
tensity of  lioentgen  rays.  A  cham.ber  termed  the  ionto  quanti meter  for  the 
clinical  measurement  of  x-rays,  suggested  by  Szillard  of  Paris,  is  de- 
scribed by  Knox.  Duane  made  a  similar  apparatus  and  placed  it  between 
the  source  of  the  x-rays  and  the  object  to  be  rayed.    Glockner  and  Reuscli 


» Amplified  after  U.  S.  A.  X-ray  Manual.     New  York:  Paul  B.  Hoebcr,  1919. 


IXFLUEXCE  OF  ROENTGEN  RAYS  UPON  METABOLISM  873 

have  also  described  an  ionization  chamber  for  measurement  of  the  dosa^-e 
of  Roentgen  rays.  Kronig  and  Friederich  have  made  ionization  cham- 
bers, the  so-called  ionto  quantimeters,  so  small  that  they  can  be  placed 
within  a  cavity  in  close  proximity  to  the  part  of  the  body  to  be  rayed. 
Such  ionization  chambers  connected  with  an  electroscope  or  an  electro- 
meter give  an  indication  of  the  relative  or  absolute  dosage  of  x-rays  and 
should  therefore  greatly  facilitate  a  comparison  of  x-rays  and  radio- 
active substances. 

Estimation  of  the  activity  of  ]-adioactive  substances  when  expressed  in 
milligrams  may  be  misleading  unless  it  is  based  upon  the  activity  of  the 
gamma  radiation  of  the  radioactive  element  solely,  as  indicated  by  its 
power  of  ionization.  This  is  the  method  adopted  by  the  United  States 
Bureau  of  Standards.  Unless  the  standardization  by  weight  conforms 
to  the  above  there  may  be  gi-eat  variation  due  to  the  type  of  salt  used,  to 
the  presence  or  absence  of  water  of  crystallization  and  particularly  to 
the  variable  amount  of  impurity  such  as  barium.  The  unit  activity  of 
radium  salt  should  be  expressed  as  above  indicated  in  milligTaras  of 
radium  element.  The  emanation  or  radioactive  gas  in  equilibrium  with 
one  milligram  of  radium  element  has  been  designated  one  millicurie.  For 
measuring  the  radioactive  strength  of  solutions  for  bathing  and  drink- 
ing and  of  air  for  inhalation  the  so-called  ^'Mache"  unit  is  commonly 
used.  One  ^lache  unit  is  equivalent  to  one  three-millionth  part  of  a  milli- 
curie. Three  thousand  Mache  units  are  equivalent  to  one-thousandth  of 
a  milligram  of  radium  element.  One-thousandth  of  a  milligram  is  equiva- 
lent to  one-millionth  of  a  gi-am  and  is  frequently  designated  as  a  micro- 
gram. The  French  formerly  took  the  radioactivity  of  uranium  as  their 
standard.  Uranium  was  considered  as  having  a  radioactivity  of  1  and 
pure  radium  2,000,000  times  as  great.  An  activity  of  500,000  frequently 
reported  in  literature  would  represent  one-fourth  of  pure  radium  and 
three-fourths  of  impurity. 

In  a  quantitative  study  of  the  effect  of  radium  radiations  on  the  fer- 
tilization membranes  of  Nereis  limbata  Redfield  and  Bright  obtained 
a  physiological  reaction  to  these  radiations  which  could  be  measured  with 
such  precision  that  the  thickening  of  the  membrane  served  as  a  physio- 
logical index  of  the  intensity  of  the  radiation.  Wood  and  Prime  suggest 
for  an  intensity  unit  of  radium  the  rays  emitted  by  1  milligram  of  radium 
element  (1  millicurie  of  radium  emanation)  located  at  a  point  1  centimeter 
distant  and  they  designate  this  as  1  milligram  or  millicurie  centimeter. 
Mottrarn  and  Russ  consider  the  biological  x-ray  unit,  which  they  designate 
by  the  name  rad,  as  equal  to  the  exposure  to  beta  and  gamma  rays  from 
2.75  milligrams  of  RaBr2ll20  per  square  centimeter  for  one  hour.  Tliis 
is  just  sufficient  to  prevent  the  growth  of  a  rat  sarcoma  and  to  produce  an 
erytliema  when  applied  to  human  skin, 


874         THOMAS  ORDWAY  AND  ARTHUR  KNUDSOX 

Distribution  and  Elimination. — Radioactive  substances  differ  from 
the  x-rays  from  the  fact  tliat  in  solution  in  the  form  of  a  salt,  or  as  active 
deposit  of  radium  emanation,  or  the  emanation  itself  in  solution,  they 
may  be  ingested  or  injected  into  the  animal  body.  The  emanation,  the 
radioactive  gas  evolved  from  a  solution  of  radium,  may  also  be  taken 
into  the  body  by  inhalation.  A  method  of  condensing  the  emanation  and 
the  deposition  of  the  active  deposit  upon  sodium  chlorid  which  may  be 
dissolved  in  water  to  make  an  isotonic  solution  has  been  described  by 
Duane. 

Berg  and  Welker  found  that  after  subcutaneous  injections  the  radium 
(bromid)  like  barium  and  calcium  is  eliminated  chiefly  by  the  intestinal 
tract.  Meyer  after  intravenous  injection  of  solutions  of  radium  bromide 
showed  the  presence  of  radium  in  the  liver,  lungs,  and  kidneys.  The 
ultimate  fate  was  not  materially  different  if  the  radium  was  injected  in  any 
other  manner,  that  is,  subcutaneously  or  intraperitoneally  or  if  a  solu- 
tion were  taken  by  mouth. 

Salant  and  ^leyer  conclude  that  the  elimination  of  radium  is  chiefly 
by  way  of  the  liver,  kidneys,  and  the  small  intestine  and  to  a  less  extent 
through  the  large  intestine  in  some  herbivora.  Brill  and  Zehner  found 
that  radium  chlorid  injected  into  dogs  and  rabbits  was  eliminated  almost 
exclusively  by  the  feces  and  there  was  very  little  in  the  urine.  Bagg(a) 
found  that  following  the  injections  of  active  deposit  from  radium  emana- 
tion there  is  diffusion  of  radioactive  substance  throughout  the  animal 
body,  resulting  in  pathological  changes  in  various  organs,  notably  the 
liver,  lungs,  kidneys,  adrenals,  spleen,  lx>ne  marrow,  brain  and  vascular 
system. 

Effect  on  Tissues. — It  is  well  known  that  radiations  of  Roentgen  rays 
and  radioactive  substances  affect  different  tissues  to  a  varying  degree 
and  that  the  lymphatic  tissue,  spleen,  lymph  glands,  bone  marrow  and 
sex  glands  are  particularly  susceptible  (Heinecke  and  Warthin).  Hauscht- 
nig  in  describing  the  technique  for  radium  treatment  shows  that  the  mucosa 
of  the  intestines  and  bladder  is  sensitive  to  one  erythema  dose  while 
the  muscles  of  the  cervix  uteri  are  resistant  to  forty,  those  of  the  corpus 
uteri  to  thirty,  and  the  vaginal  mucosa  to  five  or  six  erythema  doses.  The 
dose  which  destroys  carcinoma  cells  is  practically  the  same  as  the  erythema 
dose  of  the  skin.    ISTervous  tissues  are  very  resistant  to  radiations. 

Xakahara,  and  Xakahara  and  Murphy  believe  that  by  a  carefully 
measured  dose  of  x-rays  (Coolidge  tube,  spark  gap  %  inch,  milliamperage 
25,  distance  8  inches,  time  10  minutes)  within  foiu*  days  there  is  an  ab- 
normally large  number  uf  mitotic  fignr€\s  found  in  the  lymphoid  tissue 
of  the  spleen  and  lymph  glands.  They  believe  that  this  indicates  accelera- 
tion of  the  proliferative  activity  of  this  tissue  by  exposure  to  x-rays  of 
low  voltage.  The  great  variation  in  the  activity  of  lyniphoid  tissue  nat- 
urally at  different  ages  and  also  when  due  to  intercurrent  infections  and 


IXFLUEXCE  OF  ROEXTGEX  RAYS  UPOX  METABOLISM  876 

of  the  small  number  of  animals  in  these  experiments  render  the  results 
uncertain. 

Kimura  has  studied  the  effects  of  x-rays  on  living  carcinoma  and  sar- 
coma cells  in  tissue  cultures  giown  in  guinea  pig  plasma  to  which  was 
added  mouse  serum  diluted  with  Ringer's  solution  and  found  that  the 
outspreading  growth  was  not  stopped  by  the  action  of  the  x-rays  with 
a  dosage  of  E  4  to  E  12.  The  mitotic  figures  were  limited  to  a  minimum 
after  an  exposure  to  a  dosage  of  E  8  and  after  an  exposure  to  E  12  the 
mitoses  disappeared  entirely  and  the  tissue  so  treated  produced  no  tumors 
when  inoculated  into  mice.  The  gTOwing  power  of  the  sarcoma  after 
exposure  to  a  dose  of  E  4  was  apparently  somewhat  stimulated  and  the 
carcinoma  was  not  appreciably  influenced.  The  process  of  oxidation  of 
the  tissues  in  both  the  sarcoma  and  carcinoma  cultui-es  was  stimulated 
by  x-ray  action  of  the  dosage  of  E  4  and  retarded  by  exposures  to  E  12. 

The  histological  changes  in  tissue,  induced  by  exposure  to  radiations 
of  x-rays  and  radium,  have  been  described  in  detail  by  many  investigators. 
They  consist  of  a  necrobiosis  of  the  cells,  a  chronic  inflammatory  reaction, 
followed  by  fibrosis.  The  changes  depend  on  the  intensity  of  the  radia- 
tion and  the  type  of  tissue  radiated. 

Effect  on  the  Blood  and  Blood  Forming  Organs. — The  chemical  ef- 
fect of  radiations  of  radium  and  x-ray  upon  the  blood  will  be  referred 
to  later.  Gudzent(^)  has  summ.arized  the  work  prior  to  1913.  It  may  be 
briefly  stated  that  the  lymphocytes  are  apparently  stinmlated  to  both 
relative  and  absolute  increase  by  small  doses  and  reduced  in  number 
by  large  doses  of  x-rays ;  and  that  the  spleen  and  lymph  glands  undergo 
profound  change  by  destruction  of  the  cellular  elements  as  the  result  of 
exposure  to  x-rays  and  radium.  Gudzent  and  Halbei-staedter  found 
in  the  blood  of  radium  workers  striking  relative  increase  in  lymphocytes 
(36  to  (53  per  cent),  in  an  average  of  ten  cases  40.4  per  cent  and  a  relative 
and  absolute  decrease  in  neutrophils,  the  average  number  being  60.3  per 
cent.  There  was  little  change  in  the  red  blood  corpuscles,  slight  diminu- 
tion in  the  white  cells,  the  hemoglobin  was  lowered  in  only  two  cases,  70 
and  71  per  cent  respectively.  Ordway(c)  found  a  similar  though  some- 
what less  marked  change  in  a  series  of  clinical  workers  who  showed  local 
occupational  injuries  due  to  the  handling  of  radium. 

Millet  and  Mueller  in  a  study  of  the  blood  of  ten  patients  with  squam- 
ous cell  carcinoma  of  the  cervix  uteri  and  the  vagina,  for  the  immediate  and 
remote  effects  of  radium  and  x-rays,  found  an  immediate  drop  in  the  total 
white  count  reaching  a  maximum  in  one-half  to  six  hours  after  applica- 
tion, and  a  return  to  normal  within  twelve  to  twenty-four  hours.  Oc- 
casionally there  was  a  secondary  rise  in  from  12  hours  to  3  days.  The 
polymorphonuclear  count  followed  the  total  white  count.  The  total  lym- 
phocytes tended  to  follow  the  white  count  but  were  not  constant.  There 
was  a  tendency  for  the  relative  lymphocyte  count  to  drop  and  the  poly- 


876         TIIO^IAS  OKDWAY  AND  AKTHUR  KXUDSOX 

morphomiclear  to  rise  during  treatment  but  this  tendency  was  reversed 
immediately  following  the  removal  of  the  radiations.  The  remote  effects 
consisted  of  a  fall  in  the  lymphocyte  count  for  two  to  four  weeks  after 
treatment,  sometimes  lasting  until  the  end  of  the  second  month.  The  fall 
in  the  polymorphonuclears  was  usually  less  than  the  lymphocytes,  the  lat- 
ter after  from  three  to  nineteen  weeks  rose  to  the  normal  level.  When 
the  patient's  resistance  weakened  they  found  an  increase  in  the  polymor- 
phonuclear leucocytes  and  decrease  in  the  lymphocytes  but  without  leu- 
cocytosis  duo  chiefly  to  an  absolute  increase  in  the  pol)'niorphonuc]ear  leu- 
cocytes and  usually  a  decrease  in  the  lymphocytes.  Such  changes  in  the 
blood,  however,  are  subject  to  considerable  fluctuations  owing  to  secondary 
infections.  This  is  not  only  true  in  human  beings  but  particularly  in 
the  experimental  study  of  radiation  effects  in  the  blood  of  animals. 

Woglam  and  Itami  have  shown  that  it  is  not  easy  to  establish  a  norma! 
standard  for  certain  laboratory  animals,  notably  mice,  that  there  is  great 
variation  in  the  activity  of  the  hematopoietic  tissues  in  apparently  healthy 
individuals.  The  age  as  well  as  intercurrent  infections  are  factors  which 
must  be  taken  into  consideration. 

Aubertin  and  Eeaujard  studj'ing  the  action  of  x-rays  on  the  blood 
and  bone  marrow  show  that  the  marrow  is  much  less  sensitive  to  raying 
than  the  lymphoid  tissue.  They  believe  that  leukopenia  may  be  produced 
by  the  x-ray,  either  by  tlie  direct  action  of  the  rays  upon  the  leucocytes  in 
the  circulation  or  by  its  action  on  hematopoietic  tissue  which  prevents 
normal  regeneration  of  white  blood  cells.  Brill  and  Zehner  injected  a 
soluble  salt  of  radium  (RaCla)  subcutaneously  into  dogs  and  rabbits 
in  doses  of  0.0025  and  0.093  mgm.  and  found  that  almost  immediately  the 
number  of  red  cells  per  cu.  mm.  was  greatly  increased.  On  the  day  fol- 
lowing there  was  another  marked  increase.  This  polycythemia  persisted 
for  a  week  and  for  several  weeks  the  number  of  red  blood  cells  was  con- 
siderably above  normal;  the  hemoglobin  did  not  rise  so  markedly.  The 
leucocytes  increased  rapidly  after  small  injections  and  in  certain  instances 
rose  to  200  per  cent  above  the  normal.  The  larger  injections  on  the  other 
hand  inhibited  leucocyte  production. 

Effect  on  Immunity. — X-rays  and  radioactive  substances  have  such 
a  pronounced  effect  on  the  blood  and  blood  forming  organs,  the  bone 
marrow,  spleen,  and  lymphoid  tissue  generally  that  it  is  not  surprising 
that  variations  in  immunity  and  susceptibility  are  produced  by  exposure  to 
radiations.  Hektoen(rt)  (h)  found  that  long  exposure  to  x-ray  at  the  time 
the  antigens  were  injected  into  white  rats  markedly  reduced  the  production 
of  hemolytic  antibodies.  He  assumed  that  this  was  due  to  the  destructive 
effect  on  the  lymphatic  tissues,  spleen  and  bone  marrow.  In  some  further 
experiments  he  exposed  dogs  to  x-rays  for  ten  minutes,  followed  the  next 
day  by  a  two  and  a  half  minute  exposure  (approximately  371/2  Kienl>oeck 
units)  ;  they  showed  slight  apparent  disturbance  of  general  health  and  no 


IXFLUEXCE  OF  ROEXTGEX  RAYS  UPOX  METABOLISM  877 

great  change  in  the  leucocytes  in  the  peripheral  blood  but  there  was  a 
marked  reduction  in  the  production  of  antibodies  hemolytic  for  red  blood 
corpuscles  of  the  rabbit. 

Morton  found  that  exposure  of  guinea  pigs  to  x-rays  rendered  these 
animals  more  susceptible  to  experimental  tuberculosis  and  suggested 
such  preliminary  radiation  for  tlie  routine  diagnosis  by  the  guinea  pig 
method.  Kessel  and  Sittenfield,  however,  believe  that  after  a  certain  stage 
radiation  tends  to  prolong  the  life  of  a  tuberculous  guinea  pig  and  to 
promote  healing.  Kellert  finds  that  in  routine  work  preliminary  radiation 
does  not  hasten  the  diagnosis  by  rendering  guinea  pigs  more  susceptible  to 
tuberculosis  but  that  the  increased  susceptibility  of  such  animals  to  sec- 
ondary invaders  and  contaminating  organisms  interferes  with  the 
routine  work.  Corper  and  Chovey,  by  subjecting  mice  to  a  single  non- 
lethal  dose  of  x-rays  or  to  a  single  non-fatal  injection  of  thorium-x,  sub- 
sequently found  that  these  animals  showed  an  increased  susceptibility  when 
inoculated  with  pneumococci  (four  types)  and  hemolytic  streptococci  (hu- 
man and  bovine). 

Euss,  Chambers,  Scott  and  Mottram  in  experimental  studies  with 
small  doses  of  x-rays,  following  the  work  of  ^lurpliy  and  Morton  (a),  on 
the  blood  of  rats  in  its  relation  to  rat  susceptibility  in  Jensen,  rat  sar- 
coma find  that  the  natural  immunity  which  these  animals  have  towards 
inoculation  of  spontaneous  tumors  can  be  broken  down  by  an  x-ray  ex- 
posure sufficient  to  cause  the  disappearance  of  the  lymphocytes.  Prime 
on  the  other  hand  did  not  succeed  in  rendering  rats  naturally  immune  to 
the  Elexner-Jobling  rat  carcinoma,  more  susceptible  by  reducing  the  lym- 
phocytes as  advocated  by  !Murphy.  Murphy  and  Taylor  have  shown  that 
the  acquired  immunity  resulting  from  the  inoculation  of  blood  or  other 
cells  into  normal  animals  can  be  similarly  destroyed.  The  acquired  im- 
munity found  in  animals  in  which  tumors  have  disappeared,  accordingly 
to  Mottram  and  Russ,  can  be  broken  down  only  so  long  as  lymphoid  cells 
are  reduced  in  number.  Tumor  cells  from  a  foreign  species  which  on  in- 
oculation will  grow  only  with  gi'cat  rarity  multiply  rapidly  in  an  x-rayed 
animal  until  such  a  time  as  the  depleted  h-mphoid  tissues  are  well 
advanced  in  regeneration  (']\rurphy). 

On  the  other  hand  Russ.  Chambers,  Scott  and  IVIottram,  and  Murphy 
and  ^^Forton  (a)  have  shown  that  an  immune  condition  can  be  produced  in- 
stead of  dcstro^^ed  by  suitable  doses  of  x-ray.  After  the  removal  of  tumors 
from  mice  by  operation  ^lurphy  and  ^rorton(&)  gave  small  dose  of  x-rays 
and  found  that  grafts  of  the  same  tumors  when  inoculated  did  not  grow 
in  twenty-six  out  of  fifty-two  mice  and  that  there  was  no  recurrence  at 
the  site  of  operation  in  forty-one  animals.  In  twenty-nine  control  mice 
who  were  not  given  small  doses  of  x-rays  the  gi^afts  gi'cw  in  twenty-eight 
and  there  was  local  recurrence  in  fourteen. 


878       Trro:\rAS  ordwav  axd  Arthur  kxudsox 

From  the  above  it  appears  that  the  x-rays  have  two  actions  aside  from 
the  direct  effect  upon  the  tumor.  Fii-st  a  large  dose  destroying  the  im- 
mune condition  will  favor  the  growth  of  tumor,  a  small  dose  producing 
the  immune  condition  helps  to  inhibit  the  growth  of  tumor. 

Such  studies  indicate  that  in  treating  growths  by  radium  or  x-ray  a 
treatment  diiected  solely  toward  the  primary  growth  may  favor  metastasis 
by  lowering  the  natural  powers  of  resistance  of  the  patient,  especially  if 
comparatively  large  doses  are  repeated  at  too  frequent  intervals.  ]\Inrphy 
believes  that  gi*eat  caution  should  be  used  about  destroying  the  lymphocytes 
which  seem  to  play  the  defensive  role  in  malignant  growths. 

L"p  to  the  present  time  the  x-ray  has  only  increased  the  resistance  to 
inoculated  cancer.  Yet  there  is  a  distinct  analogy  between  such  and 
metastatic  deposits  of  a  spontaneous  growth.  Hence  it  is  suggested  by 
Murphy  that  repeated  small  doses  of  x-rays  at  intervals  might  similarly 
increase  resistance  against  the  development  of  secondaiy,  metastatic 
growths. 

Rohdenburg  and  Bullock  by  heat  and  exposure  to  radium  have  in- 
creased the  susceptibility  in  mice  and  rats  to  the  immunizing  action  of 
homologous  living  cells  and  the  additional  immunity  thus  obtained  may 
be  one  hundred  per  cent  over  the  usual  figure.  The  growth  energy  of 
transplanted  tumors  also  can  be  depressed  by  radium  (Wedd  and  Russ). 
This  retardation  of  gi'owth  energy  persists  only  a  few  generations  of 
transplants  (Wood  and  Prime). 

Believing  that  there  might  be  a  relation  between  the  number  of  lym- 
])hocytes  in  the  disease  poliomyelitis  and  the  susceptibility  of  monkeys  to 
experimental  poliomyelitis  Amoss,  Taylor  and  Witherbee  reduced  the 
circulating  lymphocytes  in  such  animals  by  properly  controlled  doses  of 
x-rays  such  as  were  used  by  Taylor,  Witherbee  and  Murphy.  Six  Holz- 
knecht  units  of  unfiltered  x-rays  was  given  at  each  dose  on  the  dorsal  and 
ventral  surface  of  the  animal.  Spark  gap  was  three  inches,  milliamperage 
ten,  distance  twelve  inches  (Coolidge  tube),  time  four  minutes.  The 
animals  were  treated  every  day  or  every  other  day  until  the  total  lym- 
phocytes per  c.mm.  were  about  1000  to  2000.  Animals  tlius  exposed  to 
x-rays  Avere  susceptible  to  three-fourths  of  a  dose  which  was  not  infective 
for  non-rayed  controls.  This  suggests  a  relation  between  the  lymphocytes 
and  one  factor  of  resistance  in  poliomyelitis.  They  were  not  able  to  reduce 
the  immunity  by  cxjmsnrc  to  x-rays  in  a  monkey  immune  from  a  previous 
attack  of  poliomyelitis. 

Effect  on  Enzymes. — Richards (&)  believes  that  the  biological  reactions 
resulting  from  exposure  to  radiations  are  due  in  large  part  to  the  effect 
upon  the  body  ferments.  Richter  and  Gerhartz  in  studying  the  action 
of  x-rays  upon  rennin,  yeast,  jxipsin,  pancreatin  and  papain  concluded 
tlier(^  was  no  effect  on  these  ferments.  Richards(rt  ),  however,  believes  that 
the  experiments  of  these  authors  do  show  slight  changes  which  may  be  at- 


INFLUENCE  OF  KOENTGEN  RAYS  UPON  .METABOLISM  879 

tributable  to  the  otFect  of  x-rays.  He  concludes  from  his  experiments  on 
the  digestion  of  egg  allnimiii  by  pepsin  and  of  starch  by  diastase  that  a 
sliort  radiation  by  x-rays  has  the  effect  of  accelerating  enzyme  activity 
while  a  longer  radiation  inhibits  it,  and  that  between  these  two  intervals 
there  is  a  non-effective  point.  The  experiments  of  Richards  show  that  the 
effects  are  slight  but  definite. 

Radium  rays,  which  are  in  general  comparable  with  x-rays  in  their 
action,  have  been  thought  to  be  the  cause  of  quite  marked  changes  in  the 
course  of  enzymatic  action.  Neuberg(6)  found  an  acceleration  of  theauto- 
lytic  processes  under  the  action  of  radium  emanation.  Packard  considers 
that  radium  radiations,  by  activating  autolytic  enzymes,  act  indirectly 
upon  the  chromatin  an<l  protoplasm  and  thus  bring  about  the  degenera- 
tion of  the  complex  proteins  and  probably  affect  other  protoplasmic  sul)- 
stances  in  the  same  manner.  Influence  of  radium  emanation  upon 
autolysis  of  normal  and  pathological  tissues  has  been  studied  by  l^wen- 
thal  and  Edelstein.  They  found  that  the  rate  of  increase  in  autolysis 
varied  with  the  character  of  the  raiiterial  allowed  to  autolyze,  but 
the  greatest  accelerating  influence  was  found  in  the  case  of  human  car- 
cinoma. 

Henri  and  Mayer  in  studying  the  action  of  radium  on  ferments  found 
that  invertin,  emulsin  and  trypsin  exposed  to  radiations  decreased  and 
finally  lost  their  activity.  Bergdell  and  Bichel  observed  that  the  activity 
of  pepsin  is  enhanced  by  the  influence  of  radium  rays.  Sclimidt-Nielson 
showed  that  radium  preparation  of  1,800,000  activity  has  slight  inhibiting 
action  upon  rennin.  Wilcock  has  reported  that  radium  rays  are  in- 
jurious to  digestive  ferments  such  as  pepsin,  trypsin,  and  ptyalin.  Ac- 
cording to  Lowenthal  and  Wolgemuth  radium  emanation  is  capable  of  ac- 
celerating the  activity  of  the  diastatic  enzyme  of  the  blood,  liver,  saliva,  or 
pancreas,  that  there  may  be  a  slight  retardation  which  is  replaced  by 
acceleration  if  the  experiment  is  sufficiently  prolonged.  Brown  found 
that  the  very  radioactive  radium  D,  radium  E,  and  radium  F  have  a 
marked  inhibitory  action  upon  pepsin  and  pancreatic  diastase;  but  no 
effect  upon  the  autolytic  enzyme  of  the  dog's  liver.  Marshall  and  Rown- 
tree^s(«)  investigation  showed  that  the  radium  emanation  has  ]io  accelerat- 
ing influence  upon  the  lipase  of  the  pig's  liver  or  castor  oil  bean,  while  in- 
hibition of  the  enzymatic  activity  is  suggested.  Schulz(&)  observ^ed  that 
radium  emanation  has  a  certain  amount  of  accelerating  action  upon  the 
uric-acid  forming  enzymes  of  the  spleen. 

From  the  fact  that  alterations  in  permeability  may  cause  cell  division 
and  such  metabolic  changes  as  increased  elimination  of  carbon  dioxid,  of 
catalase,  and  an  increase  of  oxygen  absorption  and  various  other  physio- 
logical reactions  in  the  cell  Richards (c)  performed  experiments  on  x-radia- 
tion  as  a  cause  of  permeability  changes  but  was  unable  to  find  any  evidence 
that  alterations  in  cell  metabolism  are  due  to  permeability  changes.    Min- 


8S0    THOMAS  ORDWAY  AXD  ARTHUR  KXUDSON 

anu  lias  shown  that  thorium-x  emanation  accelerates  or  retards  peptic, 
tryptic  and  diastatie  digestion.  The  duration  of  such  action  depends  in 
part  on  the  time  the  radiations  act.  He  believes  that  possibly  the  autolytic 
ferments  are  influenced  by  the  alpha  rays. 

From  the  foregoing  it  will  be  seen  that  radiation  affects  enzymes  defi- 
nitely, but  the  effects  are  variable,  probably  depending  upon  the  duration 
or  the  amount  of  radiation. 

Funk(c)  investigated  the  influence  of  radium  emanation  on  the  yeast 
vitamins  and  reported  that  radium  emanation  has  no  destnictive  action  on 
beri-beri  vitamin  or  on  the  growth-promoting  factors  in  yeast.  Sugiiira 
and  Benedict,  however,  subjected  portions  of  yeast  to  the  rays  of  radium 
and  tested  this  for  their  grov/th-promoting  powers  upon  young  white  rats 
as  compared  with  the  same  yeast  not  treated  with  radium.  They  ob- 
served that  the  growth-promoting  factors  in  yeast  may  bo  partially  in- 
activated by  means  of  exposure  and  believe  that  this  may  account  for 
some  of  its  effects  on  tumors. 

Effect  on  Normal  Metabolism. — ^llost  of  the  contributions  dealing 
with  metabolism  studies  undei-  the  influence  of  radioactive  substances  and 
x-rays  have  been  concerned  with  abnormal  human  beings,  but  some  work 
has  been  done  upon  normal  animals  and  human  beings.  Quadrorae  studied 
the  influence  of  x-rays  on  one  guinea  pig  and  six  rabbi t-s  and  altliough  his 
results  were  not  uniform  he  got  in  most  cases  a  slight  increase  in  the  urine 
of  the  total  phosphates  (PgOg).  Baermann  and  Linser  obtained  an  in- 
creased nitrogen  excretion  immediately  after  raying  their  patients;  this 
increase  lasted  two  or  three  days  and  on  the  third  or  fourth  day  the  nitro- 
gen excretion  usually  returned  to  normal.  In  a  man,  nonnal  except  for 
chronic  eczema,  Bloch  observed  after  repeated  raying  a  small  increase 
of  basic  nitrogen  output  in  urine  also  an  increase  of  phosphates.  The  me- 
tabolism of  one  dog  rayed  with  large  doses  of  roentgen  rays  was  studied  by 
Benjamin  and  V.  Reuss.  An  immediate  increase  in  nitrogen  elimina- 
tion was  obsei-ved  after  the  first  exposure  and  rapidly  returned  to  normal. 
In  a  second  exposure  to  the  rays  the  increased  elimination  lasted  several 
days.  The  basic  nitrogen  (product  formed  by  precipitation  with  phos- 
photungstic  acid),  non-basic  nitrogen,  ammonia  and  urea,  which  were 
determined  on  the  urine  specimens  along  with  the  total  nitrogen,  all 
showed  an  increase.  The  basic  nitrogen  increased  proportionately  more 
than  the  others.  The  phosphate  output  of  the  urine  also  increased  tran- 
siently. In  the  first  exposure  it  rose  to  33  per  cent  above  normal  and  the 
second  to  over  100  per  cent.  During  the  high  phosphate  output  in  the 
urine  a  transient  appearance  of  cholin  in  the  blood  was  demonstrated, 
which  the  authors  attributed  to  the  breaking  up  of  lecithin  and  substances 
derived  therefrom.  Metabolism  observations  reported  by  Lommel  on  three 
young  dogs  showed  similar  results;  that  is,  increased  nitrogen  and  phos- 
phate elimination.     Linser  and  Sick,  in  studying  the  effect  of  x-rays  on 


IXFLUEXCE  OF  ROEXTGEX  RAYS  UPOX  METABOLISM  881 

several  individuals  with  various  skin  diseases,  noted  in  all  an  increase 
in  the  urinary  nitrogen.  The  uric  acid  output  was  tripled  in  some  cases 
and  the  purin  bases  also  increased.  Similar  results  were  ohsen'ed  in  one 
experiment  on  a  normal  dog. 

The  effect  of  radium  salts  upon  the  metabolism  of  dogs  has  been  studied 
by  Berg  and  Welker.  The  doses  employed  were  very  small  and  thej 
concluded  that  the  ingestion  of  radium  per  os  was  without  any  special 
influence  on  metabolism.  In  one  experiment  a  stimulation  of  the  cata- 
bolic  processes  as  indicated  by  slightly  increased  output  of  nitrogen  in 
the  urine  was  noted,  but  in  another  experiment  the  catabolic  processes  were 
inhibited  to  about  the  same  degree.  An  increased  volume  of  urine  was  also 
noted.  In  order  to  determine  the  eflFect  of  the  active  rays  upon  the  general 
metabolism  of  the  dog  Theis  and  Bagg  used  a  solution  of  sodium  chlorid 
which  contained  active  deposit  from  radium  emanation.  The  dogs  were 
given  doses  of  two  to  six  millicuries  per  kilogram.  One  dog  was  a  Dal- 
matian in  whi(?h  variety  uric  acid  is  excreted  in  the  urine.  The  total  nitro- 
gen in  the  urine  always  increased  reaching  a  maximum  of  ten  to  twenty- 
five  per  cent  on  the  second  day  after  injection.  Urea  nitrogen  paralleled 
the  total  nitrogen,  but  the  ammonia  nitrogen  increased  in  greater  propor- 
tion than  the  total  nitrogen  indicating  a  possibility  of  acidosis.  Uric 
acid  in  the  Dalmatian  dog  increased  both  absolutely  (15  to  50  per  cent) 
and  relatively  to  the  total  nitrogen.  This  may  have  been  due  to  the 
destruction  of  the  white  cells  for  the  phosphate  excretion  was  also  in- 
creased. Creatinin  in  one  experiment  was  increased  but  not  proportion- 
ately to  the  total  nitrogen.  Jastrowitz  has  recently  reported  that  injection 
of  thorium  into  dogs  has  a  tendency  to  increase  excretion  of  uric  acid 
above  normal. 

After  deep  massive  doses  of  hard  Roentgen  rays  Hall  and  Whipple 
noted  marked  metabolic  changes  in  exj)eriments  on  dogs.  The  nitrogen 
excretion  of  the  urine  increased  immediately  following  exposure  to  rays 
and  remained  high  until  death.  There  was  often  an  increase  of  fifty 
to  one  hundred  per  cent  above  normal.  A  marked  increase  (twdce  normal) 
of  the  non-protein  nitrogen  of  the  blood  was  commonly  observed  on  the 
day  before  death  and  often  more  than  three  times  normal  on  the  day  of 
death.  The  authors  do  not  believe  that  the  heaping  up  of  nitrogenous 
split  products  can  be  explained  alone  on  an  increased  breakdown  of  body 
protein  but  that  there  may  be  faulty  elimination.  They  could  observe, 
however,  no  evidence  of  any  nephritis  from  a  study  of  the  urine  nor  by 
anatomical  changes. 

Denis  and  Martin  in  studying  the  relative  toxic  effects  produced  by 
regional  radiation  found  that  exposure  with  massive  doses  of  Roentgen 
rays  over  the  intestines  of  a  rabbit  gave  evidence  of  the  presence  of  an 
acidosis.  This  was  shown  by  a  fall  in  the  alkaline  reseiTO  and  a  rise  in 
fat  and  inorganic  phosphates  of  the  blood  of  most  of  the  rabbits  whip]'. 


882         THOMAS  ORDWAY  AXD  ARTHUR  KKUDSON 

received  the  heavy  exposure  over  the  intestine.  In  some  of  the  rabbits 
a  slight  increase  in  non-protein  nitrogen  was  also  noted. 

A  nlimber  of  investigations  on  the  influence  of  radioactive  substances 
and  x-rays  on  uric  acid  and  purin  base  metabolism  have  led  to  the  gen- 
eral belief  that  these  agents  lead  to  an  increased  elimination  of  uric 
acid  and  purin  bases,  endogenous  as  well  as  exogenous.  Gudzcnt  and 
Lowenthal  believe  that  radium  emanation  has  a  very  pronounced  eifect  on 
purin  metabolism  and  is  due  to  the  activation  of  those  enzymes  i-e- 
sponsible  for  the  building  up  or  cleavage  of  uric  acid.  Purin  metab- 
olism is  altered  according  to  whether  synthesizing  or  cleavage  enzyme 
action  predominates.  Wilke  and  Krieg  report  increases  of  uric  acid  excre- 
tion with  ingestion  of  radioactive  water.  Kikkoji  obtained  a  similar  result 
with  water  impregnated  with  radium  emanation  and  in  one  of  his  cases 
obser\'ed  an  increase  of  ninety-five  per  cent.  Kaplan  reports  that  ingestion 
of  alkaline  radium  water  increases  the  excretion  of  uric  acid  and  purin 
bases.  Abl  also  obser\'ed  increased  elimination  of  endogenous  uric  acid  by 
use  of  thorium-x. 

The  mechanism  of  these  eifects  is  not  established.  Gudzent(a)(^) 
claims  to  have  induced  a  complete  and  lasting  disappearance  of  blood  uric 
acid  by  inhalation  of  air  containing  two  or  four  Machc  units  of  emanation 
per  liter.  In  apparent  confirmation  of  this  fact  he  noted  in  vitro  experi- 
ments an  increase  in  the  solubility  and  gradual  decomposition  of  sodium 
urate  by  radium  D,  which  is  relatively  very  inactive  and  is  a  further  decom- 
position product  of  radium  emanation.  Falta  and  Zehner  claim  that 
thorium-x  also  increases  the  solubility  of  urates  and  destroys  uric  acid. 
]\resemitzky(&)(e)  reported  that  radium  emanation  can  destroy  trioxy- 
purin  (uric  acid)  very  well  but  that  it  had  slight  effect  on  dioxypurin 
(xanthin)  and  no  effect  on  oxypurin  (hypoxanthin).  Ho  also  claims  that 
uric  acid  in  the  blood  is  decreased  under  the  influence  of  radium  emanation 
and  that  there  is  an  increased  excretion  of  uric  acid  in  the  urine.  Other 
observers  have  been  unable  to  confirm  these  results.  Kerb  and  Lazarus  were 
unable  to  detect  any  influence  of  radium  emanation  upon  sodium  urate. 
Using  radiation  from  radium  emanation  in  very  large  amounts  Knafil-Lenz 
and  Weichowski  likewise  failed  to  note  any  increase  in  the  solubility  or 
decomposition  of  sodium  urate.  Kerb  and  Lazai-us  were  of  the  opinion  that 
the  increase  in  solubility  and  decomposition  of  sodium  ui-ate  noted  by 
Gudzent  is  to  be  attributed  to  bacterial  contamination  or  accidental  intro- 
duction of  small  amounts  of  alkali,  either  of  which  conditions  could  cause 
decomposition  of  the  urate. 

Schultz  could  detect  no  change  in  the  activity  of  the  uricolytic  enzyme 
of  the  liver  and  kidney  under  the  influence  of  radium  emanation  but  did 
observe  a  ten  to  twenty  per  cent  increase  in  the  formatio)!  of  uric  acid 
in  autolyzing  spleen  imder  these  conditions.  This  latter  observation 
and  that  of  Kehrer  (which  bespeaks  a  mobilization  oF  uric  acid -in  the 


IXFLUENX'E  OF  KOENTGEX  RAYS  UPON  METAB0LIS:M  883 

body  attributable  to  emanation)  would  lead  one  to  expect,  if  any  change  at 
all,  rather  an  increased  concentration  of  uric  acid  in  the  blood  than  a  de- 
crease, much  less  complete  disappearance  as  Gudzent  would  have  us 
believe. 

Investigations  by  Fine  and  Chace  with  inhalation  of  radium  emana- 
tion (containing  as  high  as  one  hundred  Mache  units  per  liter)  over 
long  periods,  radium  emanation  in  drinking  water,  and  injection  of  fifty 
micrograms  of  soluble  radium  bromid  in  no  case  had  any  influence  what- 
ever upon  the  concentration  of  uric  acid  in  the  blood.  Likewise  they  could 
observe  no  increase  in  the  excretion  of  uric  acid  in  the  urine. 

Very  few  observations  have  been  made  on  the  effect  of  radiation  on 
the  basal  metabolism  in  nonnal  animals  and  human  beings.  Silbergleit(&) 
studied  the  influence  of  baths  containing  radium  emanation  on  the  gaseous 
exchange  of  normal  men,  but  his  results  were  negative.  Kikkoji  found  a 
distinct  increase  in  the  basal  metabolism  of  noi-mal  men  who  received 
during  the  experimental  period  three  doses  of  830  Mache  units  per  os. 
The  respiratory  quotient  was  also  sometimes  increased.  Bernstein  de- 
termined the  basal  metabolism  of  several  }xn-sons  before  and  after  a  two- 
liour  interval  in  an  emanatorium  containing  from  220  to  440  Mache  units 
per  liter  of  air.  One  of  these  was  carried  out  on  a  normal  individual 
and  showed  an  increase  of  about  six  per  cent.  A  slight  increase  of  the 
respiratory  quotient  was  likewise  noted.  The  respiratory  quotient  re- 
mained practically  unafl^ected  according  to  Benczur  and  Fuchs(a)  with  in- 
gestion of  radiimi  emanation  water  containing  300,000  to  400,000  Mache 
units.  With  radium  alkaline  waters  Staehelin  and  Maase  found  the  gas- 
eous exchange  considerably  decreased.  This  decrease  refers  only  to  values 
follow  ing  the  taking  of  food  and  not  to  fasting  values. 

The  carbohydrate  metabolism  is  apparently  increased  according  to 
the  observations  of  Kikkoji  and  Bernstein  who  found  in  their  basal  metab- 
olism studies  an  increase  in  the  respiratory  quotient  in  most  cases. 
Lipine(c)  found  that  exposure  of  dogs  to  x-rays  for  one  hour  is  followed 
by  an  increased  glucolysis  which  is  more  mai'ked  if  impacted  with  eosin 
before  radiation. 

That  radioactive  substances  and  x-rays  have  an  effect  upon  normal 
metabolism  is  wxdl  established  by  the  results  of  investigations  reported 
above.  According  to  Musser  and  Edsall  the  effect  of  x-rays  upon  metab- 
olism is  unqualled  by  any  other  therapeutic  agent  and  we  might  apply 
that  statement  equally  to  radium.  The  changes  produced  by  these  agents 
is  manifested  by  an  excessive  elimination  of  the  products  of  protein  de- 
struction indicated  by  the  increased  elimination  of  total  nitrogen,  uric 
acid,  purin  bases  and  phosphates,  and  the  accumulation  in  some  cases 
of  non-protein  nitrogen  in  the  blood.  That  these  agents  have  an  effect  upon 
carbohydrate  metabolism  and  fat  metabolism  is  not  so  well  established 
by  the  meager  results  so  far  reported. 


884         THOMAS  OliDWAY  AXD  ARTHUR  KXUDSOX 

The  cause  of  these  effects  on  metabolism  is  at  present  difficult  of 
explanation.  One  may  ascribe  the  effects  of  x-rays  either  to  a  stimulating 
ettVet  upon  autolytic  enzymes  or  as  Xeuberg(a)  does  to  an  inhibitory  action 
(jf  x-rays  and  radium  rays  upon  the  other  intracellular  enzymes  without 
corresponding  deleterious  eff'ect  upon  the  autolytic  enzymes  present.  This 
hypothesis  agrees  with  the  facts  at  hand  but  more  details  concerning  the 
ellV'cts  of  these  rays  upon  various  enzymes  are  needed. 

Effect  on  Metabolism  in  Disease. — The  metabolic  changes  produced 
hy  x-rays  and  radioactive  substances  in  various  diseases  have  been  studied 
quite  extensively.  The  protein  destruction  by  these  agents  arising  partly 
from  the  lymphatic  structures  has  led  to  their  study  particularly  in 
connection  with  the  treatment  of  leukemia.  Following  tlie  therapeutic  use 
of  x-ray  and  radium  in  leukemia  there  has  been  obsen-cd  a  marked  effect 
on  metabolism. 

Lossen  and  IMorawitz  in  a  case  of  myeloid  leukemia  treated  by  x-rays 
found  that  the  volume  of  urine  was  decreased,  that  total  nitrogen,  uric 
acid  and  pliosphoriis  excretion  lowered.  Heile  found  an  increase  in  both 
uiic  acid  and  purin  bases  in  three  cases.  Koniger  in  myeloid  leukemia 
found  that  under  influence  of  Roentgen  rays  the  nric-acid  excretion  in- 
creases parallel  with  the  diminution  in  size  of  the  spleen  and  the  break- 
ing up  of  the  leucocytes  and  that  the  uric-acid  excretion  is  a  positive 
measure  of  cell  breakage,  but  not  an  index  to  the  extent  of  the  cell  destruc- 
tion. Ammonia  and  phosphates  were  also  increased  at  times,  generally 
parallel  with  the  nitrogen  increase  and  also  with  the  betterment  in  the 
leukemic  symptoms.  Ko  increase  in  the  total  nitrogen  or  uric  acid 
could  be  found,  however,  by  Cavina  in  a  case  of  lymphatic  leukemia  treated 
with  Roentgen  rays. 

In  this  connection  the  observations  of  ^^fusser  and  Edsall  are  of  interest. 
In  those  cases  in  which  the  roentgen  ray  caused  a  reduction  in  number 
of  white  cells  and  there  was  clinical  improvement,  there  was  a  definite 
increase  in  uric  acid  and  purin  base  output,  a  marked  loss  of  nitrogen 
and  an  increased  elimination  of  phosphates.  In  a  case  in  which  x-rays 
had  no  beneficial  effect  clinically,  there  was  likewise  no  effect  or  very 
little  on  the  nitrogenous  metabolism. 

Murphy,  Means  and  Aub  studied  the  basal  metabolism  of  a  man  with' 
chronic  lymphatic  leukemia.  Observations  were  made  before  and  after 
exposure  to  x-ray  and  also  after  exposure  to  radium.  When  first  observed 
the  metabolism  was  44  per  cent  above  the  average  nonnal,  falling  a  little 
with  rest  in  bed.  Intensive  treatment  with  x-rays  caused  a  drop  in  the 
leucocyte  count  but  did  not  appreciably  affect  the  level  of  the  metabolism. 
Water  elimination  through  the  skin  and  respiratory  passages  was  imusually 
high.  Direct  and  indirect  calorimetry  gave  total  results  which  were  al- 
most identical  and  no  abnormal  respiratory  quotients  were  found.  After 
treatment  wath  radium  a  further  very  marked  fall  occurred  in  the  leuco- 


IXFLUEXCE  OF  ROEXTGEN  RAYS  UPON  METABOLISM  885 

eyre  count,  at  the  same  time  there  was  a  slight  fall  in  the  basal  metaV 
olism. 

Radium  has  been  found  to  have  a  similar  effect  up<in  the  nitrogenous 
metabolism  in  leukemia  as  do  x-rays.  Knudson  and  Erdos  in  a  case  of 
myelogenous  leukemia  treated  by  surface  application  of  radium  observed 
in  each  of  the  three  series  of  treatments  marked  changes  in  metabolism. 
The  total  niti^jgen,  urea,  ammonia  and  phosphates  are  immediately  in- 
creased and  reach  a  maximum  in  about  seven  days  after  each  application. 
The  uric  acid  excretion  also  increased  some  tlie  first  seven  days  and  then 
remained  at  about  the  same  level  throughout  the  observations.  An  exam- 
ination of  the  uric  acid  in  the  blood  at  relatively  long  intervals  during  the 
treatment  showed  little  change.  In  another  case  of  myelogenous  leukemia, 
Ordway,  Tait  and  Knudson  obtained  results  in  conformity  with  the  case 
described  above.  An  examination  of  the  blood  for  creatinin  and  non- 
protein nitrogen  before,  during  and  immediately  following  radium  treat- 
ment shows  that  there  is  apparently  no  change  during  the  radiation. 

Martin,  Denis  and  Aldrich  have  studied  the  chemical  changes  in  tlie 
blood  following  Roentgen  ray  treatment  in  leukemia.  In  the  more  severe 
cases  they  found  the  non-protein  nitrogen  was  high  and  after  treatment 
a  gradual  but  steady  fall  was  noted.  The  creatinin  was  not  aifected.  The 
uric  acid  content  was  much  increased  but  a  large  diminution  in  the  num- 
ber of  white  cells  which  occurred  as  a  result  of  treatment  caused  no  ap- 
preciable decrease  in  this  constituent. 

The  iron  metabolism  in  myelogenous  leukemia  before  and  after  expos- 
ure to  x-rays  has  been  studied  by  Bayer(?>).  He  found  that  isolated  ex- 
posure of  spleen  to  x-rays  causes  an  absolute  increase  in  iron  excretion  in 
the  feces  greater  than  in  the  isolated  exposure  of  the  long  bones.  The  iron 
excretion  in  pathological  conditions  of  the  spleen  is  greater  after  exposure 
to  x-rays  than  in^the  normal. 

The  chemical  changes  observed  in  the  treatment  of  leukemia  with  x-rays 
and  radium  apparently  depend  upon  the  excessive  quantity  of  leucocytes 
and  lymphoid  tissue,  which  undergo  processes  of  disintegration  during 
treatment,  with  the  result  that  products  of  nucleoprotein  destruction  (total 
nitrogen,  uric  acid,  purine  bases,  and  phosphates)  appear  in  the  urine  in 
increased  quantities. 

The  use  of  radium  in  the  treatment  of  gout  directed  early  the  attention 
of  investigators  to  the  influence  of  radium  on  uric-acid  metabolism.  As  a 
result  of  the  investigations  in  His'  clinic  it  was  affirmed  that  uric  acid 
occurs  in  the  blood  in  gout  in  a  specially  insoluble  modification  and  that 
under  the  influence  of  radium  the  insoluble  pathological  form  of  uric  acid 
becomes  changed  to  a  more  soluble  physiological  form  which  is  easily 
destroyed  and  excreted ;  the  net  result  being  a  rapid  solution  of  the  gout 
tophi,  an  increased  elimination  of  uric  acid  in  the  urine  and  a  disappear- 
ance from  the  blood  (Gudzent  and  Lowcnthal,  Gudzent(a)(6)(^)). 


886         TIICMAS  ORDWAY  AND  ARTHUR  KXUDSON 

The  experiments  on  \vhich  these  investigators  based  their  theory  of 
gout  and  action  of  radium  were  at  first  apparently  confirmed.  Mesernitsky 
and  Kemen,  Kikkoji,  Von  Xoorden  and  Faha,  and  Skorczewski  and  8ohn 
report  increased  excretion  of  uric  acid  in  cases  of  gout  under  the  influence 
of  radium  emanation.  Plesch  and  Karczag  obser\'ed  a  similar  effect  with 
thorium-x. 

With  reliable  methods  and  carefully  controlled  observations  Chace  and 
Fine  could  not  confirm  these  observations.  Inhalations  of  radium  emana- 
tion (containing  as  high  as  100  ^lache  units  per  liter)  and  injection  of 
fifty  micrograms  of  radium  bromid  in  no  case  had  any  influence  upon 
uric  acid  concentration  in  the  blood  of  patients  with  gout.  McCnidden  and 
Sargent (6)  likewise  could  observe  no  effect  on  the  concentration  of  uric 
acid  in  the  blood  of  a  patient  with  gout  receiving  water  impregnated  with 
radium  emanation.  The  patient  received  daily  20,000  ]Machc  units.  Xo 
effect  could  be  found  on  the  rate  of  uric  acid  and  total  nitrogen  excretion 
but  they  did  observe  a  slight  increase  in  the  creatinin  excretion  which  per- 
sisted for  a  few  days  after  discontiniiing  the  radium  treatment. 

Chace  and  Fine  and  McCnidden  and  Sargent (Z^)  have  also  studied  the 
effect  of  radium  emanation  on  cases  of  chronic  arthritis.  They  could  ob- 
serve no  effect  on  the  concentration  of  uric  acid  in  the  blood  or  the  rate  of 
its  excretion  in  the  urine.  McCrudden  did  observe,  however^  a  slight 
increase  of  creatinin  excretion.  In  a  case  of  rheumatoid  arthritis  treated 
by  intravenous  injection  of  fifty  micrograms  of  radium  salts  Rosen- 
bloom  (6)  noted  an  increased  nitrogen  exci'etion  and  a  marked  increase  in 
the  amount  of  total  sulphur  and  neutral  sulphur  in  the  urine.  The  increase 
of  nitrogen  and  sulphur  lasted  for  about  three  days  following  the  injection; 

The  metabolism  of  cases  of  pernicious  anemia,  rheumatoid  arthritis, 
and  unresolved  pneumonia  treated  by  x-ray  have  been  reported  by  Edsall 
and  Pemberton.  In  the  cases  of  pernicious  anemia  and  rheumatoid  ar- 
thritis x-ray  exposure  produced  a  toxic  reaction.  The  chief  point  of  interest 
in  these  two  cases  is  the  remarkable  drop  in  excretion  of  niti'ogen,  phos- 
phates and  uric  acid  that  followed  the  exposure.  The  drop  was  followed 
subsequently  by  an  equally  striking  rise  in  excretion  to  a  point  much  be- 
yond that  at  which  it  had  previously  been.  In  the  first  case  the  drop  oc- 
cUi  red  directly  after  exposure  and  in  the  second  it  was  postponed  two  days 
but  occurred  as  in  the-first  case  when  the  man  had  become  seriously  ill.  In 
the  cases  of  unresolved  pneumonia  the  effects  were  striking.  There  was  an 
immediate  marked  increase  in  the  nitrogen  and  chlorid  excretion.  The 
phosphates  were  increased  somewhat  less  and  uric  acid  was  little  affY^cted. 
This  eft'ect  upon  metabolism  was  coincident  with  a  rapid  improvement. 
The  only  apparent  explanation  the  authors  give  to  these  results  is 
that  in  those  cases,  such  as  luiresolved  pneumonia  and  leukemia,  which 
responded  favorably  to  x-ray  treatment  an  increased  tissue  destruction 
occurs   directly   after   exposure  resulting  in   an   increased   excretion   of 


IXFLUEXCE  OF  ROENTGEN  RAYS  UPON  METABOLISM  887 

the  products  of  metabolism.  The  cases  without  an  immediate  increase 
in  the  nitrogen  excretion  were  unfavorably  influenced  by  x-ray  applica- 
tion. It  seems  to  the  authors  that  the  organism  in  these  two  eases  was 
overwhelmed  by  the  enormous  amount  of  the  products  of  tissue  destruc- 
tion, resulting  in  a  retention  of  decomposed  tissue  products.  After  a  time 
the  organism  reacted  somewhat  and  a  complete  distintegration  could 
be  accomplished  and  the  products  were  excreted. 

Ordway,  Tait  and  Knudson  have  studied  the  influence  upon  metabolism 
of  surface  application  of  radium  emanation  upon  a  case  of  sarcoma  and  of 
carcinoma  respectively.  In  the  former  they  observed  increases  in  the  vol- 
ume of  urine,  in  total  acidity,  ammonia,  total  nitrogen,  urea,  and  uric  acid. 
Creatinin  and  phosphates  were  considerably  increased.  In  the  case  with 
carcinoma  there  was  no  increase  of  the  nitrogenous  fractions  or  phosphates 
of  the  urine.  The  changes  in  the  nitrogen  metabolism  depend  apparently 
upon  the  amount  and  nature  of  tissue  autolysis.  In  the  case  of  sarcoma 
there  was  a  definite  softening  and  fluctuation  of  the  gi'owth  Avhile  in  the 
case  of  carcinoma  of  the  breast  the  lesion  consisted  of  hard  brawny 
fibrous  tissue  in  which  one  would  expect  little  or  no  autolysis. 

Ludin  has  observed  that  radium  reduces  the  high  cholesterol  values 
observed  in  the  blood  of  carcinoma  patients  and  emphasizes  the  fact  that 
this  may  play  an  important  part  in  the  beneficial  effect  of  radium  therapy. 
De  Niord,  Schreiner,  and  De  Niord  have  studied  the  influence  of  Roent- 
gen rays  on  the  blood  of  cancer  patients  in  order  to  note  whether  radia- 
tion produces  any  appreciable  change  in  their  blood  chemistry.  Blood 
specimens  were  taken  before  exposure  to  x-rays,  one  half  hour  and 
twenty-four  after  exposure.  Radiation  had  no  eft'ect  upon  the  sodium 
chlorid  content  nor  upon  the  percentage  of  corpuscles  and  plasma.  Tlie 
changes  in  the  urea  nitrogen,  creatinin,  uric  acid,  sugar  and  diastatic 
activity  are  inconsistent,  which  makes  it  difficult  to  draw  any  conclusions. 
In  a  number  of  the  cases  these  constituents  were  found  to  be  increased 
and  in  an  equal  number  they  were  found  to  be  decreased  or  to  have  no 
effect.  The  cholesterol,  fatty  acids  and  total  fats  were  found  to  be 
generally  increased  in  the  cases  of  malignancy.  After  exposure  to  x-rays 
the  total  fatty  acids  were  found  to  be  reduced  in  72  per  cent  of  the  cases 
and  the  total  fat  w^as  reduced  in  83  per  cent.  The  cholesterol  content 
in  61  per  cent  of  the  cases  was  higher  and  in  31  per  cent  was  lower  after 
exposure.  The  increase  in  cholesterol  was  not  proportional  to  the  time 
of  exposure  or  the  type  of  tumor. 

Rudinger  studied  the  influence  of  Roentgen  rays  on  protein  metabolism 
in  Basedow^s  disease.  lie  found  exposure  to  the  rays  induced  a  retention 
of  nitrogen  as  indicated  by  a  gTadual  fall  of  elimination.  No  relation 
could  be  found  between  the  phosphorus  and  nitrogen  metabolism. 

Constitutional  Effects. — The  local  inflammatory  reactions  produced 
by  x-rays  and  radioactive  substances  in  those  engaged  in  such  work  are 


888  THOMAS  ORDWxVY  A:NrD  ARTHL^R  KNUDSOA^ 

now  well  known.  The  action  of  x-rays  may  also  result  in  the  develop- 
ment of  cancer,  even  with  metastases  (Tyzzer  and  Ordway).  The  more 
acute  constitutional  effects  of  radiations  have  also  been  the  subject' of 
research. 

Edsall  and  Pemberton  have  described  a  toxic  constitutional  reaction 
following  exposure  to  x-ray  and  advanced  a  theory  which  they  believe 
to  be  the  basis  of  this  reaction,  that  is,  that  the  tissue  destruction  accom- 
plished by  Roentgen  rays  involves  chiefly  tissues  rich  in  nucleoprotein. 
The  decomposition  products  of  this  form  of  protein  are  especially  rich 
in  substances  that  are  more  or  less  toxic  and  difficult  to  metabolize  and 
excrete.  The  intoxication  does  not  seem  to  be  dependent  directly  upon 
alterations  of  the  excreting  power  of  the  kidneys  because  examinations 
of  the  urine  of  two  patients  showed  no  evidence  of  retention.  It  is  prob- 
able, however,  according  to  the  view  of  Edsall  and  Pemberton  that  in  many 
cases  after  a  time  the  kidneys  do  become  overtaxed  by  the  added  labor 
thrown  upon  them  and  their  excreting  power  fails  to  a  gi-eater  or  lesser 
degree  and  this  may  increase  the  toxic  symptoms. 

Hall  and  Whipple  suggest  that  Roentgen  ray  intoxication  is  due  to 
a  disturbance  in  protein  metabolism.  They  have  pi-oduced  this  in  dogs 
by  deep  massive  doses  of  hard  Roentgen  rays.  The  dogs  were  given  lethal 
doses  of  x-rays  and  showed  remarkably  unifoim  and  constant  general 
constitutional  reaction.  There  was  usually  a  latent  period  of  twenty-four 
hours  or  longer  when  the  dogs  appeared  perfectly  normal.  After  this 
there  were  vomiting  and  diarrhea ;  death  usually  occurred  on  the  fourth 
day.  Upon  post-mortem  examination  the  spleen  of  these  animals  was  small 
and  fibrous;  the  intestinal  mucosa  was  congested  and  mottled  and  there 
was  evidence  of  epithelial  injui-y.  The  crypts  occasionally  showed  in- 
vasion of  polymorphonuclear  leucocytes.  The  epithelium  showed  re- 
markable speed  of  autolysis.  The  authors  believe  that  this  injury  to 
the  small  intestine  explains  the  general  intoxication.  They  find  no 
support  for  Roentgen  ray  anaphylaxis  or  hypersensitiveness  to  a  second 
properly  timed  exposure,  but  there  was  on  the  other  hand  some  evidence 
of  a  slightly  increased  tolerance  to  a  second  dose.  There  was  no  evidence 
of  a  Roentgen  ray  nephritis.  The  severity  of  the  constitutional  reaction 
was  greatly  increased  by  widening  the  spark  gap.  The  long,  latent  period, 
even  three  weeks,  was  not  explained  by  these  investigators. 

Dennis  and  Martin  in  experiments  on  rabbits  limited  the  exposure 
to  various  areas  of  the  body  and  found  that  toxic  constitutional  reactions 
were  produced  only  in  animals  exposed  over  areas  in  which  some  iX)rtion 
of  the  intestine  was  included.  Even  those  rabbits  exposed  over  areas 
containing  only  a  small  portion  of  the  intestinal  tract  developed  toxic 
symptoms  after  a  rather  long  latent  period,  while  a  particularly  severe 
reaction  followed  radiation  over  an  area  which  contained  none  of  the 
viscera  other  than  portions  of  the  intestinal  tract.     The  animals  radiated 


IXFLUEXCE  OF  ROENTGEX  RAYS  UPOX  METABOLISM  889 

over  tlie  thighs,  the  nook  and  chest  cantinnofl  in  good  conditi«^>n  and  showed 
absohitely  no  symptoms  although  kept  under  observation  for  a  period  of 
several  weeks.  It  seems  to  these  authors,  therefore,  tending  to  confirm 
the  opinion  of  Hall  and  Whipple,  that  injury  to  the  intest'mai  epithelium 
plays  no  small  part  in  the  systemic  reaction  followintr  exposure  to 
roentgen  rays.  Denis  and  Martin  have  suggested  also  that  the  reaction 
after  exposure  of  the  abdomen  may  be  due,  in  part  at  lejHr,  to  acidosis 
on  the  basis  of  a  lowering  of  the  alkaline  reserve,  since  the  administration 
of  sodium  bicarbonate  by  mouth  for  twenty-four  hours  following  ex- 
posure serves  to  ameliorate  or  prevent  the  constitutional  symptoms  iu 
many  instances. 

Strauss  in  a  study  of  the  local  reaction  due  to  x-rays  concludes  that 
there  is  no  real  idiosyncrasy  but  a  lessened  local  resistance  in  some  cases. 

Various  general  symptoms  such  as  headache,  malaise,  weakness,  undue 
fatigue,  unusual  need  of  sleep,  fretfulness,  irritability,  disorders  of  men- 
struation, attacks  of  dizziness  have  been  said  by  Gudzent  and  Halber- 
staedter  to  be  caused  by  repeated  and  long  continued  exposure  to  radio- 
active substances.  Ordway(c)  in  a  study  of  the  occupational  injuries  due 
to  radium  points  out  that  such  symptoms  are  common  in  many  people  at 
times  and  as  they  cannot  be  accurately  and  objectively  recorded  they 
may  have  been  due  to  close  confinement,  tiring  routine,  lack  of  outdoor 
exercises  and  other  causes.  The  exposures  of  some  of  the  cases  reported, 
however,  were  doubtless  large,  some  were  engaged  in  the  manufacture  of 
radium  apparatus  and  others  in  the  therapeutic  application  of  radio- 
active substances.  It  is  therefore  probable  that  certain  general  symptoms 
did  occur  as  a  result  of  this  exposure. 

Mottram  and  Clark  estimated  by  photographic  method  the  daily 
amount  of  radiation  received  by  clinical  workers  making  daily  applica- 
tions of  radium.  These  workers  received  daily  scattered  over  the  entire 
body  about  1.4  per  cent  of  the  total  radiation  received  by  a  patient  during 
a  course  of  treatment  for  superficial  carcinoma. 

Because  of  these  constitutional  symptoms  and  the  effects  of  radiation 
upon  the  blood  forming  organs  gi'eat  caution  and  even  frequent  alternation 
of  service  is  necessary  for  those  engaged  in  the  use  of  radioactive  sub- 
stances. 

We  have  personally  seen  a  profound  constitutional  reaction  in  a 
patient  injected  intravenously  with  active  deposit.  Because  of  this 
and  the  widespread  character  of  the  lesions  produced  great  care  should 
be  exercised  in  the  internal  administration  of  radioactive  substances. 

Theories  of  Action. — Ilertwig  and  his  school  believe  that  radiations 
cause  a  specific  destructive  action  upon  the  chromatin  of  the  cells.  Swartz 
considers  that  the  injury  to  the  cells  is  due  to  the  destruction  of  the 
cell  lecithin  by  the  radiations.  Packard  suggested  that  radiations  acted 
indirectly  on  the  chromatin  and  protoplasm  by  activating  autolytic  en- 


890         THOMAS  ORDWAY  AXD  ARTHUR  K^^UDSO]^ 

zymes.  Xeiiberg(ft)  ascribes  the  effects  of  radiation  to  an  inhibitory  action 
of  x-rays  and  radium  rays  upon  the  other  intracelhdar  enzymes  without 
a  corresponding  deleterious  effect  uix>n  the  autolytic  enzymes.  Rich- 
ards(&)  maintains  that  the  radiations  affect  the  activity  of  the  various 
enzymes  or  fennents;  that  a  short  radiation  may  accelerate  the  activity  and 
a  longer  be  inhibitive  so  that  life  processes  are  subject  to  marked  changes 
under  the  influence  of  radiation. 

Radium  emanation  according  to  Bovie(&)  affects  the  nucleus  in  a  man- 
ner similar  to  the  eifect  produced  by  quartz  rays.  Cell  division  is  inhibited 
as  well  as  locomotion  and  ciliary  action.  He  finds  no  reason  to  believe, 
however,  that  rays  are  more  strongly  absorbed  in  the  nucleus  than  in  the 
cytoplasm  nor  that  the  nucleus  is  more  photo  unstable  than  the  c}1;oplasm. 
The  effect  upon  the  nucleus  may  be  due  to  the  more  intricate  nature  of  its 
mechanism  and  to  its  inability  to  undergo  rapid  recovery  from  injury 
caused  by  radiation.  The  radiations  affect  the  protoplasm  at  the  place 
where  they  are  absorbed  and  the  observed  physiological  disturbances  are 
responses  on  the  part  of  the  organism  to  its  injured  protoplasm.  Bovie 
believes  that  it  is  the  instability  of  the  physiological  mechanism  rather 
than  the  wave  length  of  the  radiation  used  which  determines  the  nature 
of  the  physiological  effect  produced.  The  effect  of  course  is  different 
if  one  wave  length  penetrates  deep  and  the  other  only  affects  the  surface, 
but  the  difference  is  apparently  due  to  the  penetrating  power  rather  than 
any  specific  effect  of  the  wave  length  per  se. 

Kronig  and  Friedrich  agree  with  Bovie  that  it  is  not  the  quality  but 
the  quantity,  that  is,  the  total  energy  absorbed,  which  produces  the  bio- 
logical effect. 

II.    Li^ht 

Light  has  been  used  as  a  therapeutic  agent  for  a  number  of  years 
and  its  general  action  is  based  largely  upon  hypothesis.  From  the  prin- 
cipal action  outside  of  the  living  organism  and  from  the  constitution  of  the 
latter  as  well  as  from  its  known  action  upon  plants  and  lower  animals  a 
certain  amount  of  speculative  theory  has  been  indulged  in  to  explain 
its  action. 

Light  is  composed  of  different  kinds  of  rays.  These  rays  are  ex- 
plained as  transverse  electromagnetic  vibrations  having  their  origin  in 
the  rapidly  oscillating  electrons  whose  periods  are  the  same  as  the 
periods  of  the  wave  motion.  These  wave  impulses  travel  with  the  same 
velocity  in  free  space  (about  186,000  miles  per  second).  The  different 
colors  correspond  to  different  wave  lengths  (or  more  properly,  to  differ 
ent  rates  of  vibration)  and  vary  in  length  from  approximately  3.9  to  7.0 
ten-thousandths  of  a  millimeter.  Waves  of  a  similar  character  whose 
lengths  fall  above  or  below  the  limits  mentioned  are  not  perceptible  to 


INFLUENCE  OF  ROEXTGEX  RAYS  UPON  METABOLISM  891 

the  eje.  Those  between  3.0  to  1.0  ten-thousandths  of  a  millimeter  con- 
stitute ultra-violet  light.  Those  exceeding  7.6  ten-thousandths  of  a  milli- 
meter in  length  are  the  infra-red  waves.  The  ordinarily  used  unit  of  wave 
length  is  the  Angstrom  unit,  equal  to  one  ten-millionth  of  a  millimeter. 
Another  unit  frequently  used  is  the  micron,  [i  =^  0.001  mm. 

It  is  a  general  law  of  photochemical  action  that  only  those  rays  are 
effective  which  are  absorbed  by  the  substance  in  which  the  reaction  occurs. 
Visible  light  rays  are  not  as  a  general  rule  active  but  may  be  rendered 
active  by  impregnating  the  tissue  or  other  material  with  certain  sub- 
stances which  in  such  cases  act  as  the  photochemical  absorbent  or  senti- 
tizer.     Ultra-violet  light  rays  are  active  as  they  are  the  easiest  absorbed. 

Experience  has  shown  that  light  can  bring  about  a  variety  of  chemical 
changes.  'Nei\herg{c)(d)(e){f)(g)  obseiTed  that  the  general  effect  of 
light  acting  on  organic  substances  present  in  animal  and  plant  cells  is  to 
produce  from  carbonyl  containing  materials  aldehyds  or  ketone  compounds, 
whose  reactivity  and  availability  for  important  synthetic  changes  are  con- 
spicuous. These  changes,  however,  could  only  be  produced  by  the  addition 
of  certain  salts  such  as  uranium,  mercurv',  arsenic  and  manganese  which 
acted  as  photocata lytic  agents.  Xeuberg  and  Schwarz  have  shoAvn  that  iron 
salts  can  act  as  photocatalyzers.  They  believe  that  in  the  presence  of  light 
these  photocatalyzers  take  oxygen  from  the  air  and  pass  it  on  to  the 
organic  light  receptors.  This  photocatalytic  light  action  consists  in  oxida- 
tion and  cleavage  processes.  From  their  investigation  they  conclude  that 
sensitiveness  to  light  is  increased  by  giving  mineral  waters  containing 
heavy  metals.  Pincussohn(r)  has  reported  that  a  solution  of  sodium  urate, 
containing  eosin,  exposed  to  light  shows  a  diminution  in  the  content  of  uric 
acid.  The  proteins  of  egg  white  and  of  the  crystalline  lens  exposed  to  ultra- 
violet light  Avere  found  by  Chalupechy  to  be  considerably  altered.  The 
albumins  were  decreased,  the  globulins  increased  and  some  coagulated 
protein  was  formed. 

The  action  of  light  energy  on  tissues  and  skin  has  been  studied  quite 
extensively.  Bering  sums  up  the  work  previous  to  19 14-.  He  states  that 
the  action  of  light  manifests  itself  in  cell  destruction  produced  through 
direct  destruction  or  by  edema  and  throml>3sis  as  a  result  of  a  direct 
action  upon  the  endothelial  membrane  and  musculature  of  the  vessel  wall. 
There  also  results  a  hemorrhagic  inflammation  which  terminates  with  a 
productive  c(mnective  tissue  formation.  The  histological  changes  were 
almost  exclusively  produced  by  ultrn-violet  light  rays.  The  blue  rays 
possessed  only  a  slight  action  and  the  gi*een,  yellow  and  red  rays  produced 
no  change.  Sensitizing  of  tissues  with  substances  such  as  eosin  increased 
the  action  of  light  but  slightly. 

Schanz(fl)  has  observed  that  light  may  alter  the  cell  proteins,  especially 
in  the  presence  of  organic  and  inorganic  substances  such  a  silicates,  sugar, 
lactic  acid  and  urea  which  act  as  sensitizers.    The  pyknosis  and  hyaline  de^ 


802         TIIO.A[AS  OKDWAY  AXD  ARTILUK  KNUDSON 

generation  of  cells  resulting  from  influence  of  ultra-violet  light  rays  are  be- 
lieved by  Krebich  to  be  caused  by  the  proteins  being  rendered  insoluble, 
and  as  a  consequence  the  catalase  is  more  firmly  bound  and  inhibited 
in  its  action.  P)urge(rZ)  believes  that  ultra-violet  radiation  kills  cells  and 
tissues  by  changing  the  protoplasm  of  the  cells  in  such  a  way  that  certain 
salts  can  combine  with  the  protoplasm  to  form  an  insoluble  compound  or 
coagulum.  He  found  the  effective  region  of  spectnun  to  be  from  0.25J:  [i 
to  0.330  M-  The  action  of  the  sun's  rays  on  the  non-pigmented  skin  of 
animals  is  ascnbed  by  Beijers  to  the  action  of  the  ultra-violet  rays  on  sen- 
sitizing substances  which  are  present  in  the  blood. 

The  action  of  light  on  the  blood  of  animals  has  been  studied  quite 
extensively  by  Oei'um(fe).  He  found  that  the  blood  volume  and  the  hemo- 
globin are  decreased  in  the  dark.  Eed  light  has  a  similar  effect  but  in 
blue  light  a  plethora  is  produced  and  hemoglobin  is  increased.  Light  baths 
increase  the  blood  volimie  in  the  course  of  four  hours  about  twenty-five 
per  cent.  The  photodynamic  action  of  light  on  blood  has  been  reviewed 
by  Bering.  By  photodynamic  action  is  meant  the  ability  of  certain  fluores- 
cent substances  to  produce  in  light  strong  biological  action.  The  red  blood 
corpuscles  are  dissolved,  some  substances  attacking  the  corpuscles  within 
the  cell  membrane,  in  others  the  primary  attack  is  intercellular.  Immune 
serum  loses  its  specificity.  Poly  nuclear  leucocytes  and  lymphocytes  are 
destroyed.  The  proteins  of  serum  fonn  a  substance  having  a  hemolytic 
action.  Traugott  could  observe  no  effect  on  the  number  of  red  blood 
corpuscles  in  man  following  exposure  to  ultra-violet  rays  for  ten  to  fifteen 
minutes.  An  increase  of  leucocytes,  however,  was  noted.  Another  effect 
observed  Avas  that  blood  coagulated  sooiier  and  the  number  of  blood  plate- 
lets was  increased.  Schanz(Z>)  extended  the  observation  of  Chalupechy  and 
studied  the  effect  of  ultra-violet  light  on  proteins  in  the  blood  and  found 
that  after  exposure  of  blood  for  eight  hours  there  was  a  decrease  in  the 
albumin  from  27.0  mg.  to  3.9  mg.  per  100  c.c.  of  diluted  serum  and  an 
increase  of  globulin  from  2.1  to  24.2  mg.  per  100  c.c.  Hausmann  and 
llayerhofer  noted  that  salted  plasma  exposed  to  ultra-violet  light  did 
not  coagailate  when  diluted  with  water,  while  untreated  salted  plasma  co- 
agulated in  a  few  minutes.  Likewise  he  observed  that  oxalated  plasma 
coagulated  much  more  slowly  after  addition  of  calcium  chlorid  when 
subject  to  the  action  of  light.  From  these  observations  the  authors  em- 
phasize the  necessity  of  carefully  adjusting  the  action  of  ultra-violet 
light  upon  patients. 

The  activity  of  most  enzymes  is  found  to  be  decreased  after  exposure 
to  light.  Agiilhon  observed  that  ultra-violet  rays  may  attack  enzymes  in 
the  absence  of  oxygen.  Chauchard  found  that  the  activity  of  pancreatic 
amylase  is  rapidly  attacked  by  rays  of  wave  lengths  less  than  2800  Ang- 
strom units  but  not  appreciably  affected  by  rays  of  longer  wave  length. 
Lipase  was  destroyed  in  part  by  rays  equal  to  3300  Angstrom  units  and 


IXFLUENCE  OF  ROEXTGEX  RAYS  UPOX  METABOLISM  893 

flicir  (lostriictivo  action  increases  with  decreased  wave  length,  althou<^li 
more  slowly  than  in  the  case  of  amylase.  The  actual  percentage  loss  in 
activity  due  to  the  action  of  rays  less  than  2^00  Angstrom  units  is  much 
greater  in  the  case  of  lipase  than  in  the  case  of  amylase.  They  could 
ohserve  no  direct  i-elationship  hetween  the  absorption  of  ultra-violet  rays 
hy  pancreatic  juice  and  their  acriun  on  pancreatic  enzymes.  Pincussohn 
noted  that  the  protease  activity  «rt  the  blood  of  animals  injected  with  a 
fluorescent  substance  (eosin)  was  peater  after  exposure  to  light.  The 
rate  of  destruction  of  pepsin,  trypsin,  enterokinase,  ptyalin,  amylopsin, 
and  the  pro-enzyme  trypsinogen  was  reported  by  Burge,  Fischer  and  Xeill 
to  be  proportional  to  the  amount  of  energy  applied.  The  active  wave 
length  they  used  was  between  O.oi)2  u  and  0.207  u. 

Metabolism  in  general  is  believe<l  to  be  stimulated  by  light  energy.  The 
experiments  of  Pettenkofer  and  Voit(a.),  Johansson,  and  Lehman  and 
Zuntz  show  that  metabolism  with  curaplete  muscular  rest  is  slightly  greater 
during  the  day  than  at  night.  Zuntz  was  first  to  call  attention  to  the 
significant  fact  that  even  when  perfect  muscular  relaxation  ejisues  there 
may  be  still  influences  such  as  light  on  the  retina  or  sounds  which  may 
act  reflexly  on  the  organism  and  slightly  increase  the  metabolism. 

Cleaves  who  has  reviewed  the  literature  to  1004:  concludes  that  one 
set  of  experiments  apparently  proves  that  light  increases  the  oxygen 
carrying  capacity  of  the  red  blood  cells  and  therefore  influences  oxidative 
processe^s  of  the  organism.  Other  experiments  show  increased  output  of 
CO2  when  animals  experimented  on  were  exposed  to  light  and  this  in- 
crease was  supposed  to  be  due  to  stimulation  of  the  protoplasm,  prob- 
ably due. to  both  stimulation  and  the  increased  supply  of  oxygen.  Adult 
animals  therefore  fattened  more  easily  in  the  dark  as  there  is  less 
combustion. 

Rubner(«)  remarks  that  while  the  radiant  energy  of  the  sun  is  large 
in  quantity,  ho  has  been  unable  to  find  any  influence  upon  a  man  under 
ordinary  circumstances.  Zuntz  while  living  on  the  summit  of  a  high 
mountain  of  the  Alps  observed  the  basal  metalx)lism  increased  as  much 
as  40  per  cent  and  that  exposure  to  sunlight  was  almost  without  effect 
on  the  metabolism.  Hasselbalch(6  )  found  that  if  the  naked  body  of  a  man 
was  strongly  exposed  to  ultra-violet  rays  the  rate  of  respiration  was  di- 
minisluHl  while  the  depth  was  iiu-reased.  The  skin  was  red  with  dilated 
capillaries  and  the  blood  pressure  fell.  LindhardCa),  in  1910,  showed 
there  is  a  yearly  periodicity  of  the  respiratory  rate  in  the  Arctic  region,  it 
being  less  in  the  spring  and  sun:mier  than  in  the  winter.  The  enormous 
variations  in  the  chemical  intensity  of  the  sun's  rays  in  the  Arctic  region 
are  undoubtedly  the  cause  of  this  effect.  The  same  phenomenon  has 
been  obseiTed  by  LindhardfZ^)  in  Copenhagen.  The  volume  of  respiration 
increases  25  per  cent  in  the  summer  but  the  intensity  of  metabolic  proc- 
esses are  not  affected.     While  these  invest iarators  noted  that  the  ultra- 


894         THOMAS  ORDWAY  AND  AKTIIUR  KNUDSON 

violet  rays  of  the  sun  reduce  the  frequency  and  increase  the  depth  of 
respiration,  Ilasselbalch  and  Lindhard(a.)  found  that  exposure  to  the  effect 
of  such  rays  in  the  high  Alps  has  no  effect  upon  raetaholism. 

Animals  injected  with  fluorescent  substances  such  as  eosin  showed, 
according  to  Pincussohn(6)  (c),  gTeatly  increased  metabolism  after  ex- 
posure to  light.  The  purin  bases,  amino  acids,  ammonia  and  oxalic  acid 
of  the  urine  were  increased.  Hoogenhuyze  and  Best  have  studied  the  influ- 
ence of  light  on  the  endogenous  metabolism  of  man  as  indicated  by  the 
elimination  of  creatin  and  creatinin  of  the  urine.  The  experimental  sub- 
jects were  put  on  a  creatin  and  creatinin  freo  diet  and  noi-mal  excretion  de- 
temiined.  Following  the  nonnal  period  the  subjects  were  put  in  a  box  lined 
with  incandescent  lamps  for  a  twenty-minute  period  and  the  temperature  of 
the  box  was  40M5°  C.  when  closed  and -SO^-oS^  C.  when  ventilated. 
A  series  of  four  experiments  showed  that  exposure  to  liglit  and  heat  or  to 
light  alone  always  produced  a  considerable  increase  in  the  creatinin. 
Creatin  was  always  absent.  A  negligible  effect  was  produced  by  exposure 
to  heat  alone.  A  similar  increase  in  creatinin  occurred  in  two  patients 
after  a  sun  bath. 

The  entire  subject  of  light  energy  in  the  physiological  relation  still 
calls  for  careful  scientiflc  study  and  experiment.  That  liglit  energy 
influences  metabolism  is  apparently  evident  by  its  action  on  various 
organic  substances  of  plant  and  animal  origin ;  by  its  well-known  action  on 
skin  and  tissues;  its  action  on  the  blood  and  enzymes;  and  by  the  in- 
creased respiratory  and  endogenous  metabolism. 


III.    Electricity 

Various  forms  of  electricity  have  been  used  for  many  years  in  treat- 
ing a  wide  range  of  pathological  conditions  but  in  a  very  few  instances 
have  carefully  controlled  metabolism  studies  been  made.  A  literature 
has  grown  up  among  those  dealing  in  electrotherapeutics  containing  a 
terminology  which  is  peculiar  to  this  form  of  medicine.  It  is  for  the 
most  part  difficuh  for  the  scientifically  trained  physicist  to  interpret 
and  to  estimate  dosage  accurately  in  units  of  electrical  measurement.  With 
the  active  cooperation  of  competent  physicists  and  clinicians  it  may  be 
possible  to  denote  measurements^  forms  and  conditions  for  use  of  elec- 
tricity so  accurately  that  the  results  of  metabolic  and  therapeutic  work 
can  be  more  carefully  controlled. 

Electricity  in  various  forms  is  a  powerful  agent  for  stimulating  nerves 
and  contracting  muscles  in  experimental,  diagnostic,  and  therapeutic 
procedures.  As  is  well  known,  death  may  be  caused  by  electric  currents. 
When  these  are  of  low  voltage,  according  to  Tousey  death  is  usually  due 
to  the  production  of  fibrillation  of  the  ventricles  and  to  interference  with 


"Tf^ 


IXFLUEXCE  OF  KOEXTGEX  RAYS  UPGX  METABOLISM  805 

the  respiration  from  the  muscular  contraction  produced.  With  currents 
of  high  voltage  there  is  impairment  of  the  respiratory-  penter.  The  path 
of  the  electrical  current  through  the  body  and  the  conditions  under  which 
the  exposure  occurs  are  variable  but  very  important  factors  in  determin- 
ing the  etVect  produced. 

Electrolysis  is  commonly  used  in  various  conditions  for  its  local  de- 
structive effects,  notably  in  tlie  removal  of  supei-fluous  hair  and  for  the 
treatment  of  certain  skin  diseases  such  as  nevi.  A  method  has  been  em- 
ployed known  as  ionic  medication  by  which  certain  substances  are  intro- 
duced a  varying  distance  through  the  skin  by  means  of  electrical  current. 

Hardy  in  a  study  of  the  coagulation  of  protein  by  electricity  has  shown 
that  under  the  influence  of  a  constant  current  the  particles  of  protein 
in  a  diluted  and  boiled  solution  of  egg  white  move  with  the  negative 
stream  if  the  reaction  of  the  fluid  is  alkaline  and  with  the  positive  stream 
if  the  reaction  is  acid.  The  particles  under  this  directive  action  of  the 
current  aggi'egate  to  form  a  coaguhim. 

Stewart (^t)  (b)  has  shown  that  the  red  blood  corpuscles  have  a  very  low 
electrical  conductivity  in  comparison  with  that  of  the  serum  or  the 
plasma  and  that  the  conductivity  of  the  blood  serum  in  which  the  hemo- 
globin of  red  blood  cells  has  been  dissolved  by  various  methods  of  laking  is 
increased. 

Burge(a)  has  foimd  that  in  a  solution  containing  both  pepsin  and  ren- 
nin  the  passage  of  a  direct  current  of  ten  milliampercs  for  twenty-five  hours 
results  in  the  complete  disappearance  of  the  peptic  power,  as  tested  on 
milk  and  fibrin,  while  the  action  of  the  rennin  is  apparently  unchanged. 
In  further  experiments  Burge(&)  has  demonsti'ated  that  ptyalin  is  de- 
stroyed by  the  passage  of  the  direct  electric  current.  This  destruction  is 
not  due  to  the  electrolytic  products ;  the  rate  of  destruction  is  uniform,  that 
is,  2.5  per  cent  per  coulomb.  The  rate  of  destruction  of  pepsin  by  the 
passage  of  the  direct  electric  current  has  been  estimated  by  Burge(c)  by 
the  decreased  amount  of  egg  white  digested  in  proportion  to  the  number 
of  coulombes  that  were  allowed  to  pass.  His  conclusion  is  that  the  di- 
gestive activity  of  a  solution  of  pepsin  is  decreased  by  the  passage  of  the 
direct  electric  current  at  a  uniform  rate  per  unit  of  current.  The  solu- 
tions were  kept  from  polarizing  by  rapid  shaking. 

Tousey  in  his  extensive  work  has  described  the  use  of  electricity  in 
many  pathological  conditions.  Meyer  and  Gottlieb  in  their  clinical  and 
experimental  pharmacology^  state  that  nothing  is  known  about  the  direct 
action  of  electric  energy  on  the  metabolic  processes  of  the  cells.  Steel  has 
reviewed  the  literature  up  to  1916  on  the  influence  of  electricity  on  metaV 
olism  and  concludes  that  two  or  more  totally  difl^erent  types  of  electrical 
currents  may  have  practically  the  same  effect  on  metabolism.  The  high 
frequency  type  whose  action  is  largely  thermic  seems  to  cause  an  increase 
in  practically  the  same  urinary  constituents  as  the  static  type  whose  ac- 


896  THOMAS  ORDWAY  AND  AKTIIUR  KNUDSOI^^ 

tion  is  largely  mechanical,  yet  it  is  obvious  that  the  data  analyzed  is  ob- 
tained by  the  work  of  various  investigators  under  different  conditions; 
particularly  to  be  mentioned  is  the  variation  in  the  amount  and  form  of 
electrical  energy  and  in  the  diet  of  the  patients.  Steel  finds  that  no  ex- 
tensive metabolic  study  had  been  previously  attempted  and  presents  the 
results  of  his  own  experiments,  using  various  fomis  of  electricity  desig- 
nated by  him  as  faradic  sinusoidal  current,  directional  and  autocondensa- 
tion  current  with  thick  dielectric,  autoconduction  method,  the  direct 
d'Arsonval  current,  combination  of  direct  d'Arsonval  current  with  the 
autocondensation  current  with  thin  dielectric,  the  static  wave  current,  the 
galvanosinusoidal  current.  The  si>ecial  physiological  properties  of  high 
frequency  cun-ents  were  first  published  by  d'Arsonval(&)  in  1891. 

Steel  has  shown  that  relatively  strong  electric  currents  of  the  various 
types  demonstrated  caused  a  stimulation  of  metabolic  processes.  The 
volume  of  urine  is  increased  by  those  currents  which  do  not  bave  a  pro- 
nounced thermic  effect  and  decreased  by  those  currents  which  have  a 
strong  thermic  effect  and  the  latter  type  causes  perspiration.  All  cur- 
rents increased  the  total  solids,  total  nitrogen  and  sulphur  of  the  urine; 
the  most  striking  and  consistent  effects  were  an  increase  in  the  urea  and 
creatinin.  The  greatest  increase  of  urea  was  obtained  with  a  static  wave 
current  and  the  greatest  increase  of  creatinin  with  the  faradic  sinusoidal. 
Increased  elimination  of  urea  w^as  attributed  to  quickened  cellular  metab- 
olism and  the  increased  elimination  of  creatinin  to  muscular  contraction. 
It  is  noteworthy  that  recovery  was  always  prompt  and  complete  in  so  far 
as  the  data  indicated.  Usually  after  two  days  tliere  w^as  no  effect.  It 
is  important  that  further  study  be  made  of  the  effect  upon  metabolism 
of  electrical  currents  using  standard  units  of  physical  measurement  that 
can  be  readily  duplicated. 

Many  patients  suffering  from  a  wide  variety  of  conditions  "undoubtedly 
derive,  at  least  temporarily,  benefit  from  the  various  forms  of  electrothera- 
peutic  procedures  yet  there  is  no  definite  agi-eement  as  to  the  phanna- 
cological  action  and  much  more  carefully  controlled  experimental  work 
is  necessary  before  such  physical  agents  as  light  and  electricity,  x-rays 
and  radioactive  substances  can  be  said  to  be  established  in  the  rational 
therapy  of  internal  diseases. 


Climate Edward  C.  Schneider 

Temperature  and  Humidity — Air  Movement  and  Winds — Light — The  Psycho- 
logical Factor  in  Climatotherapy — The  Variety  of  Climate — General  Con- 
siderations in  the  Choice  of  Climate — Altitude — Altitude  Sickness — 
Acclimatization — The  Blood  Adaptive  Changes — Respiratory  Adaption  to 
High  Altitudes — Metabolism — The  Circulatory  Mechanism — General 
Considerations. 


Climate 


EDWARD  C.  SCHNEIDER 

MIDDLETOWN 

The  old  view  which  placed  the  influence  of  climate  upon  health  above 
all  other  factors  has  very  largely  been  replaced  by  the  view  that  good 
hygiene  is  the  all-important  health  factor.  Doubtless  careful  and  intelli- 
gent attention  to  hygiene  is  more  important  than  climate,  and  every  health 
seeker  should  realize  that  ^^care  without  climate  is  better  than  climate 
without  care."  However,  the  influence  of  climate  is  by  no  means  to  be 
disregarded.  The  pendulum  has  swung  too  far  to  the  side  of  hygienic 
living.  It  must  be  admitted  that  even  though  the  health  seeker  recognizes 
that  the  results  of  following  the  simple  rules  of  hygiene  are  restored  health, 
and  possibly  high  efficiency ;  yet  the  average  individual  finds  these  simple 
things  irksome,  and  that  it  requires  streng-th  of  mind  to  follow  them  day 
in  and  day  out.  Climate  affects  our  bodily  comforts  and  causes  physio- 
logical changes  which  may  play  an  important  part  in  the  curative  process. 
Huntington  has  demonstrated  that  human  efficiency,  as  tested  by  the 
amount  of  daily  work  performed,  is  deteraiined  by  physical  atmospheric 
conditions  and  that  the  development  of  the  human  race  is  controlled  by 
climate.  *'Man  can  apparently  live  in  any  region  where  he  can  obtain 
food,  but  his  physical  and  mental  energy  and  his  moral  character  reach 
their  highest  development  only  in  a  few  restricted  limited  areas." 

Climate,  as  ordinarily  defined,  is  the  resultant  of  the  average  atmos- 
pheric conditions,  considered  daily,  monthly  and  annually.  It  is  made  up 
of  temperature  (including  radiation)  ;  moisture  (including  humidity,  pre- 
cipitation and  cloudiness);  wind  (including  storms);  pressure;  evapora- 
tion ;  and  also,  but  of  less  importance,  the  chemical,  optical  and  electrical 
properties  of  the  atmosphere.  It  is  only  recently  that  definite  progress 
in  our  knowledge  of  the  physiological  action  of  atmospheric  conditions  has 
been  made.  Even  now  this  knowledge  is  fragmentary;  so  that  medical 
climatolog}',  which  deals  with  the  hygienic  effects  of  climate,  is  still  far 
from  being  anything  like  an  exact  science. 

The  physical  influences  that  cause  physiological  changes  are  tem- 
perature, humidity,  air  movement  and  pressure,  as  met  at  high  altitudes. 
Light  has  apparently  been  found  to  be  a  minor  factor.     The  physiological 

899 


900  EDWAKD  C.  SCH]S:EIDEil 

influence  of  each  of  these  atmospheric  factors  will  be  briefly  considered. 
Pressure  will  be  discussed  under  altitude. 


Temperature  and   Humidity 

Although  man  is  a  homothermal  organism,  there  is  a  certain  relation- 
ship between  his  body  temperature  and  the  temperature  of  his  environ- 
ment. His  internal  temperature,  in  health,  remains  fairly  constant  wher- 
ever he  may  be,  varying  not  more  than  1^  or  2^  F.  Man  readily  adapts 
himself  to  extremes  of  temperature  through  responses  made  by  his  vaso- 
motor system  and  sweat  glands.  He  is  constantly  and  of  necessity  elimi- 
nating heat.  The  loss  of  heat  results  from  radiation,  conduction  and  evapo- 
ration. The  amount  of  heat  lost  by  radiation  and  conduction  depends 
largely  upon  the  temperature  of  the  surrounding  air,  while  the  amount 
lost  from  evaporation  depends  upon  the  relative  humidity  of  his  immediate 
environment.  Some  conditions  permit  loss  of  heat  by  radiation  and  con- 
duction only.  In  a  dry  hot  climate  loss  of  heat  by  evaporation  is  at  its 
maximum.  The  New  York  State  Commission  on  Ventilation  found  that 
during  the  months  of  June  and  July  the  rectal  temperature  of  man  at  8 
A.  M.  was  conditioned  by  the  average  atmospheric  temperature  of  the 
preceding  night  and  that  a  difference  of  about  1°  F.  resulted  from  a 
difference  of  36°  F.  in  atmospheric  temperature.  The  temperature  of  a 
chamber  influenced  the  body  temperature  of  healthy  human  beings,  con- 
fined for  periods  ranging  from  4  to  7  hours,  the  body  temperature  falling 
in  an  atmosphere  of  68°  F.  and  fifty  per  cent  relative  humidity;  rising 
in  one  of  86°  F.  and  80  per  cent  relative  humidity;  and  remaining 
nearly  stationary  in  air  of  75°  F.  and  50  per  cent  relative  humidity.  A 
stay  of  three  and  one  quarter  hours  in  an  atmosphere  of  101.7°  F.  and  05 
per  cent  relative  himiidity  caused  the  body  temperature  to  rise  6°  F.  (25), 

Shaklee,  working  with  the  native  monkey  in  the  Philippine  Islands, 
found  that  exposure  to  the  sun  by  placing  the  animal  on  the  gi'ound  or  a 
roof  caused  death  within  six  hours  from  a  rise  in  body  temperature.  It 
was  possible  to  gradually  acclimatize  the  animals,  this  being  accomplished 
by  an  increased  capacity  for  sweating,  which  kept  the  body  heat  well 
within  the  killing  temperature,  although  it  rose  several  degrees. 

In  hot  climates  radiation  and  conduction  become  less  imjwrtant  and 
evaporation  the  most  important  factor  in  eliminating  heat.  Evaporation 
in  its  turn  depends  upon  the  relative  humidity  of  the  air  and,  to  some 
extent,  upon  the  presence  of  winds. 

The  circulatory  system  is  also  affected  by  the  temperature  and  hu- 
midity of  the  atmosphere,  the  rate  of  heart  beat  being  increased  con- 
comitantly with  the  body  temperature;  it  is  increased  in  warm  humid 
air  and  decreased  in  cool,  dry  air.    Eastman  and  Lee  found  that  the  pulse 


CLIMATE  901 

rate  increased  by  39 — from  67  to  106 — as  the  atmospheric  temperatiiro 
rose  from  74^  to  110"^  F.  and  the  relative  humidity  from  58  to  90  per 
cent.  The  effect  of  humid  heat  upon  the  blood  pressure  does  not  appear 
to  be  uniform.  Youn^,  Breinl,  Harris  and  Osborne  found  the  systolic 
pressure  rose  at  times  and  fell  slightly  at  others.  The  Xew  York  State 
Commission  on  Ventilation  observed  that  excessively  high  temperatures 
and  high  humidities  were  accompanied  by  an  elevation  of  both  systolic 
and  diastolic  pressures.  The  reactions  of  the  vasomotor  mechanism,  as 
judged  by  Crampton's  scale  of  vasotone,  indicate  that  a  distinct  vascular 
benefit  follows  the  exposure  of  the  body  to  a  cool  dry  air. 

The  influences  of  atmospheric  heat  and  humidity  on  the  respiration  are 
varied  in  character.  A  moderate  degree  of  both  seems  to  be  without  effect 
on  the  rate  of  respiration;  but  more  extreme  rises  cause  a  quickening  of 
the  breathing,  which  is  probably  accompanied  by  more  shallow^  respira- 
tions. Young  and  collaborators  found  that  the  alveolar  air  in  inhabitants 
of  tropical  Queensland  showed  a  lower  carbon  dioxid  content  than  the 
European  average.  A  slight  seasonal  influence  has  been  noticed  by  Boy- 
cott and  Ilaldane,  in  which  a  higher  alveolar  carbon  dioxid  partial  pressure 
was  found  in  cold  and  a  lower  in  warm  months.  These  changes  were  not 
attributed  to  variations  in  the  hotly  temperature  but  to  the  contact  of  the 
body  with  cold  or  warm  air.  A  marked  increase  in  relative  humidity  also 
lowers  the  alveolar  carbon  dioxid  content. 

The  influence  of  high  temperature  and  high  humidity  on  the  capacity 
for  physical  work,  the  amount  of  blood  per  kilogi*am  of  body  weight,  and 
the  concentration  of  sugar  in  the  blood  is  pronounced.  Lee  and  Scott  ex- 
posed cats  for  periods  of  six  hours  to  an  abundance  of  moving  air,  varying 
in  respect  to  tem}>erature  and  humidity,  using  a  ^^low''  condition  in  which 
the  average  temperature  was  69'^  F.  and  the  hiimidity  52  per  cent;  an 
"intermediate"  condition  in  which  the  average  temperature  was  75^  F. 
and  the  humidity  70  per  cent;  and  a  "high"  condition  in  which  the 
temperature  was  91*^  F.  and  the  humidity  90  per  cent.  Muscles  taken 
from  these  animals  and  stimulated  to  exhaustion  showed  that  the  average 
duration  of  the  w^orking  periods  and  average  total  amounts  of  work  per- 
formed decreased  ])rogressively  from  the  low,  through  tlie  intci'mediate, 
to  the  high  condition.  The  amount  of  blood  taken  from  the  cats  was  less 
after  exposures  to  the  high  than  the  low  condition.  The  concentration  of 
sugar  in  the  blood  also  decreased,  progressively  in  the  three  gi-oups  from 
the  low  to  the  high  condition.  The  evidence  indicates  that  the  distaste 
for  physical  labor  which  is  felt  on  a  hot  and  humid  day  has  a  deeper  basis 
than  mere  inclination ;  that  it  is  founded  uix)n  physiological  factors. 

Atmospheric  conditions  likewise  influence  the  nasal  mucosa.  Miller 
and  Cocks  demonstrated  that  exposure  of  the  body  to  heat  increased  the 
swelling,  redness  and  secretion  of  the  nasal  mucosa;  and  that  the  effects 
wore  more  marked  when  the  humidity  of  the  air  was  high.     High  tern- 


902  EDWAKD  C.  SCHKEIDER 

perature  with  draughts  diminished  the  swelling,  secretion  and  redness; 
while  cold  draughts  increased  these  conditions.  The  effects  produced 
upon  the  nasal  mucosa  are  direct  rather  than  reflex  in  nature. 

Miller  and  Xoble  found  that  respiratory  infection  of  rabbits  was 
favored  by  chilling  after  they  had  been  accustomed  to  heat.  They  con- 
.  elude  that  the  weight  of  experimental  evidence  does  not  justify  the 
I  elimination  of  exposure  to  cold  as  a  possible  though  secondary  factor  in 
I  the  incidence  of  acute  respiratory  disease.  A  change  from  low  to  high 
'  temperature  has  even  a  more  marked  predisposing  influence  than  that 
from  high  to  low. 

Environmental  temperatures  likewise  exert  an  influence  upon  the 
metabolism  of  men.  Voit(f5)  subjected  fasting  men  to  many  different  tem- 
peratures, in  the  Pettenkofer-Voit  respiration  apparatus,  while  he  de- 
termined the  carbon  dioxid  and  nitrogen  elimination.  Changes  in  tem- 
perature from  57°  to  80.6°  F.  scarcely  changed  the  carbon  dioxid  output; 
a  lowering  of  temperature  to  50°  and  less  stimulated  the  metabolism; 
also  above  80.6°  it  was  markedly  increased,  as  shown  by  the  rise  in  carbon 
dioxid  elimination.  These  observations  on  man  are  similar  to  metabolic 
changes  recorded  by  Rubner(j)  for  the  dog  and  other  animals.  Rubner  has 
shown  that  increased  humidity  at  tem])eratures  above  82°  F.  increases 
the  metabolism.  For  a  given  high  temperature  the  rise  in  metabolism 
will  not  be  as  gieat  where  the  evaporation  of  perspiration  occurs  readily 
as  when  there  is  difficulty  in  evaporation,  due  to  increased  humidity,  that 
prevents  effective  elimination  of  heat. 

All  studies  on  the  influence  of  temperature  and  humidity  indicate  that 
cool  and  comfortable  atmospheres,  with  a  temperature  of  about  68°  F. 
and  50  per  cent  relative  humidity  are  beneficial;  while  a  temperature  as 
high  as  86°  F.  and  80  per  cent  relative  humidity  are  deleterious.  The 
bad  effects  are  due  primarily  to  the  inability  of  the  body  to  properly  cool 
itself  because  of  the  temperature  and  moisture  conditions  of  the  sur- 
rounding air. 

Air  Movement  and  Winds 

Here  again  the  gain  to  the  body  is  to  be  found  chiefly  in  the  influence 
of  moving  air  on  heat  loss.  The  air  surrounding  the  body  soon  becomes 
saturated  with  moisture  and  approaches  the  body  heat  in  temperature. 
Hence  this  thin  envelope  of  air  surrounding  the  body  may  establish 
the  degrees  of  temperature  and  humidity  that  are  known  to  be  delete- 
rious. 

The  effect  of  wind  of  moderate  humidity  and  different  temperatures 
on  the  metabolism  of  a  man  clad  in  summer  clothes  as  compared  with  the 
metabolism  in  calm  air  was  shown  by  Wolfert(&)  to  be  stimulating.  A 
breeze  having  a  temi)erature  of  59°  to  68°  F.  and  moving  at  the  rate  of 


CLIMATE  903 

about  15  miles  per  hour  increased  the  metaholisra  approximately  19  per 
cent. 

A  recent  investigation  by  Aggazzotti  and  Galeotti  on  the  influence  of 
wind  on  the  respiration  and  the  pulse  has  shown  that  if  the  wind  is  not 
too  strong-  the  lung  ventilation  is  favored.  The  alveolar  carbon  dioxid 
tension  is  lowered.  In  strong  wind  the  breathing  shows  irregularity  in 
rate  and  depth. 

Li^ht 

The  opinion  has  been  held  that  the  intense  light  of  the  tropical  skies 
causes  the  backwardness  of  mankind  in  these  countries.  Sun  baths  have 
been  employed  in  the  treatment  of  tuberculosis  with  some  degree  of  success. 
However,  the  physiological  effects  of  light  have  not  been  clearly  demon- 
strated. Wohlgemuth,  in  a  study  of  desert  climates  at  Assuan,  found 
the  number  of  hmI  corpuscles  and  the  per  cent  of  hemoglobin  to  be  slightly 
increased.  That  the  increase  was  not  the  result  of  the  loss  of  water  from 
the  blood  because  of  sweating  was  shown  by  the  observations  that  neither 
the  sodium  chlorid  nor  the  sugar  content  of  the  blood  Avas  changed.  He 
attributes  the  increase  in  red  corpuscles,  wdiich  in  one  man  rose  from 
4,900,000  to  5,080,000  in  five  months,  to  the  action  of  light;  and  cites 
that  Bickel,  on  exposing  rabbits  to  the  light  of  the  mercury  arc,  produced 
an  increase  in  the  red  corpuscles.  Other  possibilities  were  not  eliminated. 
Huntington,  in  his  investigation  on  human  efficiency,  as  measured  by  the 
amount  of  daily  work  performed,  found  that  the  eifcct  of  light  was  at 
best  only  slight. 

Eubner,  under  ordinary  conditions,  and  Durig  and  Zuntz,  on  Monte 
Rosa,  did  not  find  that  sunlight  influenced  metabolism.  Hasselbalch  and 
Lindhard(rt),  studying  the  ultra-violet  rays  of  the  sun,  obtained  no  effect 
upon  the  metabolism.  They  did,  however,  find  a  reduction  in  the  fre- 
quency and  an  increase  in  the  depth  of  respiration  as  the  effect  of  the 
exposure  to  such  rays. 

The  importance  of  climatic  conditions  in  the  life  and  efficiency  of 
mankind  has  been  well  demonstrated  by  Ellsworth  Huntington  in  his 
book  on  "Civilization  and  (vJimate.'^  He  points  out  that  for  the  pro- 
duction of  good  fruit  the  three  factors  of  good  stock,  proper  cultivation, 
and  favorable  climatic  conditions  are  absolutely  necessary.  Recognizing 
the  importance  of  these  three  for  man,  he  then  proceeds  to  study  con- 
ditions of  human  progress  and  power  of  achievement.  He  finds  that 
wherever  civilization  has  risen  to  a  high  level,  the  climate  appears  to  have 
possessed  those  qualities  which  to-day  are  recognized  as  most  stimulating. 
He  derives  the  important  climatic  factors  by  various  statistical  com- 
parisons. Assuming  that  the  best  and  fullest  test  of  efficiency  is  a  person'3 
daily  w^ork,  the  thing  to  which  he  devotes  most  of  his  time  and  energy,  he 


904  EDWARD  C.  SCHNEIDER 

studies  the  output  of  thousands  of  industrial  workers  in  various  parts  of 
the  United  States;  mental  activity  of  certain  classes  at  West  Point  and 
Annapolis;  and  stren^h  tests  of  school  children  in  Denmark.  The  annual 
work  curves  are  quite  similar.  The  lowest  period  of  efficiency  occurs  in 
December,  January  and  February,  reaching  the  minimum  at  about  the 
end  of  January.  The  efficiency  curve  then  gradually  rises  to  a  first 
maximum  in  May  and  June,  falling  moderately  until  the  end  of  July, 
rising  again  in  September,  with  the  greatest  maximum  in  Xovember.  He 
also  presents  a  curve  of  gain  in  body  weight  based  on  a  report  of  patients 
suffering  from  tuberculosis  in  a  sanatorium  at  Saranac  Lake.  This  is 
similar  to  the  work  output  curve  with  the  least  gain  or  no  gain  in  February 
and  March,  and  the  maximum  gain  in  October.  A  study  of  death  rate 
reveals  another  of  the  same  typo  of  curves,  a  marked  reduction  in  May  and 
June,  an  increase  in  July  and  August;  followed  by  another  reduction  in 
which  the  low  death  rate  occurs  in  October,  i^ovember,  and  December, 
with  Is'ovember  showing  the  lowest  rate  for  the  year.  All  these  data 
combine  to  demonstrate  that  the  period  of  greatest  physical  and  mental 
efficiency  occurs  in  the  late  spring  and  late  autumn. 

An  analysis  has  convinced  Huntington  that  changes  in  the  barometer, 
in  the  localities  studied,  seem  to  have  little  effect.  Humidity  possesses  a 
considerable  degree  of  importance,  but  the  most  important  factor  is  clearly 
temperature.  He  came  to  the  conclusion  that  the  optimum  temperature 
of  outside  air  for  physical  well  being  is  from  60°  to  65°  F.,  that  is  when 
the  noon  temperature  rises  to  70°  F.  or  even  more;  and  for  mental  work 
the  optimum  is  reached  when  the  outside  temperature  averages  38°  F. 
Another  highly  important  climatic  condition  is  that  of  the  temperature 
change  from  day  to  day.  *'It  seems  to  be  a  law  of  organic  life  that  variable 
temperature  is  better  than  uniformity."  The  ideal  conditions  are  mod- 
erate temperature  changes,  ^'especially  a  cooling  of  the  air  at  frequent 
intervals."  Variations  in  temperature  give  one  of  the  best  tonics  provided 
by  nature. 

All  experimentation  and  observation  go  to  demonstrate  that  climate 
exerts  a  notewoi-thy  influence  on  the  physical  and  mental  life  of  mankind. 
This  effect  is  largely  due  to  the  movement,  humidity  and  temperature  of 
the  air.     Another  physical  factor,  altitude,  is  still  to  be  discussed. 


The  Psychological   Factor  in  Climatofherapy 

The  principles  of  climatic  treatment  are  founded  on  psychology  as  well 
as  physiology.  The  external  conditions  which  we  see  and  feel  make  a 
greater  conscious  impression  than  the  physiologic  effects  which  do  not  come 
into  the  field  of  consciousness;  unless,  as  is  rarely  the  case,  they  are  ex- 
treme and  unusual.     A  climate  that  is  conducive  to  out-of-door  living 


CLIMATE  905 

awakens  an  interest  and  zest  and  produces  a  cheerful  serenity  and  happi- 
ness that  pemiit  the  physiological  climatic  effects  to  more  completely  re- 
store health.  Unquestionably  both  physiological  and  psychological  con- 
ditions influence  })hysical  well-being;  a  patient  worried  about  financial 
resources  and  family  cares  rarely  secures  the  full  advantage  of  the  physio- 
logical effects  of  climate,  because  of  the  absence  of  serenity  and 
cheerfulness. 

The  only  way  to  use  a  climate  is  to  give  it  every  chance  to  help  in  the 
cure.  Careful  and  intelligent  attention  to  personal  hygiene  and  to  the 
psychical  side  of  the  environment  are  essential.  Climate  does  not  cure, 
but  it  is  an  important  help  to  the  body  in  overcoming  weakness  and  disease. 

The  Variety  of  Climate. — The  physical  factors  have  served  as  a  basis 
for  classifications  of  climate.  It  has  long  been  recognized  that  there  are 
four  factors  that  enter  into  the  production  of  the  climate  of  any  locality: 
(1)  Distance  from  the  equator;  (2)  distance  from  the  ocean;  (3)  height 
above  the  sea-level ;  and  (4)  the  prevailing  winds. 

The  classic  zones,  tropical,  temperate  and  polar,  recognize  the  relation 
to  the  sun  and  are  based  on  sunshine  distribution.  Irregularities  in  the 
distribution  of  land  and  water  and  the  prevalence  of  particular  winds 
break  the  uniformity  of  these  zones  and  lead  -to  a  more  rational  scheme 
of  classification.  ^*The  great  differences  in  the  climatic  relations  of  land 
and  water,  recognizes  a  first  large  subdivision  of  each  zone  into  land 
and  w^ater  areas.  Then  as  continental  interiors  differ  from  coasts,  and  as 
■windward  coasts  have  climates  unlike  those  of  leeward  coasts,  a  further 
natural  subdivision  would  separate  these  different  areas.  Finally,  the 
control  of  altitude  over  climate  is  so  marked  that  plateaus  and  mountains 
may  well  be  set  apart  by  themselves  as  separate  climatic  districts." 

A  maritime  climate  is  equable,  that  is  without  extremes  of  tempera- 
ture, with  a  prevailing  high  relative  humidity,  a  large  amount  of  cloudi- 
ness and  a  comparatively  heavy  rainfall.  The  continental  climate  is  more 
severe;  the  annual  temperature  ranges  increase,  as  a  whole,  w^ith  increasing 
distance  from  the  ocean  :  the  regular  diurnal  ranges  are  also  large,  reaching 
35°  or  40°  F.,  and  even  more.  The  humidity  is  lower  and  cloudiness, 
as  a  rule,  decreases  inland,  reaching  its  minimum  in  the  arid  plains  and 
deserts.  The  evaporating  power  of  a  continental  climate  is  much  gi-eater 
than  that  of  the  more  humid  and  cloudier  coast  climate.  A  climate  with  a 
relative  humidity  up  to  50  per  cent  is  unusually  dry,  -vvith  50  to  70  per  cent 
relative  humidity  is  dry,  with  70  to  85  per  cent  relative  humidity  is 
moist,  and  with  85  to  100  per  cent  relative  humidity  is  unusually  moist. 

General  Considerations  in  the  Choice  of  Climate. — While  climatic 
studies  are  difficult  to  evaluate  certain  things  now  stand  out  somewhat 
clearly.  The  humid  tropics  are  disagreeable  and  hard  to  bear.  Energetic 
physical  and  mental  actions  are  difiicult  or  even  impossible.  "The  monot- 
onously enervating  heat  of  the  humid  tropics  weakens,  so  that  man  becomes 


906  EDWARD  C.  SCHNEIDER 

sensitive  to  slight*  temperature  changes.''  James  is  of  the  opinion  that 
an  even  temperature  lowers  the  tone  of  the  vasomotor  system  by  lack 
of  proper  exercise.  In  drier  tropics,  cooled  by  trade  winds,  as  found  in 
the  Hawaiian  Ishmds,  the  white  population  lives  and  carries  on  business 
in  "American  style'*  without  signs  of  tropical  enervation  and  deteriora- 
tion. It  appears  that  many  elderly  persons  and  others  who  are  over- 
worked may  find  rest  from  nervous  tension  in  portions  of  the  tropics. 

Extraordinarily  low  temperatures  are  easily  borne  if  the  air  is  still 
and  dry,  and  large  ranges  in  temperature  are  well  tolerated  when  the  air 
is  dry.  On  the  other  hand,  cold  air  with  a  high  moisture  content  has  a 
depressing  effect.  At  the  margins  of  the  polar  zones  the  change  from 
winter  to  summer  is  so  sudden  that  the  transitional  season  disappears. 
Hence,  in  the  seasonal  changes  the  intennediate  periods  that  add  so  much 
to  human  etficieucy  are  lacking. 

It  has  been  suggested  that  unless  invalids  are  of  v^ry  delicate  constitu- 
tion, or  greatly  run  down  in  health,  the  bracing  qualities  of  a  northern 
winter  in  a  dry  climate  under  proper  safeguards  will  probably  do  thena 
more  good,  though  at  times  they  wnll  be  less  comfortable,  than  a  warm 
southern  atmosphere.  Too  large  variations  of  daily  temperature  may  be 
over  trying,  but  as  a  rule  a  definite  drop  in  the  daily  temperature  is  a 
necessity  for  stimulation. 

Altitude 

The  mountain  and  high  plateau  are  characterized  by  a  similar  climate 
in  all  the  geographical  zones.  The  characteristics  are  decrease  in  pressure, 
temperature  and  absolute  humidity ;  an  increase  in  the  intensity  of  sun- 
light and  radiation ;  and  larger  ranges  in  soil  temperature.  The  climatic 
action  of  the  heat,  humidity  and  light  have  been  discussed,  leaving  only 
the  factor  of  pressure  for  consideration.  Some  maintain  that  the  real 
benefit  of  mountain  climate  to  the  health  seeker  is  to  be  found  in  the 
favorable  heat  and  humidity  and  the  mental  reaction  to  the  beauty  of 
the  environment. 

An  early  suggestion  made  by  Jourdanet  is  still  to  be  home  in  mind 
when  mountain  and  high  plateau  climates  are  recommended.  He  divided 
these  climates  into  the  mountain  climate,  below  6,500  feet,  and  altitude 
climate  above  that  height.  The  former  was  considered  beneficial  because 
of  the  stimulating  quality  of  clean,  clear,  cool  air  and  the  latter  injurious 
because  of  low  pi-essure.  ^len  live  comfortably  and  work  well  in  the 
mines  of  the  Andes  at  15,400  to  16,200  feet.  Such  altitudes,  however, 
are  for  the  robust  and  not  the  health  seeker. 

Residence  at  a  high  altitude  brings  about  striking  and  definite  physio- 
logical changes  in  the  body.  There  have  been  many  opinions  held  as  to 
the  essential  cause.     A  common  belief  has  been  one  that  recrarded  the 


CLIMATE  907 

pressure,  acting  in  a  mechanical  manner,  as  tlie  rcs|K»ni*ible  cause.  It  Iiaa 
been  natural  to  ex|)ect  that  a  diminution  of  external  pressure  would  have  a 
''cupping  glass"  effect  that  -would  lead  to  a  congestion  of  the  skin  and 
lungs  and  in  some  way  cause  a  readjustment  of  inTcrnal  parts  of  the  bodv. 
Flowevrr,  all  recent  investigators  hold  that  the  physiological  effects  noted 
at  high  altitudes  are  due  to  the  lack  of  oxygen,  resulting  from  the  lowered 
partial  pressure  of  oxygen  that  occurs  pi'oportionately  with  the  decrease 
in  barometric  pressure. 

Altitude  Sickness. — It  is  now  clearly  established  that  during  the  iirst 
few  days  s[>ent  at  a  high  altitude  an  attack  of  altitude  sickness  may  occur. 
S<ime  persons  are  affected  at  a  comparatively  h.w  and  others  at  a  higher 
altitude.  An  elevation  of  10,000  feet,  or  even  h.-ss,  provokes  it  in  a  few 
individuals ;  but  many  go  to  14,000  and  more  ieet  without  distress. 
There  are  two  forms  of  altitude  ("mountain")  sickness;  the  acute,  which 
breaks  out  suddenly  on  entrance  into  the  rarefied  air ;  and  the  slow,  which 
manifests  itself  much  later. 

The  acute  form  is  characterized  by  a  rapid  pulse,  nausea,  vomiting, 
physical  prostration  which  may  even  incapacitate  for  movement,  livid 
color  of  the  skin,  ringing  sensation  in  the  ears,  dimmed  sight  and  faint- 
ing attacks. 

In  the  slow  form,  which  may  be  called  the  normal  type,  lasting  from 
one  to  three  days,  the  newcomer  at  first  complains  of  no  symptoms.  Some 
hours  later  he  begins  to  feel  "good  for  nothing '  and  disinclined  for 
exertion.  He  goes  to  bed  to  spend  a  restless  and  troubled  night.  A  frontal 
headache  and  periodic  or  Cheyne-Stokes  breathing  interfere  with  sleep, 
there  may  be  nausea  and  vomiting.  The  next  morning  the  patient  may 
feel  slighly  giddy  on  arising  and  any  attempt  at  exertion  increases  the 
headache.  The  face  may  be  slightly  cyanosed  and  the  eyes  dull  and  heavy, 
with  a  tendency  to  water.  The  tongue  is  coated  and  appetite  gone.  There 
may  be  diarrhea  and  abdominal  pain.  The  pulse  and  arterial  blood 
pressure  are  ustially  high.  The  temperature  is  normal  or  slightly  imder. 
There  are  wide  divergencies  from  this  slow  type  of  which  Ravenhill  has 
well  described  those  in  which  cardiac  and  nervous  symptoms  predominate. 
A  weakened  heart  does  not  seem  to  predispose  to  the  cardiac  type  of 
altitude  sickness. 

Acclimatization. — The  process  of  acclimatization  is  slow,  while  certain 
of  the  changes  may  begin  almost  at  once  with  entrance  into  rarefied  air, 
it  ordinarily  requires  several  days  for  these  to  wholly  restore  the  patient 
to  normal  well  being.  The  complete  process  of  acclimatization  requires 
six  and  more  w^eeks. 

Adaptation  to  altitude  consists  in  physiological  responses  that  increase 
the  supply  of  oxygen,  which  is  at  first  decreased  because  of  lowered 
pressure,  until  it  again  reaches  normal.  These  include,  among  others,  the 
following:     (1)  An  increase  in  the  percentage  and  the  total  amount  of 


90S      .  EDWARD  C.  SCHNEIDER 

hemoglobin  in  the  blood  of  the  body;  (2)  a  fall  in  the  lung  alveolar  carbon 
dioxid  partial  pressure  and  a  rise  in  the  alveolar  oxygen  pressure,  the 
result  of  increased  ventilation  of  the  lungs  due  to  deeper  breathing;  and 
(3)  at  some  altitudes  a  temporary  or  permanent  increase  in  the  rate  of 
blood  flow. 

The  Blood  Adaptive  Changes. — In  spite  of  an  occasional  contrary 
observation  the  prediction  made  by  Paul  Bert  in  IS 78  that  the  blood  at 
high  altitudes  would  be  found  to  have  a  greater  oxygen  capacity  than  the 
blood  of  similar  individuals  at  lower  levels,  has  been  demonstrated  to  be 
true.  Investigators  have  found  an  increase  in  the  number  of  red  corpuscles 
per  cubic  millimeter  and  in  the  percentage  of  hemoglobin.  Miss  Fitz- 
gerald (a)  (6),  by  a  study  of  inhabitants  of  the  Southern  Appalachian  and 
the  Rocky  ^fountains,  found  that  as  the  altitude  increases  the  percentage 
of  hemoglobin  in  the  blood  is  augmented  about  10  per  cent  of  the  normal 
value,  for  men  and  women  at  sea  level,  for  every  100  nnn.  fall  of  barometric 
pressure.  The  physiological  significance  of  this  increase  in  hemoglobin 
and  red  corpuscles  is  that  a  unit  volume  of  blood  can  carry  for  a  given 
oxygen  pressure  more  oxygen  than  normally. 

When  a  rapid  ascent  is  made  to  a  high  altitude,  as  in  an  aeroplane, 
the  changes  in  the  blood  may  be  detected  as  early  as  in  from  20  to  60 
minutes.  When  the  ascent  is  made  more  slowly,  as  by  automobile  or 
railway,  it  may  not  be  evident  for  12  or  more  hours.  The  increase  is 
rapid  for  the  first  two  to  four  days  and  is  followed  by  a  more  gradual 
increase  extending  over  a  period  of  six  weeks.  The  increase  occurs  most 
rapidly  in  subjects  in  excellent  physical  condition.  Fatigue,  as  from 
walking  up  a  mountain,  delays  the  increase  in  hemoglobin  and  red 
corpuscles. 

At  the  present  time  the  evidence  accounts  for  tb.e  increase  in  hemo- 
globin and  erythrocytes  as  follows:  the  initial  rapid  increase  is  due  to  a 
concentration  by  a  loss  of  fluid  from  the  blood  and  possibly  by  throwing 
into  the  general  circulation  a  large  mass  of  reserve  corpuscles.  The  more 
gi-adual  increase,  extending  over  several  weeks,  is  brought  about  by  the 
increased  activity  of  the  bone  marrow^  resulting  in  an  increase  in  the  total 
number  of  corpuscles  and  amount  of  hemoglobin  which  may  finally  not 
only  restore,  but  sometimes  actually  increase,  the  low  altitude  blood 
volume. 

The  number  of  leukocytes  per  cubic  millimeter  is  not  increased  with 
altitude,  but  the  larger  lymphocytes  are  increased  and  the  polymorpho- 
nuclear cells  diminished.  The  blood  platelets  are  also  increased  at  high 
altitudes. 

Respiratory  Adaptation  to  High  Altitudes. — The  first  effects  observed 
on  going  to  a  high  altitude  are  caused  by  an  insufficient  supply  of  oxygen 
to  the  tissues.  It  is  to  be  expected,  therefore,  that  the  amount  of  air 
pumped  in  and  out  of  the  lung's  will  be  increased  almost  immediately. 


CLIMATE  909 

The  respiratory  response  to  altitude  is  ordinarily  the  first  of  the  several 
compensatory  changes  to  apjK'ar.  Miss  Fitzgerald  found  that  the  breath- 
ing of  persons  living  permanently  at  an  altitude  of  2,200  feet,  as  indicated 
by  the  alveolar  carbon  dioxid,  showed  a  larger  lung  ventilation  than  under 
similar  conditions  at  sea  level;  and  further  established  the  law  that 
approximately  a  10  per  cent  increase  in  the  ventilation  occurred  for  each 
100  mm.  of  diminution  of  the  barometric  pressure.  The  full  extent  of 
the  change  in  breathing  is  reached  in  from  7  to  11:  days. 

The  type  of  breathing  that  is  best  suited  to  the  need  of  the  body  at 
high  altitudes  is  slow  and  deep  rather  than  rapid  and  shallow.  After 
adaptation  the  depth  rather  than  the  rate  of  breathing  will  ordinarily  have 
increased.  However,  during  vigorous  physical  exertion,  where  even  at 
sea  level  the  depth  of  breathing  is  about  maximal,  at  a  high  altitude 
such  as  Pikes  Peak  the  rate  shows  a  marked  increase.  A  subject,  who 
had  breathed  when  in  bed  at  sea  level  at  the  rate  of  16.8  breaths  i)er 
minute,  on  Pikes  Peak  had  a  rate  of  only  17.3;  while  w^alking,  at  the 
rate  of  5  miles  per  hour  at  sea  level,  the  rate  was  20,  and  on  Pikes  Peak 
36  breaths  per  minute. 

The  increased  breathing  augments  the  alveolar  oxygen  tension  in  the 
lungs.  If,  for  example,  on  Pikes  Peak,  with  a  barometric  pressure  of 
457  mm.,  the  respiration  did  not  change,  then  the  alveolar  oxygen  tension 
in  the  dry  alveolar  air  would  fall  proportionately  with  the  bai-ometer  to 
about  36  mm.  The  increase  in  breathing,  however,  raises  this  at  that 
altitude  to  about  52  mm.  As  a  result  the  blood  will  be  just  that  much 
more  saturated  with  oxygen,  thus  remedying  to  some  extent  the  defective 
saturation  of  the  arterial  blood  with  oxygen. 

The  explanation  of  the  manner  in  which  respiration  is  modified  has 
recently  been  more  fully  elucidated.  The  hormone  of  breathing  is  tlie 
hydrogen  ion  concentration  in  the  blood,  and  not  the  total  carbon  dioxid 
in  the  blood,  nor  the  concentration  of  HCOo  ions  as  has  sometimes  been 
claimed.  Haldane(^7)  has  pointed  out  that  the  Il-ion  concentration  of  the 
blood  is  regulated  with  great  delicacy  by  the  respiration  on  the  one  hand 
and  the  kidneys  and  liver  on  the  other.  The  respiration  doing  the  rough 
and  immediate  work  by  increasing  or  dccrea.-ing  the  elimination  of  the 
carbon  dioxid,  and  the  kidneys  the  finer  and  slower  work.  "When  a  person 
goes  to  a  high  altitude  the  want  of  oxygen  acts  as  an  additional  stimulus 
to  the  respiratory  center  with  the  result  that  an  excess  of  carbon  dioxid 
is  eliminated.  This  decreases  the  Il-ious  and  causes  a  state  of  alkalosis 
in  the  blood.  To  offset  the  excess  of  alkali  the  kidneys  and  liver  attempt 
to  redress  the  balance.  It  Las  been  shown  by  Ilaldane,  Kallas,  and  Kenna- 
way  and  by  Hasselbalch  and  Lindliard(a  )  (b)  that  excretion  of  acid  and  of 
ammonia  diminish  for  a  period  of  several  days.  During  this  time  the 
alkalosis  wdll  have  been  diminished  and  the  normal  Il-ion  concentration 
of  the  blood  almost  restored  to  its  previous  level.     This,  as  Haggard  and 


910  EDWARD  C.  SCHXEIDER 

Henderson  (a)  have  shown,  results  in  a  reduction  of  blood  alkali.  .  \Miile 
ai'ter  acclimatization  the  H-ions  are  again  probably  nearly  the  same  as  at 
sea  level,  the  restoration  is  never  complete  and  in  the  end  the  stimulating 
action  of  diminished  oxygen  leads  to  a  greater  ventilation  of  the  lungs 
than  on  the  first  day,  and  a  permanent  level  is  then  established  for  that 
barometric  pressure.  Haldane  makes  clear  that  if  the  initial  alkalosis 
should  be  maintained  the  dissociation  of  oxyhemoglobin  would  Ixi  less 
than  normal,  thus  accentuating  oxygen  want  in  the  body.  By  restoring, 
or  nearly  restoring,  the  Il-ion  concentration  of  the  blood  the  cuiTe  of 
oxyhemoglobin  dissociation  is  again  shifted  back  to  or  toward  the  normal 
for  sea-level. 

Metabolism. — Investigations,  in  spite  of  an  occasional  positive  finding, 
lead  to  the  opinion  that  metabolism  is  independent  of  the  variations  in 
atmospheric  pressure.  Sundstroem  found  that  the  assimilative  power  for 
the  energy  in  the  food  remains  normal  at  all  altitudes. 

In  1883  Fraenkel  and  Geppert  placed  a  fasting  dog  under  the  influ- 
ence of  diminished  barometric  pressure  and  found  an  increased  pi-otein 
metabolism.  Zuntz(a)  and  collaborators,  on  Monte  Eosa  at  2,000  m.,  failed 
to  show  an  increase  in  metabolism;  but  at  4,560  m.,  barometer  443  mm., 
obtained  an  increase  of  approximately  15  per  cent.  Later  Durig  and 
Zuntz,  in  an  expedition  to  Teneriffe,  altitude  of  3,160  m.,  failed  to  show 
an  essential  difference  in  metabolism.  The  Anglo-American  expedition 
to  Pikes  Peak  found  no  difference  in  metabolism  either  during  rest  or 
when  taking  exercise.  Hasselbalch  and  Lindhard  observed  a  man  for  14 
days  in  a  pneumatic  cabinet,  at  455  mm.  barometric  pressure,  and  found 
that  the  consumption  of  oxygen  and  the  urinary  ammonia  and  amino-acids 
were  unaffected.  Sundstroem  showed  that  the  iron  balance  did  not  alter 
nor  the  retention  of  iron  exceed  that  observed  in  low  altitudes. 

The  diminished  excretion  of  ammonia  observed  by  Hasselbalch  and 
Lindhard  and  by  Haldane  and  collaborators  during  the  period  when  blood 
alkalosis  was  being  overcome  has  already  been  pointed  out.  Hasselbalch 
and  Lindhard  found  that  an  increased  oxygen  consumption  might  occur 
during  the  process  of  acclimitization.  Von  Wendt(/^)  noticed  a  retention 
of  nitrogen,  iron  and  potassium  on  Monte  Rosa  which  he  attributed  to  the 
construction  of  new  red  corpuscles. 

The  Circulatory  Mechanism. — Altitude,  if  great  enough,  increases  the 
heart  rate;  but  it  is  generally  recognized  that  at  moderately  high  alti- 
tudes, 6,000  to  8,000,  or  even  J),000  feet,  there  is  no  aug-mentation. 
Shortly  after  ascending  to  such  an  altitude  as  14,000  feet  the  heart  rate 
gradually  increases  during  a  j^eriod  of  several  days.  In  persons  who 
develop  "altitude  sickness"  and  in  those  fatigued  by  climbing,  the  accelera- 
tion begins  sooner  and  is  greater.  With  the  development  of  acclimatiza- 
tion the  heart  rate  will  return  towai'd,  and  in  some  cases  reach,  the  low 


CLIAFATE  911 

altitude  iionnal.  TJie  same  amount  of  pliysical  exertion  inei-eases  tlie 
pulse  rate  more  at  a  lii^ih  than  at  a  low  altitude.  The  ditference  becomes 
greater  as  the  amount  of  work  done  increases. 

Tlie  arterial  blood  pressures  are  not  altered  by  altitude  in  the  majoritv 
of  men  ;  but  in  a  considerable  number  of  cases  there  occurs  a  slight  lower- 
ing of  the  systolic  pressure;  while  occasionally,  very  likely  in  a  poor 
reactor,  there  is  a  rise  in  both  the  systolic  and  diastolic  pressures.  During 
an  attack  of  "altitude  sickness"  there  is  usually  a  marked  increase  in 
both  pressures. 

The  blood  pressure  in  the  capillaries  is  either  unchanged  or  less  than 
at  sea-level.  In  the  veins,  at  altitudes  of  more  than  G,000  feet,  the  pressure 
is  less  than  at  sea-level.  Contrary  to  common  opinion  bleeding  from  the 
nose,  lips,  lungs,  and  stomach  rarely  occurs.  The  experience  of  aviators 
has  dispelled  the  belief  that  altitude  causes  hemorrhages. 

Physical  exertion  makes  gieater  demands  on  the  heart  and  blood  vessels 
at  high  than  at  low  altitudes.  The  rise  in  arterial  pressure  is  greater 
for  a  given  exertion  at  a  high  than  a  low  altitude,  the  difference  being 
less  after  acclimatization.  It  would  be  an  easy  matter  to  seriously  injure 
the  heart  during  the  early  days  of  residence  at  high  altitude.  However, 
in  men  who  are  physically  strong  because  of  athletic  training  the  risk  is 
slight ;  and  in  all  who  become  acclimated  the  ordinary  forms  of  exercise 
will  be  well  tolerated. 

General  Considerations. — Anemia  is  regarded  by  Sewall  as  the  domi- 
nant disorder  at  high  altitudes.  Anemia  reduces  the  working  efficiency 
and  the  reserve  power  of  the  tissues  insofar  as  it  permits  deprivation  of 
oxygen.  That  the  physiological  response  to  the  stimulation  of  lowered 
barometric  pressure  may  be  slow  or  deficient  is  a  common  observation. 
Hence  it  is  to  be  expected  that  many  functional  disorders  are  originated 
or  accelerated  at  moderate  altitudes  owing  to  the  existence  of  com- 
paratively mild  grades  of  anemia.  Moleen  has  called  attention  to  the 
fa^t  that  individuals  who  exhibit  nervous  symptoms  or  complain  of 
"nervousness''  while  living  at  high  elevations  show  a  relative  or  abso- 
lute anemia.  It  is  significant  that  the  plethoric  type  of  person  rarely 
finds  it  necessary  to  leave  high  altitudes  foi*  "nervousness."  It  is  main- 
tained that  if  measures  are  taken  to  stimulate  the  blood  forming  centers 
there  is  no  more  difficulty  in  living  tranquil  lives  in  the  high  altitudes 
than  at  sea  level. 

The  dangers  to  the  heart  in  high  altitudes  are,  according  .to  Hall, 
precisely  the  same  as  elsewhere,  but  very  sharply  exaggerated  in  certain 
directions;  particularly  because  the  newcomer  is  likely  to  overdo  in 
physical  exertion.  Cardiac  overstrain  from  exercise  is  often  the  real  cause 
of  distress  and  not  the  altitude.  Schrampf  found  in  Switzerland  that  up 
to  7,000  feet  pathological  blood  pressures  are  improved,  that  is,  high 
pressures  are  reduced  and  low  ones  increased,  together  with  an  improve- 


912  EDWARD  C.  SCHNEIDER 

ment  in  the  general  condition.  Compensated  valvular  lesions  and  mild 
cases  of  myocarditis  were  also  favorably  influenced. 

Because  the  adaptive  compensations  to  high  altitudes  are  slow  in  tlieir 
development,  the  newcomer  should  remain  quiet  for  a  day  or  two.  If 
s^1nptoms  of  ''altitude  sickness"  occur  rest  in  bed  with  windows  open  is 
advisable  and  at  least  a  day  of  quiet  after  all  symptoms  have  disappeared. 
During  the  first  days  it  is  best  to  make  no  exertion  which  causes  any 
considerable  dyspnea. 

The  changes  in  the  breathing  and  the  blood  are  permanent  in  character, 
and  do  not  diminish  during  a  protracted  residence  at  the  high  altitude. 
Changes  in  pulse  rate  and  in  the  rate  of  blood  flow  are  less  peniianent, 
and  tend  to  disappear  with  acclimatization.  On  returning  from  a  liigh 
to  a  low  altitude  the  changes  in  the  respiration  and  blood  are  maintained 
for  a  time  as  an  "after  effect."  The  longer  the  residence  at  the  high 
altitude  the  more  prolonged  the  period  of  "after  effect."  During  this 
period  the  individual  may  gain  in  weight  and  health. 


INDEX 


Abderhalden's  experiments,  on  nitrog- 
enous equilibrium  and  body  weight, 
12'i,  124,  125. 

Absorption,  of  alcohol,  297. 

distribution  after,  299. 

—  of  carbohydrates,  249. 

—  effect  on,  of  alkalies,  318. 

of  calcium,  318. 

of  water,  291. 

—  of  fat  from  the  intestine,  194. 

changes  in  fats  during,  196. 

emulsification,  200. 

factors  in,  bile,  198. 

pancreatic  secretion,  197. 

in  fat  metabolism,  paths  of,  196. 

synthesis  of  fats  during,  196. 

—  in  fat  metabolism  of  stomach,  190. 

—  of  magnesium,  323. 

—  of  vitamins,  347. 
Acapnia,  741. 
Acclimitization,  907. 

Acetates,  effect  of,  on  metabolism,  726, 

Acetone  bodies  in  the  blood,  449. 

Acid-alkali  metabolism,  effect  on,  of 
anesthetics,  general,  chloroform  and 
ether,  762. 

of  antipyretics,  771.  . 

of  mercury,  756. 

of  opiates,  766. 

Acid-base  equilibrium,  and  blood  poi- 
sons, 744. 

—  effect  on,  of  arsenic,  754. 

of  phosphorus,  750. 

Acidosis,  alkalies  treatment  of,  734. 

—  of  anesthesia,  734. 

—  cause  of,  458. 

—  definition  of,  733. 

—  of  diabetes,  734. 

—  in  diarrheal  attacks  of  infants,  al- 
kaline treatment  for,  735. 

—  intravenous  injection  of  sodium  bi- 
carbonate for,  792. 

—  of  nephritis;  735. 

—  retention,  735. 

Acid>,  effects  of,  on  metabolism,  733. 
Acids  or  acid-forming  foods,  prolonged 

administration   of,  334. 
Acrf.iuegaly,    effect    on,    of    pituitary 

glnnd  substances,  785. 


x\damkiewiez-Hopkins-Cole  reaction  of 
proteiu.s,  98. 

Adenase,  distribution  of,  156. 

Adenine,  137,  138. 

Adrenalin,  influence  of,  on  blood  sugar, 
258. 

Adrenals,  and  sympathetic  system,  in- 
fluence of  on  glycogenolysis,  glyco- 
genesis  and  glucolysis,  257. 

Age,  influence  of,  on  basal  metabolism, 
612. 

of  infants  from  two  weeks  to 

one  year,  646. 

—  old.  See  Old  Age. 
Agglutination  test  for  transfusion,  835. 

—  method  of  performing,  833. 
Air,  coml)ustion  and  respiration  of, 

Boerhaave  (1668-1738),  11. 

Robert  Boyle  (1621-1679),  8. 

Plales,  Stephen  (1677-1761),  11. 

John  Mayow  (1640-1679),  9. 

Stahl  (1660-1734),  IJ. 

Willis  (1621-1675),  11. 

—  dephlogisted,  16. 

—  "eminently  respirable"  of  Lavoisier, 
or  oxygen,  22. 

—  fire,  of  Scheele,  17. 

—  fixed,  15. 

— '  —  Lavoisier,  22. 

—  in  history  of  metabolism,  Robert 
Boyle,  8. 

—  inflammable,  or  hydrogen,  15,  23. 

—  outdoor,  analysis  of,  541. 

—  residual,  or  nitrogen  gas,  16. 

—  spoiled,  or  nitrogen,  of  Scheele,  17. 
Air  analyzers,  Haldane's  method,  540. 
Air  currents,  cooling  power  of,  at  dif- 
ferent velocities,  604. 

Air  movements,  effects  of,  902. 
\lanin,  84,  107. 
\lbumin,  428. 
Mbumins,  82. 
\lbuminoid5,  83.  / 

Alcohol,  absorption  <5t,  297. 

—  combustion  of,  300. 

—  in  diabetes,  301. 

—  distribution  of,  after  absorption,  299. 

—  eff^^ct  of,  on  metabolism,  764. 
carbohydrate,  764. 


913 


914 


IXDEX 


Alcohol,  effect  of,  on  metabolism,  fat, 
765. 

protein,  300,  764. 

purin,  300. 

reproduction  and  growth,  765. 

total,  299,  764. 

—  excretion  of,  298. 

—  metabolism  of,  von  Liebig,  49. 

—  and  muscular  work,  301. 

—  nutritive  value  of,  297. 

—  in  rectal  feeiling,  S12. 
Alcohol  soluble  proteins,  83. 
Aldol  condensation,  225. 
Aldohexoses,  dulcital  series,  224. 

—  isomerism  of,  222. 

—  mannitol  series  of,  223. 

Aldopentoses,  table  of,  241. 

Alimentary  catarrh  in  children,  sul- 
phur water  as  therapeutic  agent  in, 
851. 

Alimentary  lipemia,  201. 
Alkali    therapy.    See   Alkaline   Treat- 
ment. 
Alkalies,  action  of,  227. 

—  administration  of,  to  man,  effect  of, 
334. 

—  effect  of,  on  absorption,  318. 

—  —  on  metabolism,  732. 

in  acidosis,  734. 

of  infants  during  diarrhea, 

736. 

in  anesthesia,  734. 

in  diabetes,  734. 

— ' neutrality  regulation,  732. 

in  retention  acidosis,  735. 

in  uranium  nephritis,  735. 

—  in  human  body,  315. 

Alkaline  treatment,  of  acidosis,  734, 
792. 

of  anesthesia,  734. 

of  infants  during  diarrhea,  735. 

retention,  735. 

—  in  diabetes,  316,  734. 

—  in  gout,  739. 
in  nephritis,  793. 

reaction  of  urine  in,  attention  to, 

793. 

as  routine  before  and  after  surg- 
ical procedures,  793. 

—  of  uranium  nephritis,  735. 
Alkaline-saline    waters,    effect    of,    on 

gastric  secretion,  848. 
Alkaline  waters,  carbonated,  effect  of, 
on  gastric  mucosa,  848. 

—  effect  of,  on  gastric  secretion,  848. 
on  metabolism,  849. 

on  pancreatic  secretion,  84^. 

—  therapeutic  value  of,  850. 


Alkalinity,  effect  on,  of  purin,  780. 
Alkalinization  of  urine,  849. 
Aloin,  effect  of,  on  metabolism,  719. 
Altitude,  blood  adaptive  change,  908. 

—  and  circulatory  mechanism,  910. 

—  high,  effects  of,  900. 
dangers  of,  911. 

Altitude,  high,  respirator;>'  adaptation 
to,  908. 

—  and  metabolism,  910. 
Altitude  sickness,  907. 

Aluminum,  effect  of,  on -mineral  metab- 
olism, 732. 

Amidomyelin,  of  brain,  470. 

Amino-acid  content  of  different  pro- 
teins, 96. 

—  relative,  table  of,  97. 

Amino  acids,  absorbed,  fate  of  in  the 
blood,  104. 

—  aromatic  amino  acids,  89. 

phenyl-alanin,  89,  113. 

tyrosin,  90,  113. 

—  of  the  blood,  442. 

—  of  brain,  471. 

—  compounds  of,  93,  94. 

—  possible,  number  of,  95. 

—  deaminization  of,  by  bacteria,  675. 

—  diamino-acids,  88. 

arginin,  89,  112. 

lysin,  88,  112. 

ornithin,  89,  113. 

—  dibasic  mono  amino-acids,  86. 

aspartic  acid,  86,  110. 

combinations,  87,  110. 

—  effect  of,  on  metabolism,  774. 

—  fate  of,  in  the  bodj',  table  summariz- 
ing, 115. 

in  the  tissues,  105. 

—  fate  of  non-nitrogenous  fraction  of, 
107. 

—  heterocyclic  amino  acids,  90. 
histidin,  91,  114. 

oxyprclin,  90,  114. 

prolin,  90,  114. 

tryptophan,  91,  115. 

—  hydroxy-  and  thio-<»-amino  acids,  87. 

^-hydroxy glutamic  acid,  88,  110. 

cystein,  88,  111. 

cystin,  88,  111. 

serin,  87,  111. 

—  monobasic  mono  amino  acids,  84. 
alanin,  84,  107. 

''-amino  butyric  acid,  85,  108. 

combinations  of, 

carboxyl,  80. 

glycocoll  hydrochlorid,  86. 

sodium  glycocollate,  86. 

glycocoll,  84,  107. 


IXDEX 


91i 


Amino-acids,  monobasic  mono  amino 
acids,  iso-leucin,  85,  101). 

leucin,  85,  109. 

normal  leucin,  86,  109. 

Talin,  85,  109. 

—  number  of,  95. 

—  physiological  value  of,  experiments 
illustrating,  of  Osborne  and  Mendel, 
127,  128,  129. 

—  role  of,  in  structure  of  protein  mole- 
cule, 91. 

—  of  the  urine,  490. 
Amino-butyric  acid,  85,  108. 
Amino-purins,  adenine,  137. 

chemical    relation    of,   with   oxy- 

purins,  138. 
guanin,  137. 

—  formation  of  oxy-purins  from,  151. 
Amins,  aromatic,  formation  of,  687. 
physiological  action  of,  687. 

—  formation  of,  680. 

effects  on,  of  utilizable  carbohy- 
drate, 685. 
Ammonia,  of  the  blood,  442. 

—  change  of,  into  urea,  675. 

—  effect  of,  on  metabolism,  773. 

—  endogenous,  676. 

—  of  the  urine,  489. 

Amylen  hydrate,  effect  of,  on  metabol- 
ism, 764. 
Anemia,  arsenic  waters  in,  851. 

—  and  blood  lipoids,  446. 

—  from  blood  loss,  blood  transfusion  in, 
indications  for,  832. 

—  blood  transfusion  in,  beneficial  ef- 
fects of,  822. 

—  chronic  forms  of,  blood  transfusion 
in,  indications  for,  832. 

—  chronic  hemolytic,  blood  transfusion 
in,  indications  for,  832. 

—  general  effects  of,  on  body,  821. 

—  idiopathic  aplastic,  blood  transfu- 
sion in,  indications  for,  832. 

—  iron  waters  in,  851. 

—  before  operation,  blood  transfusion 
in,  833. 

—  pernicious,  blood  transfusion  in,  in- 
dications for,  831. 

treatment  of,  by  x-rays,  886. 

Anesthesia,  acidosis  of,  alkaline  treat- 
ment of,  734. 

Anesthetics,  general,  chloroform  and 
ether,  effect  of,  on  metabolism,  760. 

acid-alkali,  762. 

carbohydrate,  761. 

fat,  762. 

ferments,  763. 

mineral.  763. 


Anesthetics,    general,    chloroform    and 

ether,  protein,  760. 

water,  763. 

Animal  calorimetrj*  or  heat.    See  Cal- 

orimetry. 
Animal  nucleic  acids,  145. 
Antiketogenesis,  271. 
Antimony,    effect    of,    on    metabolism, 

753. 

nitrogen,  754. 

on  uric  acid  excretion,  754. 

Antineuritic     vitamin     (water-soluble 

B),  342. 

sources  of,  in  food,  346. 

Antipyretics,  effect  of,  on  metabolism, 

767,770. 

acid-alkali,  771. 

carbohydrate,  770. 

ethylhydrocuprein,  772. 

in  fever,  768. 

protein,  769. 

quinin  and  its  congeners,  772. 

of    reproduction    and    growth, 

769. 
total,  767. 

—  theory  of  reduction  of  fever  by,  771. 
Antiscorbutic  vitamins,  345. 

—  sources  of,  346.' 
1-Arabinose,  241. 
Arginin,  89,  112. 

—  as  source  of  creatin  of  urine,  494. 
Aristotle,  on  food,  5. 

Aromatic  oxyacids  and  derivatives,  499. 
Arsenic,  distribution  of,  in  body,  SOS. 

—  effect   of,  on  acid-base  equilibrium, 
754. 

on  body  temperature,  765, 

on  ferments,  755. 

on  metabolism,  753. 

carbohydrate,  754. 

nitrogen,  754. 

total,  754. 

V  ater,  755. 

on  uric  acid  excretion,  754. 

Arsenic  waters,  effects  of,  851. 
Arthritis,    chronic,    treatment    of,    by 

radium,  SS6. 
-  rheumatoid,  treatment  of,  by  x-rays, 

886. 
Artificial    methods    of   feeding.      See 

Feeding,  artificial  methods  of. 
Ash,  in  the  brain,  471. 

—  in  diet,  amount  of,'  required,  394. 

—  in    diets,   ordinary   constituents   of, 
396. 

—  in  the  feces,  510. 

—  in  milk,  478,  479. 

—  minimum  of  constituents  of,  411. 


916 


TXDEX 


Ash,  relation  of  constituents  of,  to  one 

another,  413. 
Aspartic  acid,  86,  110, 
Asphyxial  glycosuria,  740. 
Aspliyxiants,  effects  of,  on  metabolism, 

740. 

asphyxial  glycosuria,  740. 

blood  poisons,  744. 

carbon  dioxid,  741. 

carbon  nionoxid,  742. 

cyanids,  745. 

Asymmetry,  218. 

Atoms,  relation  of,  to  one  another  in 

the  molecule,  Pasteur,  219. 
Atophan,  effect  of,  on  metabolism,  772. 
Atropin,  effect  of,  on  metabolism,  774. 
Atwater  and  Benedict's  apparatus  for 

measuring      respiratory       exchange, 

524. 
Atwater     and    Rosa's     apparatus     for 

measuring  respiratory  exchange,  518. 

Bacillary     dysentery,     treatment     of, 

buttermilk,  709. 

lactose-protein,  709. 

Bacteria,    analogy    between    metabolic 

waste  products  of  man  and,  C75. 

—  classification  of,  parasitic,  6G6. 
pathogenic,  667. 

saprophytic,  666. 

—  cycles  of,  667. 

—  decomposition  of  proteins  by,  of 
tryptophan,  682. 

of  tyrosin,  681. 

—  differentiation  from  majority  of 
plants  and  animals,  665. 

—  endotoxins  of,  677. 

—  —  evolution  of,  from  one  type  to  an- 

other, 668. 

—  in  the  feces,  504. 

—  intestinal,  of  normal  nurslings,  ef- 
fects of  sugar  upon  intestinal  flora, 
experimental  evidence,  694. 

relation  between  diet  and  micro- 

bic  response,  691. 

—  living  chemical  reagents,  668. 

—  pathogenic,  specificity  of  action  of, 
and  its  relation  to  proteins  and  car- 
bohydrates, 673.^ 

—  phases  in  life  history  of,  665. 

—  rate  of  increase  among,  665. 
Bacterial  action,  specificity  of,  668. 

—  ultimate  chemistry  of,  668. 
Bacterial  cells,  665. 

—  cytoplasm  of,  679. 

—  elementary  composition  of,  674. 

—  relations  between  surface  and  vol- 
ume of,  666. 


Bacterial  metabolism,  chemical  require- 
ments for  bacterial  development, 
668. 

energy,  669. 

structural,  669. 

—  chemistry  of,  678. 

decomposition       of      trv-ptophan, 

682. 

decomposition  of  tyrosin,  681. 

phases  of,  678. 

anabolic  or  structural,  678. 

ketabolic,  678. 

— ; — reactions,  effects  of  utilizable 
carbohydrates  on  formation  of  phe- 
nols, indol  and  amins,  685. 

formation     of    phenols,     indol 

and  indican,  amins,  680. 

illustrative    of    decomposition 

of  proteins  by  bacteria,  681. 

physiological  action  of  aro- 
matic amins,  687. 

—  general  nature  of  products  of  bac- 
terial growth,  arising  from  utiliza- 
tion of  proteins  and  of  carbohy- 
drates for  energy,  diphtheria  toxin, 
669. 

indol  formation,  670. 

protein-liquefying  enzymes,  for- 
mation of,  670. 

—  general  relations  between  surface 
and  volume  of  bacteria  and  the  gen- 
eral energy  requirements  of  bacteria, 
665. 

—  influence  on,  of  saprophytism,  para- 
sitism and  pathogenism,  666. 

—  intestinal  bacteriology,  690. 
adolesceni  and  adult,  696. 

exogenous    intestinal    infections, 

706. 

of  normal  nurslings,  691. 

sour  milk  therapy  and,  700. 

—  nitrogenous,  illustrative  data,  676. 

—  quantitative  measures  of,  674. 

—  significance  of,  663. 

—  sour  milk  therapy  and,  700. 

—  specificity  of  action  of  pathogenic 
bacteria  and  its  relation  to  proteins 
and  carbohydrates,  673. 

Bacterial  nutrition,  672. 

Bacterial  toxins,  complex  nitrogenous, 

composition  of,  679. 
Bacteriology,  intestinal,  adolescent  and 

adult,  696. 
exogenous    intestinal    infections, 

bromatherapy,  706. 
general  history  and  development, 

690. 
of  normal  nurslings,  691. 


IXDEX 


917 


Bacteriology,  intestinal,  of  normal 
nursling,  effects  of  sugars  upon  in- 
testinal flora,  experimental  evidence 
of,  (11*4. 

relation  between  diet  and   mi- 

crobic  response,  6t)l. 

sour  milk  therapy  and  intestinal 

metal )olism,  700. 

Bag  method  of  Kegnard,  for  measuring 
respiratory  exchange,  537. 

Barium,  in  intravenous  infusion,  SOO. 

Barral  (1819-1884),  experiments  of,  on 
metabolism  of  human  beings,  38. 

Basal  metabolic  rate,  determination  of, 
Boothby  and  Sandiford,  611. 

Basal  metabolism,  C07. 

—  in  anemia,  822. 

—  of  cliildren,  up  to  puberty,  649. 

awake  and  sleeping,  table,  G58. 

of    fat    and    thin    boys,    table, 

658. 

influence  on,  of  muscular  ac- 
tivity, 654. 

of  sex,  652. 

influence  on,  of  puberty,  654. 

—  comparison  of,  per  kgm.  and  per  sq. 
meter,  of  surface,  table,  610. 

Basal  metabolism,  of  infant,  new-born, 
632. 

influence  on,  of  crying,  637. 

of  food  and  external  tem- 
perature, 638. 

of  sex,  635. 

from   two  weeks  to   one  year  of 

age,  642. 

influence  on,  of  age,  646. 

—  influence  on,  of  age,  612. 

— ^  —  of  blood  transfusion,  828. 

of  physical  characteristics,  608. 

of  radiation,  883. 

of  sex,  614. 

Basedow's    disease,    treatment    of,    by 

roentgen  rays,  887. 
Baths,  cold,  and  cold  douches,  863. 

effects  of,  856. 

extra  energy,  858. 

fever  reduction,  856. 

on   heat  production,   Ignatow- 

ski,  857. 

Lusk,  858. 

—  Matthes,  857. 

Buhner,  858. 

redistribution  of  blood,  859. 

refreshing,  860. 

friction  in,  863. 

—  effervescent,  865. 

—  hot,  effects  of,  on  metabolism,  860, 
861. 


Baths,  hot,  effects  of,  on  oxygen  con- 

sumption,  860,  861. 
on   pulse  and  blood  pressure. 

862. 

on  respiratory  quotient,  861. 

on   temperature  of  body,  860, 

861. 
with  sand,  863. 

—  influence  of  mechanical  and  chemi- 
cal stimulation  accomi)anying,  862. 

—  mustard,  803. 

—  peat  and  mud,  867. 

—  radioactive,  867. 

—  salt,  effects  of,  863. 

on  blood  pressure,  865. 

on  metabolism,  863,  864. 

—  and  sweat  secretion,  867. 
Beeswax,  185. 

Benedict's  method  of  measuring  respir- 
atory exchange,  544. 

Benzoates,  effect  of,  on  metabolism, 
726. 

Benzol  poisoning,  blood  transfusion  in, 
832. 

Berthelot  (1827-1907),  work  of,  on  me- 
tabolism, 77. 

Berzelins  (1779-1848),  experiments  of, 
in  history  of  metabolism,  33. 

Bidder,  F.  W.  (1810-1894)  and 
Schmidt,  C.  (born  1822),  combined 
work  of,  on  metabolism,  57. 

basal  metabolism  described  by,  CO. 

bile,  excretion  of,  in  relation  to 

the  total  ingesta  and  excreta  of  body, 
.58. 

carbon  metabolism,  61. 

respiratory  quotient,  63. 

total  metabolism  computed  by,  60. 

"typical  food  minimum"  of,  63. 

weight  of  feces  following  meat  in- 
gestion, 58. 

Bile,  absorption  of,  49. 

—  character  of,  464. 

—  considered  as  both  a  secretion  and 
excretion,  464. 

—  constituents  of,  465. 
table  of,  465. 

—  digestive  action  of.  in  making  mate- 
rials more  fluid,  59. 

—  excretion  of,  its  relation  to  total 
ingesta  and  excreta  of  body,  58. 

—  as  factor  in  fat  digestion  and  absorp- 
tion, 198. 

—  function  of,  464. 

—  pigments  of,  465. 

—  urobilin  in,  165. 

clinical  significance  of  increased 

elimination  of,  168. 


018 


IXDEX 


Bile,  urobilin  in,  determination  of,  167. 

diagnostic  value  of,  169. 

Bile  salts,  Pettenkofer  reaction  for,  65. 

Biliary  calculi  or  gallstones,  couiposi- 
tion  and  character  of,  466. 

Bilirubin,  structural  formula  of,  163. 

Bitter  waters,  effect  of,  on  gastric  se- 
cretion, 850. 

Biuret  reaction  of  proteins,  96. 

Black  (1728-1799),  on  carbonic  acid 
gas,  or  "fixed  air,"  15. 

Blood,  acetone  bodies  in,  449. 

—  action  on,  of  light,  892. 

—  amino-acids  of,  442. 

—  ammonia  in,  442. 

—  amount  of,  per  kilogram  of  body 
weight,  effect  on,  of  temperature  and 
humidity,  901. 

—  as  a  body  fluid,  788. 

—  calcium  in,  321. 

during  pregnancy,  and  lactation, 

322. 

—  coagulation  of,  effect  on  factors  of, 
of  blood  transfusion,  825. 

—  composition  of,  423. 

—  —  table  of  425. 

—  creatin  of,  441. 

—  creatin  metabolism,  175. 

—  creatinin  of,  440. 

—  creatinin  metabolism  in,  177. 

—  diastatic  activity  of,  method  of  esti- 
mating, 445. 

—  effect  on,  of  roentgen  rays  and  radio- 
active substances,  875. 

—  fat  in,  alimentary  lipemia,  201.     . 
lipoids,  204. 

—  fat  in,  of  amino  acids,  104. 

—  fibrinogen  in,  429. 

—  gas  constituents  of,  in  history  of 
metabolism,  33. 

—  hemoglobin  of,  429. 

character  and  functions,  429. 

estimation  of,  429,  431. 

in  normal  males  and  females  dur- 
ing different  age  periods,  table  of, 
430. 

in  normal  and  pathological  sub- 
jects, table,  430. 

—  hydrogen  ion  concentration  of,  427. 

■ —  mineral  constituents  of,  calcium, 
450. 

chlorids,  451. 

iron,  451. 

magnesium,  451. 

phosphates,  453. 

potassium,  4.50. 

— ^  —  sodium,  450. 
sulphates,  454. 


Blood,  mineral  constituents  of,  table 
of,  307. 

—  nitrogen  of,  rest,  442. 

effect    on,    of    blood    transfusion, 

823. 

—  reaction  and  hydrogen  ion  concen- 
tration, 427. 

—  redistribution  of,  by  cold  baths, 
859. 

—  rest  nitrogen  of,  442. 

—  significance  of,  423. 

—  sodium  chlorid  in,  314. 

—  specific  gravity  of,  427. 

—  total  solids  in,  426. 

—  transfusion  of,  in  hemorrhage,  790. 
reactions  in,  800. 

—  water  content  of,  311. 

Blood  adaptive  changes  to  high  alti- 
tude, 908. 

Blood  cells,  431. 

Blood-forming  organs,  effect  on,  of 
roentgen  rays  and  radio-active  sub- 
stances, 875. 

Blood   gases,  454. 

—  carbon  dioxid,  457. 
acidosis,  458. 

—  effect  on,  of  carbon  monoxid,  742. 

—  oxygen,  455. 

content  of,  455. 

arterial,  456. 

in  pathological  conditions,  456, 

457. 
Blood  groups,  835. 
Blood    lipoids,    abnormalities    in,    and 

anemia,  446. 

—  characteristic  feature  of  pathologi- 
cal conditions,  446, 

—  cholesterol,  448. 

percentage    of,     in    normal    and 

pathological  conditions,  table,  448. 

—  content  of,  in  normal  and  pathologi- 
cal bloods,  Bloor's  table,  447. 

—  in  diabetes,  446. 

—  and  fat  metabolism,  445. 

—  fats  comprised  in,  445. 

—  lecithin,  448. 

—  in  nephritis,  446. 

—  study  of,  during  fat  assimilation, 
445. 

—  total  fat  (plasma  lipoids),  448. 
Blood  nitrogen,  non-protein,  432. 
urea,  435. 

—  total,  432. 

—  urea,  435. 

—  uric  acid,  437. 

Blood  poisons,   effects   of,   on   metabo- 
lism, acid-base  equilibrium,  744. 
carbohydrate  metabolism,  744. 


IXDEX 


919 


Blood  poisons,  effects  of,  on  metabolism, 
carbon  clioxid.  See  Carbon  Dioxid. 

carbon  monoxid.     See  Carbon 

Monoxid. 

chlorid  excretion,  745. 

methemoglobinemia,  744. 

protein  metabolism,  744. 

synthesis,  745. 

Blood  pressure,  effect  on,  of  hot  baths, 
862. 

—  —  of  salt  baths,  865. 

—  influence  on,  of  water,  291. 
Blood  proteins,  427. 

Blood  regeneration,  effect  on,  of  blood 
transfusion,  826, 

Blood  serum  proteins,  428. 

Blood  sugar,  250. 

— -concentration  of,  effect  on,  of  tem- 
perature and  humidity,  901. 

—  glucose,  absorption  of,  250. 
behavior  of,  253. 

concentration  of,  250. 

conversion  of,  into  fat,  251. 

oxidation  of,  251. 

—  history  of,  443. 

—  hyperglycemia  and  hypoglycemia, 
444. 

—  influence  on,  of  adrenalin,  258. 

—  normal  threshold  of  sugar  excretion, 
444. 

—  percentage  of,  in  normal  blood, 
443. 

—  relation  between  calcium  and,  338. 

—  in  salt  glycosuria,  722. 

Blood    sugar   curves    of    normal    indi- 
viduals, table  of,  256. 
Blood  transfusion,  amount  of,  834. 
Blood  transfusion,  in  anemia,  821. 

—  beneficial  effects  of,  823. 

upon  basal  and  nitrogen  metabo- 
lism, 828. 

upon  blood  regeneration,  826. 

on  blood  volume,  825. 

■ upon  factors  of  coagulation,  825. 

upon  immune  bodies,  828. 

upon   oxygen    capacity   of  blood, 

823. 

symptomatic,  829. 

—  choice  of  donor  for,  blood  groups, 
835. 

compatibility,  835. 

general,  835. 

—  indications  for,  830. 
as  desirable,  831. 

in    anemia    from    blood    loss, 

S:J2. 

in  anemia  before  operation,  833. 

in  benzol  poisoning,  832. 


Blood  transfusion,  indications  for,  in 
anemia  before  operation,  in  carbon 
monoxid  poisoning,  833. 

in   chronic  hemolytic  anemia. 

832. 

in   idiopathic  aplastic  anemia, 

832. 

in  idiopathic  purpura  hemor- 
rhagica, 833. 

in  nitrobenzene  poisoning,  833. 

in  other  forms  of  chronic  ane- 
mia, 832. 

in   pernicious  anemia,  831. 

in  sepsis  and  toxemias,  833. 

as  necessary,  hemorrhage,  830. 

—■- shock,  830. 

—  introduction  to,  821. 

—  methods  of,  842. 

—  reactions  from,  839. 

associated     with     instability     of 

blood  when  removed  from  body,  840. 

due  to  recognized  incompatibility, 

839. 

not  due  to  recognized  incompati- 
bility, 840. 

that  resemble  those  due  to  recog- 
nized iso-hemolysis,  840. 

Blood  volume,  425. 

—  effect  on,  of  blood  transfusion,  825. 

—  influence  on,  of  water,  291. 
Boerhaave  (1668-1738),  on  air,  on  his- 

torj'  of  metabolism,  11. 

Bone  deficiency,  calcium  in,  disease  of, 
727. 

Bones,  magnesium  in,  323. 

Boracic  acid,  effect  of,  on  metabolism, 
740. 

Borax,  effect  of,  on  metabolism,  740. 

Boussingault  (1802-1887),  experiments 
of,  on  calorimetry,  37. 

^-oxidation,  in  fat  metabolism,  208. 

Boyle,  Robert,  (1621-1679),  in  history 
of  metabolism,  8. 

Brain,  changes  in  composition  of,  dur- 
ing growth,  468. 

—  constituents  of,  solid,  467. 

cerebrosids,  470. 

cholesterol,  470. 

diamino  -  monophosphatids, 

amidomyelin,  470. 

sphingomyelin,  470. 

extractives,  471. 

lipoids,  467. 

monominophosphatids,  myelin, 

470. 

para  my  el  in,  470. 

phosphatids,  468. 

cephalin,  468,  469. 


920 


IXDEX 


Brain,  constituents  of,  solid,  phos- 
phatid3,  lecithin,  468,  469. 

proteins,  467. 

relative  proportion  of,  at  dif- 
ferent ages  in  albino  rate,  table,  469. 

siiiphatids,  470. 

table  of,^468. 

—  weight  of,  467. 
Bromatherapy,  706. 

Bromids,  effect  of,  on  metabolism,  724. 

Cadaverin,  685. 

Calcium,  adult  normal  requirement  for, 
317. 

—  of  the  blood,  321,  450. 

during  pregnancy  and  lactation, 

322. 

—  in  diseases  of  bone  deficiency,  727. 

—  effect  of,  on  absorption,  318. 
on  body  temperature,  730. 

on  carbohydrate  metabolism,  731. 

on  growth  and  reproduction,  732. 

on  mineral  metabolism,  726. 

calcium  in  diseases  of  bone  de- 
ficiency, 727. 

calcium  deprivation,  727. 

in  leprosy,  728. 

in  tetany,  728. 

on  purin  metabolism,  732. 

on  water  metabolism,  730. 

—  in  the  feces,  511. 

—  in  the  food,  317. 

—  in  leprosy,  728. 

—  relation  between  blood  sugar  and, 
338. 

—  solution  of,  in  intravenous  infusion, 
800. 

—  in  tetany,  728. 

—  in  the  urine,  503. 

—  in  urine  and  feces,  316. 
Calcium  deprivation,  727. 
Calcium  equilibrium,  318. 

Caloric  value  of  meat,  von  Liebig,  49. 
Calorific  requirements  of  body,  intra- 

Acnous  injections  of  fluids  to  assist 

in  providing  for,  795. 

glucose,  795. 

Calorimeters,  control  tests  of,  578. 

alcohol  check,  580. 

heat  check,  578. 

—  forms  of,  570. 

bath      calorimeter      of     Lefevre, 

572. 

compensation  calorimeter,  of  Le- 
fevre, 572. 

depending   on   warming   of   fixed 

quantity  of  water,  Dulong  and  Lau- 
lanie,  570,  571. 


Calorimeters,     forms     of,     distillation 

calorimeter  of  d'Arsonval,  570. 

obsolete,  571. 

emission      calorimeters,      anemo- 

calorimeter  of  d'Arsonval,  581. 
respiration     calorimeter     of 

Rubner,  582. 
siphon   calorimeter   of  Richet, 

582. 

ice  calorimeter  of  Lavoisier,  570. 

obsolete,  571 . 

respiration     calorimeter     of    At- 

water-Rosa-Benediet,  573. 
— -for   measuring   heat   production    of 

man,  constructed  by  Voit,  75. 
Calorimetry,  alimentary,  554. 

—  animal,  570. 

computations  of,  foundations  of, 

laid  by  Rubner,  75. 

conservation  of,  Lavoisier,  23. 

Crawford's    experiments    on,    in 

historj.'  of  metabolism,  17. 

direct,  570. 

forms  of,  570. 

—  basic  principles  of  energy  metabo- 
lism, basal  metabolism.  See  Basal 
Metabolism. 

conservation  of  energy  in  the  ani- 
mal organism,  584. 

determination  in  part  by  environ- 
ing temperature,  593. 

heat  production  as  affected  by 

external  temperature,  601. 

energy  of  muscular  work  defi- 
nitely related  to  potential  energy  of 
food,  586. 

indigestion  of  food  increased  the 

metabolism,  604. 

—  beginnings  of,  34. 

—  Berthelot's  obser\^ations  on,  77. 

—  direct,  76,  567. 
animal,  570. 

heat  of  combustion,  568. 

—  direct  and  indirect,  heat  production 
of  dogs  by,  584. 

heat  production  of  human  sub- 
jects by,  585. 

—  experiments  on,  of  Barral  (1819- 
1884),  38,  39. 

of  Boussingault  (1802-1887),  37. 

of  Despretz  (1792-1863),  34. 

of  Dulong  (1785-1838),  35. 

of  Dumas  (1800-1884),  36. 

of  Magendie  (1783-1855),  37. 

of  Regnault  and  Reiset,  40-44. 

—  factors  determining  level  of  energy 
metabolism,  607. 

—  how  heat  is  lost  from  body,  593. 


INDEX 


921 


and  alkalies,  737. 
general,    cliloro- 


Calorimetry,  indirect,  76. 
advantagres  of,  515. 

—  von  Liobigr's  observations  on,  46. 
methods  of  calculating:  the  heat 

production  from  respiratory  ex- 
change. See  Respiratory  Exchange. 
methods  of  measuring  the  respir- 
atory exchange.  See  Respiratoiy 
Exchange. 

—  Richet's  observations  on,  77. 

—  —  surface  area,  law  of,  594. 

criticism  of,  597. 

measurement  of,  595. 

relation  of,  to  body  weight,  598. 

Camphor,  effect  of,  on  metabolism,  776. 
Caprin,  of  the  brain,  471. 
Carbohydrate    metabolism,    absorption, 

249. 
sugar  of  the  blood,  250. 

—  antiketogenesis,  271. 

—  digestion,  248. 

action  of  ptyalin,  248. 

gastric,  249. 

intestinal,  249. 

salivary,  248. 

—  effect  on,  of  acids 

of  alcohol,  764. 

of    anesthetics, 

form  and  ether,  761. 

of  antipyretics,  770. 

of  arsenic,  754. 

of  atropin,  pilocarpin,  etc.,  774. 

of  blood  poisons,  744. 

of  calcium,  731. 

of  carbon  monoxid,  743. 

of  cocain,  777. 

of  cyanids,  748. 

of  epinephrin,  781. 

of  mercury,  756. 

of  opiates,  766. 

of  phlorizin,  759. 

of  phosphorus,  749. 

of  pituitary  substances,  785. 

of  purins,  780. 

of  roentgen  rays  and  radioactive 

substances,  883. 

of  saline  cathartics,  719. 

of  strychnine,  775. 

of  thyroid  gland  substances,  783. 

of  uranium,  757. 

—  endocrin  and  nerve  control  of  gly- 
cogenosis, glycogenolysis  and  glu- 
colysis,  257. 

adrenals,  257. 

pancreas,  258. 

pituitary,  261. 

sympathetic  nervous  system,  257. 

thyroid,  260. 


Carbohydrate  metabolism,  fat  forma- 
tion, 268. 

—  functions  of  carbohydrates  in  diet, 
271. 

—  influence  of  carbohydrates  on  inter- 
mediary metabolism  of  fat,  271. 

—  intermediary,  261. 

—  introduction  to,  213. 

—  of  rectal  feeding,  811. 

—  tolerance,  254. 

glucolysis  and,  256. 

—  - —  glycogenesis  and,  255. 

standard  of,  255. 

Carbohydrate  minimum,  411. 
Carbohydrate    residues,    in   the   urine, 

508. 
Carbohydrate  tolerance,  254. 

—  glucolysis  and,  256. 

—  glycogenesis  and,  255. 

—  standard  of,  255. 
Carbohydrates,   chemical  reactions  of, 

225. 

action  of  alkalies,  227. 

conversion  of  glucose  into  fruc- 
tose and  mannose,  231. 

conversion  of  a  higher  to  a  lower 

monosaccharose,  227. 

isolation,  234. 

isolation  of  glutose,  232. 

melting  points  of  hydrazones,  235. 

oxidation,  227. 

polymerization  (fildol  condensa- 
tion) of  simple  sugars  by  action  of 
dilute  alkali,  225. 

reactions  of  sugars  with  substi- 
tuted hydrazines,  232. 

reduction,  230. 

synthesis  of  higher  forms  from  a 

lower  monosaccharose,  226. 

—  chemistiy  of,  214. 

classification,  214,  216. 

constitution,  214. 

disaccharides,  243. 

fructose,  239. 

gelactose,  238. 

glucose,  214. 

glucosides,  235.    " 

methyl,  237. 

hexoses,  237. 

isomerism,    of    the    aldohexoses, 

222. 

and  asymmetry,  218. 

of  glucose,  221. 

mannose,  238. 

methyl  glucosides,  237. 

monosaecharids,  special  proper- 
ties, 237. 

mutarotatin,  221. 


922 


IjN^DEX 


Carbohydrates,  chemistry  of,  nomen- 
clature, 214. 

pentoses,  240. 

polysaccharides,  247. 

—  classification  of.  214.  216. 

—  constitution  of,  214. 
^ducose,  214,  215. 

—  conversion  of  glucose  into  fructose 
and  mannose,  231. 

—  disaccharides,  243. 

lactose,  245. 

formula  for,  244. 

maltose,  246. 

formula  for,  244. 

sucrose,  245. 

formula  for,  244. 

—  effects  of,  in  liver  poisoning,  689. 

—  fructose,  239. 

—  functions  of,  in  animal  world,  213. 
in  the  diet,  271. 

in  plant  world,  213. 

—  galactose,  238. 

—  general  nature  of  products  of  bac- 
terial growth,  arising  from  utiliza- 
tion of  proteins  and,  for  energy,  669. 

—  glucose,  214,  215. 

aldehydic      properties      of,      217, 

218. 

compounds  of,  215. 

conversion  of,  into  fructose  and 

mannose,  231. 

formulae  for,  214,  215,  217,  218. 

isomerism  of,  221. 

oxidation  of,  217. 

reduction  of,  215. 

specific  rotation  of  sugars,  table 

of,  225. 

—  glucosides,  235. 
methyl,  237. 

—  heat  value  of,  553. 

—  hexoses,  237. 

—  intravenous  feeding  of,  817. 

—  in  liver,  stored  in  form  of  glycogen, 
463. 

mannose,  238. 

—  methyl  glucosides,  237. 

—  moxiosaccharides,  Arabinose,  241. 
dioses,  242. 

fructose,  239. 

galactose,  238. 

glucosides,  235, 

hexoses,  237. 

mannose,  238. 

methyl  glucosides,  237. 

methyl  pentoses,  242. 

pentoses,  240. 

rhamnose,  242. 

d-ribose,  242. 


Carbohydrates,  monosaccharides,  special 
properties  of,  237. 

tetroses,  242. 

trioses,  242. 

—  - xylose,  241. 

—  nomenclature  of,  214. 

—  oxidation  of,  227. 

—  pentoses,  240. 

aldopentoses,  table  of,  241. 

1-Arabinose,  241. 

methyl,  242. 

d-ribose,  242. 

—  polysaccharides,  247. 

cellulose,  247. 

gums,  247. 

inulin,  247. 

starch,  247. 

—  reduction  of,  230. 

—  relation  to,  of  pathogenetic  bacteria, 
673. 

—  subcutaneous  feeding  of,  816. 

—  synthesis  of,  226. 

—  terminology  of,  213. 

—  thermal  quotient  for,  556. 

—  utilizable,  effects  of,  upon  formation 
of  phenols,  indol  and  amins,  685. 

upon       general       metabolism, 

674. 
Carbon,  and  hydrogen,   calculation   of 

heat  production  from  combustion  of, 

548. 
Carbon  dioxid,  in  the  blood,  457. 
acidosis,  458. 

—  conclusions  on,  of  Edwards,  32. 

—  effect  of,  on  metabolism,  741. 
acapnia,  741. 

Carbon  monoxid,  effect  of,  on  lactic 
acid  excretion,  743. 

on  metabolism,  742. 

blood  gases,  742. 

carbohydrates,  743. 

mineral  metabolism,  743. 

protein  metabolism,  743. 

total  metabolism,  742. 

Carbon  monoxid  poisoning,  blood  trans- 
fusion in,  833. 

Carbonated  waters,  effect  of,  on  gastric 
mucosa,  848. 

Carbonic  acid  gas.  Black  on,  15. 

—  first  discovery  of,  8. 

—  and  oxygen,  Spallanzani^s  experi- 
ments, 32. 

Carcinoma,   treatment  of,  by   radium, 

887. 
Carnosin,  in  muscle  tissue,  461. 
Cartilage,  466,  467. 
Catalase,  effect  on,  of  epinephrin,  781. 
of  purins,  780. 


INDEX 


923 


Cathartics,    effect    of,    on    metabolism, 

aloin,  719. 

saline,  T18. 

Cavendish    (1731-1810),    discovery    of 

water  by,  in  history  of  metabolism, 

15. 
Cell  proteins,  action  on,  of  light,  891. 
Cellular  fluid,  788. 
Cellulose,  247. 
Cephalins,  187. 

—  of  brain,  468,  469. 

Cereal  protein,  heat  value  of,  552. 
Cereals,  importance  of,  in  diet,  421. 

as  food,  365. 

Cerebrosids,  of  brain,  470. 
Cerebrospinal    fluid,    composition     of, 
metallic  elements,  473. 

mineral,  473. 

non-protein  nitrogen,  472. 

protein,  472. 

sugar,  473. 

table  of,  472. 

—  mineral  constituents  of,  chlorid, 
473. 

phosphates,  473. 

—  non-protein  nitrogen  of,  472. 

—  protein  content  of,  471. 
Cetin,  185. 

Chemical  development,  bacterial  re- 
quirements for,  668. 

energy,  669. 

structural,  669. 

Children,  basal  metabolism  of,  649. 

up  to  puberty,  awake  and  sleep- 
ing, table,  658. 

of  fat  and  thin  boys,  table,  658. 

influence  on,  of  muscular  ac- 
tivity, 654. 

influence  on,  of  puberty,  654. 

of  sex,  652. 

—  energy  metabolism  of,  up  to  pu- 
berty, 647. 

basal,  649. 

gaseous    exchange,    tables    of, 

648. 

—  gaseous  exchange  of,  648. 
Chittenden's    experiments,    on    protein 

minimum   and  optimum,  402. 
Chloral,  effect  of,  on  metabolism,  763. 
Chlorid  excretion,  in  carbon  monoxid 

poisoning,  745. 
Chlorids,  in  the  blood,  451. 
high,    pathological    conditions 

causing,  452. 

—  in  cerebrospinal  fluid,  473. 

—  in  the  feces,  511. 

—  in  sweat,  513. 

—  in  the  urine,  500. 


Chloroform,  effects  or,  on  metabolism. 

See  Anesthetics,  general. 
Chlorosis,   iron  waters  in,  therapeutic 

value  of,  851. 
Cholesterol,  448. 

—  of  brain,  470. 

—  in  human  milk,  478. 

—  of  the  liver,  463. 

—  percentage  of,  in  normal  and  patho- 
logical conditions,  448. 

Chondrosamine,  of  connective  tissue, 
467. 

Chondroitin,  466. 

Chondrosin,  466. 

Chromates,  effects  of,  on  metabolism, 
758. 

Cinchophen  (atophan),  effect  of,  on 
metabolism,  772. 

Circulatory  mechanism  and  high  alti- 
tude, 910. 

Circulatory  system,  effect  on,  of  tem- 
perature and  humidity,  900. 

Citrates,  effect  of,  on  metabolism,  726. 

Climate,  air  movement  and  winds, 
902. 

—  altitude,  blood  adaptive  change,  908. 

—  —  circulatory  mechanism,  9101. 

high,  dangers  of,  911. 

effects  of,  906. 

altitude  sickness,  907. 

and  metabolism,  910. 

process  of  acclimatization,  907. 

respiratory  adaptation  to,  908. 

—  comparative  value  of  good  hygiene 
and,  899. 

—  definition  of,  899. 

—  general  considerations  in  choice  of, 
905. 

—  influence  of,  899. 

on  food  consumption,  387. 

—  light,  effects  of,  903. 

—  physical  influences  causing  physio- 
logical changes,  899. 

—  temperature  and  humidity,  900. 
effect  of,  on  amount  of  blood  per 

kilogram  of  body  weight,  901. 
on  capacity  for  physical  work, 

901. 

on  circulatory  system,  900. 

on  concentration  of  sugar  in 

blood,  901. 

on  metabolism,  902. 

on  nasal  mucosa,  901. 

on  respiration,  901. 

radiation  and  conduction,  900. 

temperature  of  body  in  relation 

to,  900. 

—  variety  of,  905. 


924 


IKDEX 


Climatotherapy,    psychological    factor 

in,  904. 
Coagulation  of  proteins,  100. 
Cocain,  effect  of,  on  metabolism,  777. 
Cod  liver  oil,  as  vehicle  for  phosphorus, 

753. 
Cold  haths  and  cold  douches,  8G3. 

—  etlects  of,  S.jG. 

extra  energy,  858. 

and  fever  reduction,  857. 

on   heat   production,   Ignatowski, 

857. 

Lusk,  858. 

Matthes,  857. 

Kubner,  858. 

redistribution  of  blood,  859. 

refreshing,  860. 

—  -  friction  in,  863. 

Collagen,  of  connective  tissue,  466. 
Collecting    apparatus,    for    measuring 

respiratorj'  exchange,  534. 
Color  reaction  of  proteins,  96. 
Combustion,  of  alcohol,  300. 

—  of  carbon  and  hydrogen,  calculation 
of  heat  production  from,  548. 

—  heat  of,  in  calorimetry,  direct,  568. 

—  in    history    of    metabolism,    Boyle, 
Robert  (1621-1679),  8. 

Mayow,  John  (1640-1679),  9. 

Stahl      (1660 1734),      phlogiston 

theory  of,  11. 
Leonardo  da  Yinci,  6. 

—  of  organic  foodstuffs,  calculation  of 
heat  production  from,  549. 

Connective  tissues,  constituents  of,  466. 
table  of,  467. 

—  tyi>es  of,  466. 

Copper,  eifect  of,  on  metabolism,  758. 
Crawford      (1748-1795),      on      animal 

calorimetry,  17. 
Creatin,  administered,  fate  of,  179. 

—  of  the  blood,  441. 

—  of  the  brain,  471. 

—  crystals  of,  171. 

—  excretion    of,    after    menstruation, 
176. 

in  pregnancy,  176. 

—  isolation  of,  171. 

—  of  the  muscle,  493. 

origin  of  creatinin  of  the  urine, 

492.  493,  494. 

—  in  muscle  tissue,  460. 

—  origin  of,  173. 

—  oxidation    of,    successive    steps    of, 
172. 

—  preparation  of,  chemically,  172. 

—  resume  of,  179. 

—  transformed  into  creatinin,  171. 


Creatin,  of  the  urine,  493. 

and  arginin,  as  source  of,  494. 

excretion  of,  493,  494. 

Creatin  content   of  muscle  and  other 

tissues,  172. 
Creatin  metabolism,  in  blood,  175. 

—  muscle,  174. 

—  in  urine,  176. 

Creatinin,  administered,  fate  of,  179. 

—  of  the  blood,  amount  of,  in  normal 
individuals,  440. 

increase  of,  441. 

in    nephritis,    chronic,    table    of, 

439. 

—  creatin  transformed  into,  171. 

—  excretion  of,  clinical  significance  of, 
178. 

during  starvation,  178. 

relative,  in  men  and  women,  178. 

—  preparation  of,  chemically,  172. 

—  resume  of,  179. 

—  of  the  urine,  490. 
elimination   of,   490. 

origin  of,  in  creatin  of  the  mus- 
cle, 492,  493,  494. 
Creatinin  metabolism,  in  blood,  177. 

—  in  muscles,  177. 

—  in  urine,  177. 

Creatinuria,  accompanying  undernutri- 
tion, 177. 

—  after  menstruation,  176. 
Crop  failures  and  famine,  360. 
Crying,  influence  of,  on  basal  metabo- 
lism of  new-born,  637. 

Crj^stalline  structure,  Pasteur^s  studies 

on,  219. 
Cuorin,  186. 

Curare,  effect  of,  on  metabolism,  776. 
Cyanids,    effects    of,    on    metabolism, 

745. 
Cystein,  88,  111. 
Cystin,  88,  111. 
Cytosine,  137. 

—  and  uracil,  137. 

Davy,  Humphrey   (1778-1829),  oxygen 
obtained  from  arterial  blood  by,  31. 

—  "phosoxygcn"  of,  31. 
Decomposition,  enzymatic,  of  combined 

purins,  158. 

—  of  phenyl  alanin,  by  bacteria,  684. 

—  physiological,  of  nucleic  acid,  148. 

—  of  proteins  by  bacteria,  decomposi- 
tion of  tr^'ptophan,  682. 

decomposition  of  tyrosin,  681, 

Decomposition     products,     partial,     of 

thymus  nucleic  acid,  147. 
Denaturalization  of  proteins,  100. 


IXDEX 


925 


Dennstedt  and  Kumpf  s  table  of  min- 
eral constituents  of  different  organs, 
304. 

Dephlo listed  air,  16. 

J^espn^tz  (1792-1863),  experiments  of, 
on  calorimetry,  34. 

Dextro-ribose,  136. 

Dextrose,  administration  of,  in  intra- 
venous feeding,  818. 

rectal  feeding,  812. 

in  subcutaneous  feeding,  816. 

Diabetes,  alcohol  in,  301. 

—  alkali  therapy  in,  316,  734. 

—  blood  lipoids  in,  446. 

—  effect  on,  of  opiates,  T66. 

—  hyperglycemia  of,  444. 

—  threshold  of  sugar  excretion  in,  444. 
Diamino-monophosphatides,    of    brain, 

470. 

Diarrhea,  in  infants,  acidosis  accom- 
panying, alkaline  treatment  for,  735. 

Diet,  acid,  413. 

—  adequacy  of,  criteria  of,  361. 

—  cereals,  421. 

—  changes  of,  its  advantages,  408. 

—  conclusions  on,  of  Stark,  12. 

—  crop  failures  and  famine,  360. 

—  energy  content  of  food,  407. 

—  experiments  on,  of  Stark,  13,  14. 

—  functions  of  carbohydrates  in,  271. 
of  proteins  in,  121. 

—  of  infants,  artificial  feeding  with 
cow's  milk,  320. 

fat,  320. 

vegetable,  319. 

—  milk,  421. 

—  normal,  conclusions  on,  420. 
definition  of,  361. 

—  ordinary,  ash  constituents  of,  396. 

—  of  primitive  peoples,  359. 

—  protein,  question  of  optimum  versus 
minimum,  119. 

—  relation  between  microbic  response 
and,  in  normal  nurslings,  691. 

—  relative  importance  of  certain  foods, 
362. 

cereals,  365. 

meat,  363. 

— • per  capita  consumption  of,  ta- 
ble of,  364. 

—  value  of  flavor  in,  Voit,  74. 

—  value  of  protein  in,  408. 

—  vegetarian,  399. 

basal  metabolism  of,  400. 

— ■■  —  disadvantages  of,  400. 
Dietary-  constituent,  water  as,  275. 

drinkinsT  of,  with  meals,  280,  283, 

287,  288,  294.    • 


Dietary  constituent,  water  as,  influence 
on  metabolism  of  diminished  intake, 
279._ 

influence  on  metabolism  of  in- 
creased ingestion  of,  277. 

Dietary  studies,  according  to  weight 
and  age,  normal  and  below  normal, 
416. 

Symond's  table  of  basetl  on  ac- 
cepted applicants  for  life  insurance, 
419,  420. 

—  amount  and  nature  of  food  con- 
sumed in  different  countries,  370, 
371. 

—  carbohydrate  minimum,  411. 

—  changes  in  food  habits  within  recent 
times,  395. 

—  choice  of  factor  for  calculating  food 
consumed  per  man,  367. 

per  woman,   367. 

—  energy  content  and  bulk,  418. 

—  energy  requirements  for  children, 
367. 

—  of  entire  countries  and  cities,  371. 

tables,  Belgium,  372,  373. 

Denmark,  374,  375. 

Finland,  374,  375. 

France,   374,  375. 

Gennany,  376,  377. 

• Great  Britain,  378,  379. 

Greenland,  376,  377. 

India,  380,  381. 

Italy,  380,  381. 

Japan,  3S2,  383. 

Java,  380,  381. 

Russia,  382,  383. 

Sweden,  384,  385. 

Switzerland,  384,  385. 

United   States,   384,  385,  386, 

387. 

—  fat  minimum,  410. 

—  food  requirements,  amount  of  ash, 
394. 

amount  of  fat,  393. 

amount  of  protein,  392. 

—  importance  of  bread  and  flour,  418. 

—  influence  on  food  consumption  of 
climate  and  season,  387. 

of  economic  status,  391. 

-in  amount  of  protein,  392. 

of  work,  391. 

in  aniount  of  protein,  392. 

—  level  of  nutrition,  416. 

—  manner  of  conducting  and  of  calcu- 
lating results,  366. 

—  minimum  of  ash  constituents,  411. 
— •  Neumaim's   observations  on  himself 

of  reduced  war  diet,  chart,  417. 


920 


IiN^DEX 


Dietary  studies,  nitrogen  minimum, 
401. 

—  protein  minimum  and  optimum,  401. 
experiments    on,    of    Chittenden, 

402. 

of  Fisher,  405. 

of  McCay,  406. 

of  Neumann,  402. 

—  results  reported  as  food  consumed 
not  that  supposed  to  be  absorbed, 
3G9. 

—  scales  for  converting  food  recjuire- 
ment  of  women  and  children  into 
"man's  equivalents,"  368. 

—  undernutrition,  414,  415. 
war  edema,  415. 

—  war  time  foods,  in  Russia  and  Ger- 
many, 418. 

Digestion,  of  carbohydrates,  248. 

action  of  ptyalin,  248. 

gastric,  249. 

intestinal,  249. 

salivary,  248. 

—  in  fat  metabolism  in  the  intestines, 
193. 

of  stomach,  189. 

—  of  fats  in  the  intestines,  bile,  198. 
emulsification,  200. 

factors    in,   pancreatic    secretion, 

197. 

—  gastric,  influence  on,  of  water,  281. 

—  pancreatic,  influence  on,  of  water, 
289. 

—  of  the  protein,  101. 

—  s^livarj',  influence  on,  of  water,  281. 

—  of  vitamines,  347. 
Dioses,  242. 
Diphtheria  toxin,  669. 
Disaccharides,  243. 

—  lactose,  245. 

formula  for,  244. 

—  maltose,  246. 
formula  for,  244. 

—  sucrose,   245. 

formula  for,  244. 

Distilled  water,  292. 

Diuretic   property   of   mineral   waters, 

847. 
Drugs,  epinephrinemia  due  to,  782. 

—  theory  of  reduction  of  fever  by, 
771. 

Dulong  (1785-183S),  experiments  of,  on 

calorimetry,  35. 
Dumas  (1800-1884),  experiments  of,  on 

calorimetry,  36. 
Duodenal  contents,  urobilin  in,  165. 

clinical  significance  of,  168. 

determination  of,  167. 


Duodenal  feeding,  Einhorn's  routine, 
80S. 

—  indications  for,  807. 

—  metabolism  of,  807. 

—  method  of  introducing  duodenal 
tube,  807. 

Dynamic  action,  of  foods,  in  infants 
from  two  weeks  to  one  year  of  age, 
643. 

Economic  status,  influence  of,  on  food 

consumption,  391. 
Edema,  as  a  water  retention,  311. 

—  war,  or  hunger,  415. 

Edwards,  William  F.  (1776-1842),  car- 
bon dioxid,  his  conclusions  on,  32. 

Efl^ervescent  baths,  865. 

Eggs,  in  rectal  feeding,  813. 

Einhorn's   duodenal   feeding,   808. 

Elastin,  of  connective  tissue.  466. 

Electricity,  contraction  of  muscles  by, 
894. 

—  effects  of,  on  body,  894,  895. 

—  stimulation  of  nen^es  by,  894. 

—  as  a  therapeutic  agent,  894. 

—  use  of,  in.  pathological  condition, 
895. 

Electrolysis,  salting  out  of  proteins  by, 
99. 

Embryonic  growth,  and  energy  metabo- 
lism, 616. 

Endocrin  drugs,  effect  of,  on  metabo- 
lism, epinephrin,  780, 

thyroid  gland  substance,  782. 

Endocrin  glands,  and  mineral  metabo- 
lism, 336. 

Endocrin  and  ner\'e  control  of  glyco 
genesis,  glycogenolysis  and  glucoly- 
sis,  257. 

Energy,  effect  on,  of  temperature  and 
humidity,  901. 

—  extra,  called  out  by  cold  baths,  858. 

—  general  nature  of  products  of  bac- 
terial growth,  arising  from  utiliza- 
tion of  proteins  and  carbohvdrates 
for,  669. 

—  measurement  of,  Zuntz,  77. 
Energy     chemical     .requirements,     for 

bacterial  development,  669. 

Energy  content  of  food,  406. 

Energy  metabolism,  basic  principles  of, 
583. 

basal     metabolism.       See    Basal 

Metabolism. 

conservation  of  energy  in  the  ani- 
mal organism,  584. 

determination  in  part  by  environ- 
ing temperature,  593. 


IXDEX 


927 


Energy,  metabolism,  basic  principle  of, 
determination  in  part  by  environing 
temperature,  heat  production  as  af- 
fected by  external  temperature,  601. 

energy  of  muscular  work  defi- 
nitely related  to  potential  energy  of 
food,  586. 

ingestion  of  food  increases  me- 
tabolism, 604. 

—  calorimetry,  direct,  567.  See  also 
Calorimetry. 

indirect,  515.    See  also  Calorime- 

trj'. 

—  of  children,  up  to  piiberty,  647. 
basal,  649. 

gaseous    exchange,    tables    of, 

648. 

—  determined  in  part  by  environing 
temperature,  how  heat  is  lost  from 
body,  593. 

law  of  surface  area,  594. 

—  effect  on,  of  acids  and  alkalies,  736. 
of  saline  cathartics,  718. 

of  sodium  chlorid,  720. 

—  and  embryonic  growth,  616. 

—  factors  determining  level  of,  607. 

—  and  growth,  differences  between 
growth  and  maintenance,  615. 

embryonic,  616. 

post-embryonic,  619. 

—  of  infant,  new-born,  627. 

• of     parturition,     before     and 

after,  634. 

per  unit  of  body  surface,  633. 

respiratory  quotient,  627. 

See  also  Basal  Metabolism,  of 

infants. 

total  energy  requirement,  639. 

from   two   weks   to   one  year   of 

age,  640. 

basal,  642. 

dynamic    action    of   foods    in, 

643. 

influence  of  age  on  basal  me- 
tabolism, 646. 

respiratory  quotient,  640. 

—  mechanical  efficiency  of  muscular 
work,  586. 

—  methods  of  measuring  heat  produc- 
tion from  respiratory  exchange. 
See  Respiratory  Exchange. 

—  methods  of  measuring  respiratory 
exchange.  See  Respiratory  Exchange. 

—  normal  process  of,  515. 

—  of  old  age,  658. 

—  origin  of,  in  non-nitrogenous  food, 
586. 

—  and  post-embryonic  growth,  619. 


Energy  metabolism,  of  pregnancy,  621. 

comparison  of  energy  metabolism 

in  pregnant  and  non-piregnant  women, 
table,  625. 

relative   value    of   different    food 

stuffs  as  a  source  of  energy  in  mus- 
cular work,  590. 

—  -  surface  area,  law  of,  594. 

criticism  of,  597. 

measurement  of,  595. 

relation  of,  to  body  weight,  598. 

—  See  also  Muscular  Energj'. 
Energy    production,    von    Liebig's    ob- 
servations on,  47. 

Energy   relations,   Rubners   insistence 

on  importance  of,  76. 
Enzymatic  decomposition  of  combined 

Ijurins,  158. 
Enzymes,  action  on,  of  light,.  892. 

—  effect  on.  of  roentgen  rays  and  ra- 
dioactive substances,  878. 

—  -  protein-liquefying,  formation  of, 
670. 

Epinephrin,  •  effect  of,  on  metabolism, 
body  temperature,  781. 

carbohydrate,  781, 

catalase,  781. 

gj-owth,  782. 

mineral,  782. 

protein,  782. 

total,  780. 

-water,  781. 

Epinephrinemia,  due  to  drugs,  782. 

Ether,  effect  of,  on  rrietabolism.  See 
Anesthetics,  general. 

Ethereal  extract  in  the  urine,  508. 

Ethylenediamin,  effect  of,  on  metabo- 
lism, 773. 

Ethylhydrocuprein,  effect  of,  on  me- 
tabolism, 772. 

Excretion  of  alcohol,  298. 

~  of  fat,  210. 

—  of  iron,  328. 

—  of  nitrogen  in  urine,  405. 
— of  phosphorus,  326. 
Excretions,  feces.    See  Feces. 

—  mediums  for,  481. 

—  paths  for,  481. 

—  sweat,  512. 

—  Wprine.     See  Urine. 

Excretory  channel.s,  comparative  im- 
portance of  intestines  and  kidneys 
as,  511. 

Exogenous  intestinal  infections,  bro- 
matherapy.  706. 

Extractives,  of  brain,  471. 

—  of  muscles,  400. 

See  also  Muscles,  extractives  of. 


928 


IXDEX 


Famine  and  crop  failures,  360. 
Fasting,  metabolisni  during,  309. 

protein,  110,  117. 

Fat,  amount  of,  required  in  diet,  393. 

—  in  the  bluofl,  alimentary  lipemia, 
201. 

lipoids,-  204. 

—  conversion  into,  of  glucose,  251. 
of  starch,  Voit,  73. 

of  protein,  73. 

—  in  diet  of  itifants,  320. 

—  formation  of,  von  Liebig  on,  49.  . 
from  carltohydrate,  268. 

—  heat  value  of,  553. 

Fat  or  fatty  infiltration  of  liver,  463. 

Fat  excretion,  210. 

Fat  ingestion,  contents  of  feces  fol- 
lowing, 64. 

Fat  metabolism,  absorption,  in  the  in- 
testines, 194. 

factors  in,  197. 

paths  of,  196. 

from   the   intestine^s,   changes   in 

fats  during,  196. 

emulsification,  200. 

in  stonuK^h,  190. 

—  in  the  blood,  alimentary  lipemia, 
201. 

lipoids  of  the  blood,  204. 

—  digestion,  in  the  intestines,  193. 

emulsification,  200. 

factors  in,  197. 

—  • —  in  stomach,  189. 

—  effect  on,  of  alcohol,  765. 

of  anesthetics,  general,  chloro- 
form and  ether,  762. 

of  cocain,  777. 

of  mercury,  756. 

of  opiates,  766. 

of  phlorizin,  759. 

of  phosphorus,  748. 

of  saline  cathartics,  718. 

of  thyroid  gland  substance,  784. 

of  uranium,  75"^. 

—  excretion  of  fat,  210. 

—  intermediary,  influence  on,  of  carbo- 
hydrates, 271. 

absorption  of  fat,  194. 

changes  in  fats  during,  196. 

path?  of,  196. 

—  bile,  19h. 
digestion,  193. 

emulsiHcation     in     fat     digestion 

and  absorption,  200. 

factors  in  fat  digestion  and  ab- 
sorption, 197. 

lipases  of  intestinal  tract  and  di- 
gestion, 192. 


Fat  metabolism,  bile,  nature  of  food 
fat,  199. 

pancreatic  juice,  192. 

pancreatic  secretion,  197. 

passage  from  the  stomach,  191. 

sunnnary  of,  200. 

synthesis-  of  fats  during  absorp- 
tion from,  196. 

—  introduction  to,  183. 

—  later  stages  of,  /3-oxidation,  208. 

—  lipases  of  the  intestinal  tract  and 
digestion,  192. 

—  lipoids,  compound,  cephalins,  187. 

glycolipoids,  187. 

lecithins,  1S6. 

phospholipoids,  185. 

derived,  fatty  acids,  187. 

-sterols,  188. 

simple,  fats,  184. 

waxes,  185. 

—  liver  in,  207. 

—  passage  from  the  stomach  to  intes- 
tines, 191. 

—  of  rectal  feeding,  811. 

—  in  stomach,  absorption,  190. 
digestion,  199. 

—  synthesis  of  fat  during  absorption 
from  the  intestines,  196. 

—  in  the  tissues,  changes  in  fat,  206. 
storing  of  fat,  205. 

Fat  minimum,  410. 
Fat-soluble  vitamins,  345. 

—  sources  of,  346. 

Fats,  intravenous  feeding  of,  817. 

—  respiratory  quotient  of,  561. 

—  as  simple  lipoids,  184. 

—  in  subcutaneous  feeding,  815. 

—  thermal  quotient  for,  556. 

—  in  the  tissues,  changes  in,  206. 
storing  of,  205. 

—  total,  in  blood  lipoids,  448. 
Fatty  acids,  187. 

Feces,  amount  of,  normal,  505. 

—  calcium  in,  316. 

—  carbohydrate  residues  in,  508. 

—  color  of,  normal,  506. 

—  composition  of,  503. 
ash,  510. 

bacteria,  504. 

carbohydrate  residue,  508. 

ethereal  extracts,  508. 

nitrogen  content,  504. 

nitrogenous  substances,  507. 

in  pellagra,  daily  average,  table, 

509. 

—  consistency  of,  normal,  506. 

—  contents  of,  following  fat  ingestion, 
64. 


IXDEX 


929 


Feces,  ethereal  extracts  in,  508. 

—  formation  of,  von  Liehijjr,  49. 

—  nitrogen  content  of,  504, 

—  nitrogenous  substan*-*  s   in,  507. 

—  odor  of,  normal,  50G. 

—  a  true  secretion,  504. 

—  weight  of,  following  moat  ingestion, 
58. 

Feeding,  artificial  methods  of,  805. 

duodenal,  807. 

gavage,  806. 

intravenous,  817. 

rectal,  809. 

subcutaneous,  814. 

—  duodenal.    Seo  Duodenal  Feeding. 

—  intravenous.  See  Intravenous  Feed- 
ing. 

—  rectal.     See  Rectal  Feeding. 

—  subcutaneous.  See  Subcutaneous 
Feeding. 

Ferments,  eifect  on,  of  anesthetics, 
general,  chloroform  and  ether,  763. 

of  arsenic,  755. 

of  cyanids,  747. 

Fever,  effect  on,  of  antipyretics,  768. 

—  salt,  720. 

—  theory  of  reduction  of,  by  drugs,  771. 
Fevers,    disturbances    of    mineral    me- 
tabolism in,  336. 

Fibrinogen,  429. 

"Fire  air^'  of  Scheele,  17. 

Fisher's  experiments  on  protein  mini- 
mum and  optimum,  405. 

"Fixed  air,''  or  carbonic  acid  gas, 
Black  on,  in  history  of  metabolism, 
15. 

—  Lavoisier,  22. 

Fluids,  intravenous  injections  of,  in 
acidosis,  of  sodiumt  bicarbonate,  792. 

to    assist    in    providing    for    the 

calorific  requirements  of  the  body, 
795. 

glucose,  795. 

to  combat  toxemia,  794. 

for  dehydration  of  tissues,  792. 

fluids     used     for,     calcium     and 

barium,  800. 

gelatin  solutions,  791,  798. 

l?liicose  solutions,  795,  799. 

gum  acacia  or  gum-saline  solu- 
tions, 798. 

magnesium  sulphate,  800 

saline  solutions,  796. 

sodium   bicarbonate,   792,   793, 

799. 

in  hemorrhage,  700. 

blood,  790. 

^ substitutes  for  blood,  791. 


Fluids,  intravenous  injections  of,  to  in- 
crease l)uffcr  action  of  blood  in 
acidosis,  792. 

in  nephritis,  793. 

reaction  of  urine  in,  793. 

as  routine  measure  in  surgical 

procedures,  793. 

to  increase  volume  of  blood  and 

tissue  fluid,  780. 

introduction  to,  787. 

in  nephritis,  of  sodium  bicarbo- 
nate, 793. 

preparation  of  infusion  solutions 

and  tei'hnic  of  administration,  801. 

purposes  of,  789. 

reactions  due  to,  800. 

as    routine    measure    before    and 

after  surgical  procedures,  sodium  bi- 
carbonate, 793. 

of  sodium  bicarbonate,  in  acido- 
sis, 792. 

in  nephritis,  793. 

: reaction  of  urine  in,  793. 

as  routine  measure  before  and 

after  surgical  procedures,  793. 

solutions  used  for,  790. 

Fluids  of  the  bod.v,  bile.     See  Bile. 

—  blood,  788.    See  also  Blood. 

—  cellular,  788. 

—  conditions  depleting  to  store  of,  789. 

—  content  of,  787. 

—  intake  of,  789. 

—  loss  of,  789. 

—  lymphatic,  788. 

—  milk,  476. 

—  role  of,  787. 

—  saliva,  474. 

—  tissue,  788. 

—  variety  of  adjustments  to  local  con- 
ditions, 787. 

—  cerebrospinal,  471. 
Food,  calcium  in,  317. 

—  and  civilization,  359. 

—  crop  faili'.res  and  famine,  360. 

—  influence  of,  on  basal  metabolism  of 
newborn  infants,  638. 

—  —  on  composition  of  urine,  64. 

— ■  —  on  respiratory  quotient  of  new- 
born infant,  630. 

—  object  of,  121. 

—  potential  energy  of,  energy  of  mus- 
cular work  definitely  related  to,  586. 

—  and  progressive  civilization,  3. 

—  Voit's  definition  of,  74. 

Food  consumption,  influence  of  climate 

and  season  on,  387. 
of  economic  status,  391. 

—  —  of  work,  391. 


930 


INDEX 


Food  fat,  natare  of,  in  fat  metabo- 
lism, 199. 

Food  habits,  changes  in,  within  recent 
times,  395. 

Food  minimum,  typical,  of  Bidder  and 
Schmidt,  63. 

Foods,  acids,  or  acid-forming,  pro- 
longed administration  of,  334. 

—  distribution  of  vitamins  in,  346. 

—  dynamic  action  of,  in  infants  from 
two  weeks  to  one  year  of  age,  643. 

—  extract  of  meat,  v.  Liebig's,  his  de- 
fense of  the  use  of,  54,  55. 

—  oxidation  of,  various,  von  Liebig,  49. 

—  oxygen  requirement  for  combustion 
of,  von  Liebig,  50. 

—  relative  importance  of,  362. 
cereals,  365. 

meat,  363. 

per  capita  consumption  of,  ta- 
ble of,  364. 

—  used  in  gavage,  806. 

Foodstuffs,  classification  of,  Bischoff^s 
and  Voit'?  suggestions,  71. 

von  Liebig,  nitrogenous  or  plas- 
tic, 50. 

non-nitrogenous  or  respiratory, 

50. 
\i' —  combustion   of,   calculation   of  heat 
production  from,  549. 

—  heat  values  of,  cereal  protein,  652. 
-*•  heat  values  of,  fat  and  carbohydrate, 

553. 
lean  meat,  550. 

—  relative  value  of,  as  a  source  of 
energy  in  muscular  work,  590. 

Fructose,  239. 

—  conversion  of  glucose  into  mannose 
and,  231. 

Galactose,  238. 
Galen,  on  food,  5. 

Gallstones,  composition  and  character 
^  of,  466. 
Gaseous  exchange,  of  children,  up   to 

puberty,  648. 
Gaseous  metabolism,  effect  on,  of  hot 

baths,  861. 
Gases,  blood.    See  Blood  Gases. 
Gastric    digestion,    of    carbohydrates, 

249. 

—  influence  on,  of  water,  281. 
Gastric  lipase,  189,  190. 

Gastric  secretion,  effect  on,  of  alkaline- 
saline  waters,  848. 

of  alkaline  waters,  848. 

of  bitter  waters,  850. 

of  saline  waters,  846. 


Gastro-intestinal  canal,  protein  diges- 
tion in,  101. 

absorption,  103. 

schematic  illustration  of,  103. 

Gavage,  definition  of,  806. 

—  foods  used  in,  806. 

—  indications  for,  806. 

—  metabolism  in,  806. 

—  method  of  performing,  806. 

—  number  of  feedings  performed  in, 
807. 

Gay-Lussac  (1778-1850),  gas  constitu- 
ents of  blood  determined  by,  33. 

Gelatin,  as  a  substitute  for  blood  in 
intravenous  infusion  during  hemor- 
rhage, 791. 

Gelatin  solutions  for  intravenous  in- 
fusion, 791,  798. 

Globulin,  428. 

Globulins,  83. 

Glucolysis,  and  carbohydrate  tolerance, 
256. 

—  endocrin  and  nerve  control  of, 
adrenals,  257. 

pancreas,  258. 

pituitary,  261. 

sympathetic  nervous  system,  257. 

thyroid,  260. 

(ilucose,  administration  of,  in  intra- 
venous feeding,  818. 

—  aldehydic  properties  of,  217,  218. 

—  as  blood  sugar,  250. 

absorption  of,  250. 

behavior  of,  in  blood,  253. 

concentration  of,  250. 

conversion  of,  into  fat,  251. 

kidney  threshold  for  sugar,  253. 

oxidation  of,  251. 

—  compounds  of,  215. 

—  conversion  of,  into  fructose  and 
mannose,  231. 

—  formulae  for,  214,  215,  217,  218. 

—  isolation  of,  232. 

—  isomerism  of,  221. 

—  in  muscle  tissue,  460. 

—  oxidation  of,  217,  227,  228. 

—  reactions  of  sugars  with  substituted 
hydrazines,  232. 

—  reduction  of,  215. 

—  specific  rotation  of  sugars,  225. 

—  transformation  into  of  lactic  acid, 
108. 

Glucose  solutions,  for  intravenous  •  in- 
fusion, 795,  599. 

—  constituents  of,  236. 

—  definition  of,  235. 

—  formula  of,  235. 

—  hydrolysis  of,  236. 


INDEX 


931 


Glucose  solutions,  methyl,  237. 

—  preparation  of,  236. 

—  table  of,  236. 
Glucosuria,  253. 

—  renal,  253 

Glucuronic  acid,  of  connective  tissue, 

467. 
Glutamic  acid,  87,  110. 
Glutelins,  83. 
Glycocoll,  84,  107. 
Glycogen,  in  the  liver,  463. 

—  in  muscle  tissue,  460. 

—  storing  of,  by  liver,  251. 
Glycogenesis,   and   carbohydrate  toler- 
ance, 255. 

—  endocrin  and  nerve  control  of, 
adrenals,  257. 

pancreas,  258. 

pituitary,  261. 

sympathetic  nervous  system,  257. 

thyroid,  260.  ; 

Glycogenolysis,  endocrin  and  nerve 
control  of,  adrenals,  257. 

pancreas,  258. 

pituitary,  261. 

sympathetic  nervous  system,  257. 

thyroid,  260. 

Glycolipoids,  187. 
Glycosuria,  444. 

—  asphyxial,  740. 

—  salt,  722. 

Goiter,    treatment    and   prevention   of, 

by  iodin,  725. 
Gout,  treatment  of,  alkaline,  739. 
by  radium,  885. 

—  uric  acid  in,  438. 

Grafe's  apparatus  for  measuring  respir- 
ator;y'  exchange,  519. 

Growth,  embrj'onic,  and  energy  me- 
tabolism, 616. 

—  energy  metabolism  and  differences 
between  growth  and  maintenance, 
615. 

embryonic  growth,  ^'if^. 

—  metabolism  of,  effect  on,  of  alcohol, 
765. 

of  antipyretics,  769. 

of  calcium,  732. 

of  epinephrin,  782. 

of  purins,  780. 

of    thyroid    gland     substance, 

784. 
Guanase,  distribution  of,  156. 
Guanidin   bases,   effect   on,   of  purins, 

780. 
Guanine,  137,  138. 

—  in  muscle  tissue,  461. 
Guanylic  acid,  141,  142. 


Gum  acacia  or  gum-saline  solutions  for 
intravenous  infusion,  798. 

reactions  in,  800. 

Gums,  247. 


Ilaldane's  apparatus  for  measuring 
respiratory  exchange,  520. 

Hales,  Stephen  (1677-1761),  on  respira- 
tion and  blood,  in  history  of  metabo- 
lism, 11. 

Hanroit  and  Richet's  apparatus  for 
measuring  respiratory  exchange,  543. 

Heat,  animal,    ^ee  Calorimetry. 

—  of  combustion.     See  Calorimetry. 

—  lost  from  body,  manner  of,  593. 

—  surface  area  of,  law  of,  594. 

criticism  of,  597. 

measurement  of,  595. 

relation  of,  to  body  weight,  598. 

Heat  equivalent  of  CO2,  variation  in 

(Atwater  and  Benedict),  559. 
Heat  production,  actual,  554. 

—  as  effected  by  external  temperature, 
in  cold-blooded  animals,  Van't  Hoff^s 
law,  601. 

cooling  power  of  air  currents  at 

different  velocities,  604. 
in  warm-blooded  animals,  602. 

—  of  dogs  by  direct  and  indirect 
calorimetrj^  584. 

—  effect  on,  of  cocain,  777. 

of  cold  baths,  Ignatowski,  857. 

Lusk,  858. 

Matthes,  857. 

Rubner,  858. 

—  of  human  subjects,  by  direct  and  in- 
direct calorimetry,  585. 

—  increase  of,  by  indigestion  of  food, 
604.^ 

—  in  incubation  period  of  hens*  eggs, 
617. 

—  of  infants,  per  square  meter  of  body 
surface.  646. 

—  methods  of  calculating  from  respir- 
atory exchange,  548. 

alimentary  calorimetry,  554. 

combustion  of  carbon  and  h.vdro- 

gen,  548. 

combustion  of  organic  foodstuffs, 

549. 

non-protein  respiratory  quotient, 

566. 

respiratory  quotient  and  its  sig- 
nificance, 559. 

thermal  quotients  of  0»  and  COs, 

555. 

and  from  urinary  nitrogen,  563. 


932 


I^STDEX 


Heat  production,  methods  of  calculat- 
ing from  respiratory  exchange,  and 
from  urinary  nitrogen,  method  of 
successive  thermal  quotients,  563. 

method  of  Zimtz  and  Schum- 

berg,  565. 

Heat  radiation,  relation  of,  to  surface 
of  animal  body,  table,  610. 

Heat  value,  of  one  gram  of  different 
substances  in  large  calories,  571. 

Hemoglobin,  character  and  function  of, 
429. 

—  estimation  of,  429,  431. 

—  in  males  and  females  during  differ- 
ent age  periods,  table  of,  430. 

Hemoglobin  content  of  blood  in  nor- 
mal and  pathological  subjects,  430. 

Hemophilia,  typical  hereditary,  disturb- 
ances in  mineral  metabolism  in, 
336. 

Hemorrhage,  indications  for  blood 
transfusion  in,  830. 

—  intravenous  injection  of  fluids  for, 
790. 

Hexoses,  237. 
Hippocrates,  on  food,  4. 
Hippuric  acid,  of  urine,  498. 
Histamin,  action  of,  687. 

—  formation  of,  686. 
Histidin,  91,  114,  686. 
Histones,  83. 

Hopkins  and  Willcock^s  experiments, 
on  nitrogen  balance  and  incomplete 
proteins,  125,  126. 

Hoppe-Seyler's  apparatus  for  measur- 
ing respiratory  exchange,  522. 

Hot  baths,  effects  of,  on  metabolism, 
860,  861. 

on  oxygen  consumption,  860,  861. 

— ■  —  on  pulse  and  blood  pressure,  862. 

on  respiratory  quotient,  861. 

on  temperature  of  the  body,  860, 

861. 

—  sand,  863. 

Humidity.     See   Temperature  of  Air, 

and  humidity. 
Hydrazin,    effect    of,    on    metabolism, 

773. 
Hydrazones,  235. 

—  melting  point  of,  235. 

—  substituted,  reactions  of  sugars 
with,  232. 

Hydrogen,  and  carbon,  calculation  of 
heat  production  from  combustion  of, 
548. 

—  discovery  of,  15. 

Hydrotherapy,  baths  and  sweat  secre- 
tion, 867. 


Hydrotherapy,    cold    baths,    effects    of, 

856. 

extra  energy,  858. 

fever  reduction,   857. 

on   heat   production,   Ignatow- 

ski,  857. 

Lusk,  858. 

Matthe3\  857. 

Rubner,  858. 

redistribution  of  blood,  859. 

refreshing,  860. 

with  friction,  863. 

—  cold  douches,  863. 

—  effer\'escent  baths,  866. 

—  foundation  of,  in  functions  and  ac- 
tivity of  skin,  855, 

—  historical,  855. 

—  hot  baths,  effects  of,  on  metabolism, 
860,  861. 

on    oxygen    consumption,    860, 

861. 
on   pulse   and   blood   pressure, 

862. 

on  respiratory  quotient,  861. 

on   temperature  of   body,   860, 

861. 
with  sand,  863. 

—  influence  of  mechanical  and  chem- 
ical stimulation  accompanying  baths, 
862. 

—  mustard  baths,  863. 

—  peat  and  mud  baths,  867. 

—  radioactive  baths,   867. 

—  and  regulation  of  temperature  of 
body,  855. 

—  salt  baths,  effects  of,  863. 

on  blood  prossure,  865. 

on  metabolism,  863,  864.      . 

^-hydroxyglutamic  acid,  88,  110. 
Hyperglycemia,  253. 

—  conditions   causing,  444. 

—  of  diabetes,  444. 

Hypnotics,  effect  of,  on  metabolism,  of 
amylen  hydrate,  764. 

chloral,  763. 

paraldehyde,  764. 

sulphonal,  764. 

urethan,  764. 

Hypoglycemia,  conditions  causing,  444. 
Hypoxanthin,  137,  138. 

—  of  the  brain,  471. 

—  in  muscle  tissue,  461. 

Ice  water,  293. 

Immune    bodies,    effect    on,    of    blood 

transfusion,  828. 
Immunity,  effect  on,  of  roentgen  rays 

and  radioactive  substances,  876. 


IXDEX 


933 


Tncubation  period  of  hen's  eggs,  heat 

production  during,  617. 
Indican,  excretion  of,  684. 

—  formation  of,  680. 

indigestion    of    food,    metabolism    in- 
creased by,  604. 
Indol  acetic  acid,  684. 
ludol  ethylamin,  change  of,  688. 
Indol  formation,  670,  680,  68'?. 

—  effects    on,    of    iitilizable    carbohy- 
drates, 685. 

Tndol  toxemia,  683. 
Indol,  toxicity  of,  683. 
Infants,   acidosis   of   diarrheal    attacks 
in,  alkaline  treatment  for,  735. 

—  diet  of,  artificial  feeding  with  cows' 
milk,  320. 

fat,  320. 

vegetables,  319. 

—  feeding  of  vegetables  to,  319. 

—  heat-production  per  square  meter  of 
body  surface  for,  646. 

—  new-born,     basal      metabolism      of, 
632. 

influence  on,  of  crying,  637. 

of   food   and   external   tem-. 

perature,  638. 

of  sex,  635. 

energy  metabolism  of,  basal,  632. 

per  unit  of  body  surface,  633. 

respiratory  quotient,  627. 

total  energy  requirement,  639. 

intestinal   bacteria   of,   effects   of 

sugars  upon  intestinal  flora,  694. 
relation  between  diet  and  mi- 

crobic  response,  691. 

respiratory  quotient  of,  627. 

Bailey  and  Murlin,  628. 

Benedict  and  Talbot,  630. 

for  first  eight  days,  631. 

Hasselbach,  627. 

influence  of  food  on,  630. 

table,  629. 

—  two  days  of  age,  mineral  metabolism 
of,  636. 

—  from  two  weeks  to  one  year  of  age, 
basal  metabolism  of,  642. 

influence  on,  of  age,  646. 

dynamic  action  of  foods  in,  643. 

energy  metabolism  of.   640. 

basal,  642. 

dynamic    action    of    foods    in, 

643. 

respiratory  quotient,  640. 

Inflammable  air,  or  hydrogen,  23. 

—  discovery  of,  15. 
Inosinic  acid,  141. 
Inositol,  in  the  brain,  471. 


Inositol,  in  muscle  tissue,  460. 
"Insensible    perspiration"     and    food, 
Hippocrates  on,  4. 

—  Sanctorius  (1561-1636),  7. 
Intestinal  bacteriologj',  adolescent  and 

adult,  696. 

—  development  of,  C90. 

—  exogenous  intestinal  infections, 
bromatherapj',   706. 

—  general  histoiy  of,  690. 

—  of  normal  nurslings,  691. 

effects  of  sugars  upon  intestinal 

flora,  experimental  evidence  of,  GIM. 

relation    between    diet    and    mi- 

crobic  response,  691. 

—  sour  milk  therapy  and  intestinal 
metabolism,  TOO. 

Intestinal  digestion  of  carbohydrates, 
249. 

Intestinal  elimination  of  iron,  32S. 

Intestinal  flora  and  putrefaction,  in- 
fluence on,  of  water,  291. 

Intestinal  infections,  exogenous,  bro- 
matherapy,  706. 

Intestines,  comparative  importance  of 
kidneys  and,  as  excretory  channels, 
511. 

—  fat  metabolism  in,  absorption  of  fat, 
194. 

paths  of,  196. 

changes  in  fats  during,  196. 

digestion,  193. 

emulsification    in     fat    digestion 

and  absorption,  200. 

factors  in  absorption  and  diges- 
tion, bile,  198. 

pancreatic  secretion,  197. 

lipases  of,  192. 

pancreatic  Juice,  192. 

passage  from  stomach,  191. 

summary  of,  200. 

synthesis  of  fats  during  absorp- 
tion from,  196. 

Intravenous  feeding,  817. 

—  of  carbohydrates,  817. 

—  dangers  of,  817. 

—  of  fats,  817. 

—  indications  for,  817. 

—  of  proteins,  817. 

Intravenous    injection    of   fluids.     See 

Fluids. 
Inulin,  247. 

lodids,  effect  of,  on  metabolism,  724. 
lodin,  content  of,   in  thyroid   of  man 

and  animals,  332. 

—  effect  of,  on  metabolism,  724. 

—  lack  of,  in  food  and  drinking  water, 
333. 


934 


i:n^dex 


lodin,    treatment    and    prevention    of 

goiter  by,  725. 
lodin  compounds,  333. 
Ionic  substances,  important  role  of  in 

life  processes,  335. 
Iron,  effect  of,  on  metabolism,  755. 

—  in  human  body,  in  the  blood,  451. 
course  of,  327,  328. 

distribution  of,  326. 

excretion  of,  328. 

function  of,  326,  327. 

intestinal  elimination  of,  328, 

—  ^^—  in  liver,  463. 
metabolism  of,  329. 

urinary  elimination  of,  329. 

in  the  urine,  503. 

Iron-containing  foods,  327. 
Iron  metabolism,  329. 

—  role  of  spleen  in,  331. 
Iron  waters,  in  anemia,  851. 

—  in  chlorosis,  851. 

—  and  metabolism,  851. 
Iso-amylamin,  effect  of,  on  metabolism, 

773. 
Isodynamic  equivalents,  von  Liebig,  49. 
--  table  of,  50. 
Iso-leucin,  85,  109. 
Isomerism,  218. 

—  of  the  aldohexoses,  222. 

—  of  glucose,  221. 

Jaquet's   apparatus   for  measuring  re- 
spiratory exchange,  519. 

Kidney  secretion,  mechanism  of,  482. 
Kidney  threshold  for  sugar,  253. 
Kidneys,    comparative    importance    of 

intestines  and,  as  excretory  channels, 

511. 
Krogh's   apparatus   for   measuring 

spiratory  exchange,  531. 


re- 


Lactation,    calcium    in    blood    during, 

322. 
Lactic  acid,  in  the  brain,  471. 

—  excretion    of,    in    carbon    monoxid 
poisoning,  743. 

increased,    in    oxygen    deficiency, 

741. 

—  in  muscle  tissue,  460. 

—  transformation  of,  into  glucose,  108. 
Lactose,  245. 

—  feeding  of,  707. 

• —  formula  for,  244. 

—  hydrolysis  of,  708. 

—  methods  of  administration  of,  707. 
Lactose-protein  solutions,  feeding  with, 

709. 


Lanolin,  185. 

Lavoisier,  accurate  measuring  instru- 
ments of,  20,  21. 

—  "air  eminently  respirable"  of,  22. 

—  experiments  of,  animal  heat,  con- 
servation of,  23. 

on  nature  of  water,  19. 

respiration,  25, 

on  man,  25. 

-basic    facts    regarding    metab- 
olism, 25. 
respiratory  quotient,  22. 

—  history  of,  19. 

outside  his  laboratory,  28,  29. 

—  phlogiston  theory  of  combustion  de- 
molished by  (1783),  23. 

Lead,  effects  of,  on  metabolism,  758. 
Lecithin,  448. 

—  of  brain,  468,  469. 

—  in  the  liver,  463. 
Lecithins,  186. 

Lefevre,  Nicholas  (died  1674),  and  me- 
tabolism, 8. 
Leprosy,  calcium  in,  728. 

—  disturbances  in  mineral  metabolism 
in,  336. 

—  uric  acid  in,  437. 

increased  elimination  of,  498. 

Leucin,  85. 

—  of  the  brain,  471. 

—  fate  of,  109. 

Leukemia,  chronic  lymphatic,  treat- 
ment of,  by  x-rays  and  radium,  884. 

—  myeloid,  treated  by  x-rays,  884. 
Levulinic  acid,  240. 

V,    Liebig,    Justus,    activity    of   yeast 

cells  discussed  by,  54. 
V.  Liebig's  extract  of  meat,  v.  Liebig's 

defense  of  the  use  of,  54. 
Light,    action    of,   903. 

on  blood,  892. 

on  cell  proteins,  891. 

on  enzymes,  892. 

on  metabolism,  893. 

on  tissues  and  skin,  S91. 

—  chemical  changes  brought  about  by, 
891. 

—  rays  of,  890. 
effective,  891. 

—  as  a  therapeutic  agent,  890. 

—  waves  of,  890. 

Lime  metabolism,  in  infancy  and  child- 
hood, 318. 

Lipase,  gastric,  189,  190. 

Lipases,  of  intestinal  tract  and  diges- 
tion, 192. 

—  pancreatic,  192. 
Lipemia,  alimentary,  201. 


INDEX 


035 


Lipoids,  184. 

—  of  the  blood,  204.  See  also  Blood 
Lipoids. 

—  of  brain,  467. 

—  compound,  (-('phalins,  187. 

glycolipoids,   187. 

lecithins,  ISO. 

phospholipoids,    185. 

—  derived,  fatty  neids,  187. 

—  sterols,  188. 

—  simple,  fats,  184. 

Lithium,  effect  of,  on  metabolism,  724. 
Liver,  capacity  of,   to   store  glycogen, 
251. 

—  cholesterol  of,  4fi3. 

—  fat  of,  463. 

—  in  fat  metabolism,  207. 

—  functions  of,  463. 

—  glycogen  in,  463. 
• —  iron  in,  463. 

—  lecithin  of,  463. 

—  normal  constituents   of,  463. 

—  phosphatids  of,  463. 

—  proteins  of,  463. 

—  secretion  of.     See  Bile. 

—  storing  in,  of  carbohydrate,  in  form 
of  glycogen,  463. 

—  urea  formation  in,  464. 

Liver  poisoning,  effects  of  carbohydrate 
in,  689. 

Lusk's  experiments  on  protein  metab- 
olism, 131. 

Lymphatic  fluid,  788. 

Lysin,  88,  112. 


Magendie     (1783-1855),     exxperiments 

of,  on  calorimetrj',  37. 
Magnesium,  absorption  of,  323. 

—  in  the  blood,  451. 

—  effect  of,  on  mineral  metabolism, 
727. 

—  in  the  feces,  511. 

—  in  human  body,  323. 

—  in  metabolism,  323. 

—  in  the  urine,  503. 

Magnesium  sulphate,  intravenous  in- 
fusion of,  in  tetanus,  800. 

Magnus  (1S02-1S70),  experiments  of, 
in  history  of  metabolism,  33. 

Magnus-Levy's  table  of  mineral  con- 
stituents of  different  organs,  305. 

Maltose,  246. 

—  formula  for,  244. 
Mannose,  238. 

—  conversion  of  glucose  into  fructose 
and,  231. 

Masks,  for  measuring  respiratory  ex- 
change, 532. 


Mayow,  John  (1640-1679),  on  respira- 
tion, in  history  of  metabolism,  9,  10. 

McCay's  experiments  on  protein  mini- 
mum and  optimum,  406. 

Meals,  water  drinking  with,  280,  283, 
2S7,  288,  294. 

Meat,  caloric  value  of,  von  Liebig,  49. 

—  dry,  free  from  ash,  elementary  anal- 
ysis of,  60. 

—  extract  of,  v.  Liebig's,  his  defense  of 
the  use  of,  54,  55. 

—  heat  value  of,  550. 

—  importance  of,  as  food,  363. 
per  capita  consumption  of,  table 

of,  364. 

—  metabolism  of,  von  Yoit,  68. 

—  place  of,  in  diet,  400. 

—  weight  of  feces  following  ingestion 
of,  58. 

Meat  protein,  metabolism  of,  61. 
Mechanical      efficiency,     on     different 
diets,  591. 

—  of  muscular  work,  586. 
Menstruation,  creatinuria  after,  176. 
Mercury,  effect  of,  on  metabolism,  756. 
acid-alkali,  756. 

—  —  body  temperature,  756. 

carbohydrate,  756. 

fat,  756. 

mineral,  756. 

protein,  756. 

total,  756. 

water,  756.. 

Metabolism,    acid-alkali,   effect   on,    of 

anesthetics,  general,  chloroform  and 

ether,  762. 

of  antipyretics,  771 

of  mercury,  756. 

of  opiates,  766. 

—  acid-base,  effect  on,  of  arsenic,  754. 
of  phosphorus,  750. 

—  action  on,  of  light,  893. 

—  activity  of  yeast  cells,  von  Liebig'a 
discussion  of,  54. 

—  of  alcohol,  297. 

distribution  of,  after  absorption, 

299. 

excretion  of,  298. 

von  Liebig,  49. 

and  muscular  work,  301. 

nutritive  value  of,  297. 

—  alkalinity,  effect  on,  of  purins,  780. 

—  analysis  of,  in  human  beings,  by 
Barral,  38,  39. 

—  bacterial,  chemical  requirements  for 
bacterial  development,  668. 

energy,   669. 

structural,  669. 

chemistry  of,  678. 


936 


INDEX 


Metabolism,  bacterial,  chemistry  of, 
phases  of,  6T.s. 

reactions,  680. 

general  nature  of  products  of  bac- 
terial growth,  arising  from  utiliza- 
tion of  proteins  and  of  carbohydrates 
for  energj',  diphtherial  toxin,   669. 

indol  formation,  670. 

protein-liquefying        enzymes, 

formation  of,  670. 

general  relations  between  surface 

and  volume  of  bacteria  and  the  gen- 
eral energy  requirements  of  bacteria, 
665. 

influence    on,    of    saprophytism, 

parasitism,  and  pathogenism,  QQ6. 

intestinal  bacteriology,  690. 

adolescent  and  adult,  696. 

exogenous  intestinal  infec- 
tions, 706. 

of  normal  nurslings,   691. 

—  sour  milk  therapy  and,  700. 

nitrogenous,      illustrative      date, 

676, 

' quantitative  measures  of,  674. 

significance  of,  663. 

sour  milk  therapy  and,  700. 

specificity  of  action  of  pathogenic 

bacteria,  and  its  relation  to  proteins 
and  carbohydrates,  673. 

—  basal,  130,  607. 

in  anemia,  822. 

basal  metabolic  rate,  Boothby  and 

Sandiford,  610. 

of  children,  up  to  puberty,  649. 

awake  and  sleeping,  658. 

of  fat  and  thin  boys,  table, 

658. 

influence    on,    of    muscular 

activity,  654. 

of  sex,  652. 

—  influence      on,      of      puberty, 

654. 

comparison  of,  per  kgm.  and  per 

sq.  meter,  of  surface,  table,  610. 

described  by  Bidder  and  Schmidt, 

60. 

effect   on,    of   blood    transfusion, 

828. 

of  radiation.  883. 

facts  regarding,  from  Lavoisier's 

respiration  experiments,  25. 

of  infants,  new-born,  632. 

influence  of  crying,  637. 

of  sex,  635. 

from  two  weeks  to  one  year  of 

age,  642. 

influence  of  age,  645. 

• influence  on,  of  age,  612. 


Metabolism,  basal,  influence  on,  of  in- 
creased water  ingestion,  279. 

of  physical  characteristics,  608. 

of  sex,  614. 

in  vegetarian  diet,  400. 

—  basal  level,  130. 

—  bile,  digestive  action  of,  in  making 
materials  more  fluid,  59. 

relation  of  excretion  of  to  total 

ingesta  and  excreta  of  body.  Bidder 
and  Schmidt,  58. 

—  body  temperature,  effect  on,  of  epi- 
nephrin,  781. 

of  narcotics,  760. 

of  opiates,  765. 

of  purins,  779. 

of  uranium,  758. 

and    heat   production,    effect   on, 

of  cocain,  777. 

—  calculation  of,  Bischoff  and  Voit, 
69. 

its  difficulties,  von  Liebig  on,  48. 

—  caloric  value  of  meat,  von  Liebig, 
49. 

—  carbohydrate,  absorption,  249. 

sugar  of  the  blood,  250. 

antiketogenesis,  271. 

digestion,  248. 

-action  of  ptyalin,  248. 

gastric,  249. 

intestinal,  249. 

salivary,  248. 

of  anesthetics,  genera],  chloro- 
form and  ether,  761. 

of  antipyretics,  770. 

of  arsenic,  754. 

of  blood  poisons,  744. 

— of  calcium,  731. 

of  carbon  monoxid,  743. 

effect  on,  of  acids  and   alkalies, 

737. 

of  alcohol,  764. 

of  cocain,  777, 

of  eyanids,  748. 

of  epinephrin,  781. 

of  mercury,  756. 

of  opiates,  766. 

of  phlorizin,  759. 

of  phosphorus,  749. 

of  pituitary  substances,  785. 

of  purins,  780. 

of  roentgen  rays  and  radioac- 
tive substances,  883. 

of  saline  cathartics,  719. 

of  sodium  chlorid,  722. 

of  strychnin,  775. 

of    thyroid    gland    substance, 

783. 

of  uranium,  757. 


IXDEX 


937 


Metabolism,  carbohydrate,  endocrin  and 
nerve  control  of  glycogen esin,  glyco- 
genolysis  and  glucolysis,  257. 

adrenals,  257. 

pancreas,  258. 

pituitary,  261. 

sympathetic     nervous     system, 

257. 

—  thyroid,  260. 

fat  formation  from  carbohydrate, 

268. 

functions  of  carbohydrates  in  the 

diet,  271. 

influence  of  carbohydrates  on  in- 
termediary metabolism  of  fat,  271. 

intermediary,  201. 

introduction  to,  213. 

minimum,  411. 

of  rectal  feeding,  811. 

tolerance,  254. 

glucolysis  and,  256. 

glycogenesis  and,  255. 

standard  of,  255. 

—  carbon,  quantity  of  computed  by 
Bidder  and  Schmidt,  61. 

—  catalase,  effect  on,  of  epinephrin, 
781. 

of  purins,  780. 

—  classification  of  foodstuffs,  von  Lie- 
big^s  nitrogenous  or  plastic,  50. 

non-nitrogenous     or    respiratary, 

50. 

—  conversion  of  protein  into  fat  and 
into  sugar,  Voit,  73. 

—  conversion  of  starch  into  fat,  Voit, 
73. 

—  creatin,  in  blood,  175. 

muscle,  174. 

in  urine,  176. 

—  creatinin,  in  blood,  177. 

in  nmscles,  177. 

in  urine,  177. 

—  in  diabetes,  effect  on,  of  opiates,  766. 

—  in  disease,  influence  on,  of  roentgen 
rays  and  radioactive  substances, 
884. 

—  of  duodena]  feeding,  807. 

—  effect  on,  of  acids.  733. 

of  acids  and  alkalies,  732. 

of  alcohol,  764. 

of  alkaline  earths,  calcium,  726. 

magiiesium,  727. 

of  alkaline  waters,  849. 

of  aluminum,  732. 

— ■  —  of  amino-acids,  774. 

of  ammonia,  773. 

of    anesthetics,    general,    chloro- 
form and  ether,  760. 
of  antimony,  753, 


Metabolism,  effect  on,  of  antipyretics, 
767. 

— -  —  of  arsenic,  763. 

of  asphyxiants,  740. 

of  atropin,  piloearpin,  etc.,  774. 

of  blood  poisons,  744. 

of  blood  transfusion,  basal  metab- 
olism, 828. 

nitrogen  metabolism,  828. 

of  boracic  acid  and  borax,  740. 

of  bromids,  724. 

of  calcium,  727. 

of  camphor,  776. 

of  carbon  dioxid,  741. 

of  carbon  monoxid,  742. 

of  chloroform,  760. 

of  chromates,  75S. 

of  cinchophen  (atophan),  772. 

of  cocain,  777. 

of  copper,  758. 

of  curare,  776. 

of  cyanids,  745. 

of    endocrin    drugs,    epinephrin, 

780. 

parathyroid    gland    substances, 

785. 

pineal  gland,  785. 

— • pituitary,  784. 

prostate  gland,  785. 

spleen,  785. 

testis,  785. 

thymus  gland,  785. 

thyroid   gland   substance,   782. 

epinephrin,  780. 

of  ether,  760. 

of  ethylenediamin,  773. 

of  ethylhydrocurpein,  772. 

of  high  altitude,   910. 

of  hot  baths,  860,  861. 

of  hydrazin,  773. 

of  hypnotics,  763. 

of  iodin  and  iodids,  724. 

of  iron,  755. 

of  iron  waters,  851. 

of  iso-amylamin,  773. 

of  lead,  758. 

of  light,  893. 

of  magnesium,  727. 

of  mercury,  755. 

of  narcotics,  760. 

of  opiates,  765. 

of  oxygen,  740. 

of  parathyroid  gland  substances, 

785. 

of  phenylethylamin,  773. 

of  phlorizin,  759. 

of  phosphorus,  748. 

of  pilocarpin,  atropin,  etc.,  774. 

of  pineal  gland  feeding,  785. 


938 


IXDEX 


Metabolism,  effect  on,  of  pituitary  sub- 
stances, 784. 

of  pituitary  substances;  anterior 

lobe,  785. 

of  platinum,  758. 

of  prostate  gland  substances,  785. 

of  purins,  778. 

of  quinin  and  its  congeners,  772. 

of  radium,  758. 

of  salt  baths,  863,  864. 

of  salts,  718. 

of  santonin,  776. 

of  sodium   chlorid,  719. 

salt  fever,  720. 

salt  glycosuria,  722. 

salt  starvation,  723. 

of  spleen,  785. 

of  strychnin,  775. 

of    temperature     and    humidity, 

902. 

of  testis  feeding,  785. 

of  thymus  gland  substances,  785. 

of  thyroid  gland  substance,  782. 

of  tyramin,  773. 

of  water,  717. 

deficiency  of  water,  717. 

mineral  waters,  718. 

of  zinc,  758. 

—  energy,  basic  principles  of,  583. 

basal  metabolism.  See  Metab- 
olism, basal. 

• —  conservation  of  energy  in  ani- 
mal organism,  584. 

determination  in  part  by  en- 
vironing temperature,  593. 

heat  production   as  affected 

by  external  temperature,  601.  ■ 

energy  of  muscular  work  defi- 
nitely related  to  potential  energy  of 
food,  586. 

indigestion    of   food    increases 

metabolism,  604. 

calorimetry,  direct,  567.     See  also 

Calorimetry. 

indirect,  515.  See  also  Cal- 
orimetry. 

of  children,  up  to  puberty,  647. 

determined  in  part  by  environing 

temperature,  how  heat  is  lost  from 
body,  593. 

law  of  surface  area,  594. 

effect  on,   of  acids  and   alkalies, 

736. 

of  calcium,  730. 

of  saline  cathartics,  718. 

of  sodium  chlorid,  720. 

and  embryonic  growth,  616. 

factors     determining     level     of, 

607. 


Metabolism,  energy,  and  growth,  615. 

differences  between  growth  and 

maintenance,  615. 

embryonic,  616. 

post-embryonic,  619. 

of  infant,  new-bo.rn,  627. 

from  two  weeks  to  one  year  of 

age,  640. 

mechanical  efficiency  of  muscular 

work,  586. 

methods  of  measuring  heat  pro- 
duction from  respiratory  exchange. 
See  Respiratory-  Exchange. 

methods  of  measuring  respiratory 

exchange.  See  Respiratory  Ex- 
change. 

normal  processes  of,  515. 

of  old  age,  658. 

origin     of,     in     non-nitrogenous 

food,  586. 

of  parturition,  before  and   after, 

table,  634. 

and  post-embryunie  growth,  619. 

of  pregnancy,  621. 

comparison  of  energy  metab- 
olism in  pregnant  and  non-pregnant 
women,  table,  625. 

relative  value  of  different  food- 
stuffs as  source  of  energy  in  mus- 
cular work,  590. 

surface  area,  law  of,  594. 

law  of,  criticism  of,  597. 

_ measurement  of,  595. 

relation  of,  to  body  weight,  598. 

See  also  Muscular  Energy. 

—  energy  relations,  importance  of  in- 
sisted on  by  Rubner,  76. 

—  in  fasting,  309. 

von  Liebig's  obsei-vations  on,  46. 

—  fat,  absorption,  from  the  intestine, 
194. 

changes  in  fats  during,  196. 

emulsifieation,  200. 

factors  in,  197. 

paths  of.  196. 

stomach,  100. 

in  the  blood,  alimentary  lipemia, 

201. 

lipoids  of,  204. 

and  blood  lipoids,  445. 

digestion,  in  the  intestines,  193. 

— emulsifieation,  200. 

—  —  factors  in,  197. 

in  stomach,  189. 

effect  on,  of  alcohol,  765. 

of  anesthetics,  general  chloro- 
form and  ether,  762. 

of  cocain,  777. 

of  mercury,  756. 


IXDEX 


939 


^retabolisin,  fat,  effect  on,  of  opiates, 
76fi. 

of  phlorizin,  750. 

of  phosphorus,  748. 

-of  saline  cathartics,  718. 

of    thyroid    gland     substance, 

784. 

of  uranium,  758. 

fat  excretion,  210. 

intermediary,  influence  of  carbo- 
hydrates on,  271. 

in     the     intestines,      absorption, 

changes  in  fats  during,  196. 

absorption  of  fat,  194. 

paths  of,  196. 

bile,  198. 

digestion,  193. 

emulsification  in  fat  digestion 

and  absorption,  200. 

factors  in  digestion  and  ab- 
sorption, 197. 

lipases  of  intestinal  tract  and 

digestion,  192. 

nature  of  food  fat,  199. 

pancreatic  juice,  192. 

pancreatic  secretion,  197. 

passage  from  the  stomach,  191. 

— summary  of,  200. 

synthesis  of  fats  during  ab- 
sorption from,  196. 

introduction  to,  183. 

later  stages  of,  )8-oxidation,  208. 

lipoids,  compound,  cephalins,  187. 

glycolipoids,  187. 

lecithins,  186. 

phospholipoids,  185. 

derived,   fatty   acids,   187. 

sterols,  188. 

simple,  fats,  184. 

waxes,  185. 

liver  in,  207. 

minimum,  410. 

passage  from  the  stomach  to  in- 
testines, 191. 

of  rectal  feeding,  811. 

stomach,  absorption,  190. 

digestion,  189. 

synthesis  of  fats  during  absorp- 
tion, from  the  intestines,  196. 

in  the  tissues,  changes  in  fat,  206. 

storing  of  fat,  205. 

—  fat  ingestion,  contents  of  feces  fol- 
lowing, 64. 

—  ferments,  eifect  of  anesthetics,  gen- 
eral, chloroform  and  ether,  763. 

effect  on,  of  arsenic,  755. 

—  in  fever,  effect  on,  of  antipyretics, 
768. 

—  final  stage  of,  oxidation,  130. 


Metabolism,  formation  of  fat,  von  Lie- 
big  on,  49. 

—  formation  of  feces  and  absorption 
of  bile,  von  Liebig  on,  49. 

—  gaseous,  effect  on  of  hot  baths,  861. 

—  in  gavage,  806. 

—  of  growth,  effect  on,  of  epinephrin, 
782. 

of  purins,  780. 

of    thyroid     gland    substance, 

784. 
and    reproduction,    effect    on,    of 

calcium,  732. 

—  guanidin  bases,  effect  on,  of  purins, 
780. 

—  Iieat  production  of  body,  Berthelot's 
observations  on,  77. 

—  history  of,  3. 

air,  its  combustion  and  respira- 
tion, 8,  9. 

beginnings  of  calorimetry,  4. 

Barral  (1819-1884),  38. 

Boussingault   (1802-1887),  37. 

Despretz  (1792-1863),  34. 

Dulong  (1785-1838),  35. 

Bumas   (1800-1884),  36. 

Magendie   (1783-1855),  37. 

Regnault  (1810-1878),  40. 

carbonic  acid  gas,  8. 

chemical  revolution,  14. 

Black   (1728-1799),  15. 

Cavendish   (1731-1810),  15. 

Crawford  (1748-1795),  17. 

Lavoisier  (1743-1794),  19. 

resume  of,  29,  30. 

Rutherford,      Daniel      (1749- 

1819),  16. 

Scheele  (1742-1786),  17. 

classical  period,  4. 

Aristotle,  5. 

Galen,  5. 

-Hippocrates,  4. 

Socrates,  4. 

conclusions   on,  78. 

dark  ages,  5.     Voit,  Carl,  5. 

dawn  of,  3. 

"insensible  perspiration,"  4,  7. 

introduction   to,  3. 

late  French   work,   77. 

Berthelot  (1827-1907),  77. 

Bichet,     Charles     (1850 ), 

77. 

renaissance,  6. 

Boerhaave  (1668-1738),  11. 

Bo.yle,  Robert  (1621-1679),  8. 

Hales  Stephen  (1677-1761),  11. 

von    Haller,    Albrecht    (1708- 

1777),  11. 

Van  Helmont  (1577-1644),  8. 


940 


IXDi^X 


Metabolism,    history    of,    renaissance, 

Jean  Key  (1045),  8. 
Lefevre,  Nicholas  (died  1674), 

8. 

Leonardo     da     Vinci      (1452- 

.      1519),  6. 

Mayow,  John  (1640-1679),  9. 

Paracelsus  (1493-1591),  7. 

Sanctorius    (1501-1630),   7. 

-Stahl   (J600-1734),  11. 

Stark,     William     (1740-1770), 

12. 

Willis  (1621-1675),  11. 

respiration,  8,  9,  10. 

rise  of  German   science,   Bidder, 

F.  W.  (1810-1894)  and  Schmidt,  C. 

(born  1S22),  57. 
von  Liebig,  Justus  (1803-1873), 

44. 
von    Liebig,    Justus,    Munich 

period  of,  63. 
von    Pettenkofer,   Max    (1818- 

1901),  64. 

Rubner,  Max  (1854 ),  75. 

von  Voit,  Carl  (1831-1908),  65. 

Zuntz,  Nathan  (1847-1920),  76. 

science  after  the  French  Revolu- 
tion, 30. 

Berzelius  (1779-1848),  33. 

Davy,  Humphrey   (1778-1829), 

31. 
Edwards,    William    F.    (1776- 

1842),  32. 

Gay-Lussac  (1778-1850),  33. 

Magnus   (1802-1870),  33. 

— Spallanzani   (1729-1799)   32. 

—  of  a  horse,  von  Liebig's  observations 
on,  48. 

—  influence  on,  of  carbohydrates,  130. 
of  fat,  130. 

of  diminished  water  intake,  279. 

of  increased  water  ingestion,  277. 

on  basal  metabolism,  279. 

of  protein,  130. 

of  roentgen  rays  and  radioactive 

substances,  introduction  to,  871. 

in  metabolism  in  disease,  884. 

in  normal  metabolism,  880. 

—  influence  of  food  on  composition  of 
urine,  64. 

—  ingestion  of  meat,  weight   of  feces 
following,  58. 

—  isodynamic  equivalents,  49. 
table  of,  von  Liebig's,  50. 

—  lime,  in  infancy  and  childhood,  318. 

—  measurement  of,  Zuntz,  70. 

—  measurement  of  energy,  Zuntz,  77. 

—  meat,  dry,  free  from  ash,  elementary 
analysis  of,  60. 


Metabolism,  meat  protein,  fate  of.  Bid- 
der and  Schmidt,  61. 
V.  Voit,  6S. 

—  mineral,  303. 

alkalies,  315. 

ash  minimum,  411. 

calcium,  316. 

distarbances     in,     accompanying 

pathological  conditions,  330. 

effect   on,   of   acids   and   alkalies. 

736. 

of  anesthetics,  general,  chloro- 
form and  ether,  763. 

of  calcium,  726. 

of  carbon  nionoxid,  743. 

of  epinenephrin,  782. 

of  mercurj',  75(>. 

of  phosphorus,  750. 

of  purins,  780. 

of  saline  cathartics,  719. 

of  sodium  chlorid,  719. 

of  uranium,  757. 

and  endocrin  glands,  336. 

of  infants  two  days  of  age,  table, 

636. 

iodin,  332. 

iron,  326. 

magnesium,  323. 

neutrality  regulation,  333. 

phosphorus,  323. 

salt  and  salt-poor  diet,  308. 

sodium  chlorid,  312. 

sulphur,  332. 

water,  311. 

—  in  nephritic  conditions,  effect  on,  of 
purins,  778. 

—  nitrogen,  determination  of,  in  urine, 
titration  method  of  Liebig,  67. 

—  Voit's  method,  68. 

effect  on,  of  antimony,  754. 

of  arsenic,  754. 

of  blood  transfusion,  828. 

of  cocain,  777. 

of  purins,  779. 

of  sodium  chjorid,  721. 

—  nitrogen    elimination,    67. 

—  non-nitrogenous  constituents  of 
blood,  original  and  role  of,  433. 

—  nutrition  and  energy  relations  in- 
volved, as  they  concern  the  animal 
organism,  69. 

—  oxidation  of  various  foods,  von  Lie- 
big,  49. 

—  oxygen  as  cause  of,  passing  of  con- 
ception, 71. 

—  oxygen  requirement  for  combustion 
of  foods,  von  Liebig,  50. 

—  percentage  of,  taking  place  in  mus- 
cles during  rest  and  activity,  459. 


IXDEX 


941 


Metabolism,  protein,  coagulation  and 
denaturalization,  100. 

continuance  of,  in  body,  irrespec- 
tive of  any  ingestion  of  protein,  116, 
117. 

digestion,  101. 

absorption  of  products  of,  from 

the  gastro-intestinal  canal,  103. 

schematic    illustration    of,    in 

the  gastro-intestinal  canal,  103. 

effect  on,   of  acids   and   alkalies, 

739. 

of  alcohol,  300,  764. 

of  anesthetics,  general,  chloro- 
form and  ether,  760. 

of  antipyretics,  769. 

of  blood  poisons,  744. 

of  carbon  monoxid,  743. 

of  cyanids,  748. 

of  epinephrin,  782. 

on  hot  baths,  861. 

of  mercury,  756. 

of  opiates,  766. 

of  phlorizin,  759. 

of  phosphorus,  750. 

of  saline  cathartics,  719. 

of  saline  waters,  847. 

of  starvation,  116,  117. 

— of    thyroid    gland    substances, 

783. 

— of  uranium,  757. 

when     fasting,     tables     of,     116, 

117. 

fate  of  amino  acids  in  body,  ab- 
sorbed in  the  blood,  104. 

non-nitrogenous     fraction     of, 

107. 

table  summarizing,  115. 

in  the  tissues,  105. 

function  of  protein  in  diet,  121. 

higher,  when  carbohydrate  is  ab- 
sent from  diet,  118. 

incomplete,  Hopkins  and  Will- 
cock's   experiments   with,   125,   32G. 

incomplete  proteins,  122, 

Abderhalden's  experiments 

with,  123,  124,  125. 

Osborne  and  Mendel's  experi- 
ments with,  127,  128,  129. 

introduction  to,  81. 

—  • — Lusk's  experiments  with,  131. 

minimum    and    optimum.       See 

Protein  Minimum  and  Optimum. 

nitrogen  balance  and  body  weight, 

Hopkins  and  Willeock's  experiments 
on,  125,  126. 

nitrogenous  equilibrium  and  hody 

weight,    experiments    on,    of    Abder- 
halden,  123,  124,  125. 


Metabolism,  protein,  peptones  in  di- 
gested protein,  original  views  of. 
121. 

protein      factor,     obtaining     of. 

116. 

—  —  question  of  optimum  versus  min- 
imum protein  diet,  119. 

of  recital  feeding,  810. 

salt  formation  of  proteins,  100. 

state  of  negative  nitrogen  bal- 
ance, 116. 

state  of  nitrogenous  equilibrium, 

116. 

state  of  positive  nitrogen  balance. 

116. 

—  —  synthesizing   by   animal   body   of 

its    own    protein    from    elementary      * 

amino  acids,  121. 

Abderhalden's  experiment,  122. 

urea  fonnation,  105. 

of  Voit,  68,   69. 

See  also  Proteins. 

—  purin,  effect  on,  of  acids  and  alka- 
lies, 739. 

of  alcohol,  300. 

of  calcium,  732. 

of  cinchophen  (atophan),  772. 

of  purins,  779. 

—  of  rectal  feeding,  810. 

—  of  reproduction  and  growth,  effect 
on,  of  alcohol,   765. 

effect  on,  of  antipyretics,  769. 

—  respiratory  quotient  of  Bidder  and 
Schmidt,  63. 

—  salt,  of  rectal  feeding,  812. 

—  source  of  muscle  power  in,  53. 

—  total,  computation  of.  Bidder  and 
Schmidt,  60. 

effect  on,  of  acids  and  alkalies, 

736. 

of  alcohol,  764. 

of  alcohol,  299. 

of  antipyretics,  767. 

of  arsenic,  754. 

of  carbon  monoxid,  742. 

of  epinephrin,  780. 

of  mercury,  756. 

of  narcotics,  760. 

of  opiates,  765. 

of   phlorizin,   760. 

of  phosphorus,  748. 

of  pituitarj^   substances,   784. 

of  purins,  779. 

of  saline  cathartics,  718. 

of  sodium  chlorid,  721. 

' of  thyroid  substances,  783. 

of    uranium,    758. 

—  "typical  food  minimum,"  of  Bidder 
and  Schmidt,  03. 


942 


INDEX 


Metabolism,  ultimate  disposal  of 
products  of,  von  Liebig's,  51. 

—  undernutrition,  414. 
war  edema,  415. 

—  uric  acid  excretion,  effect  on,  of 
arsenic  and  antimony,  754. 

—  value  of  flavor  in  diet,  Voit,  74. 

—  of  vitamins,  341. 
end,  350. 

difrestion      and      absorption      of, 

347.  ,     .     , 
intermediary,    and    pbysiological 

action,  347. 
special  features  of,  351. 

—  Voit's  and  Pfliiger's  controversy,  72, 

—  Voit's  theory  of  "organized^ protein 
and  "circulating  protein,"  72. 

—  water,  effects  on,  of  acids  and  al- 
kalies, 736. 

of  anesthetics,  general  chloro- 
form and  ether,  763. 

of  antipyretics,  770. 

of  arsenic,  755. 

of  calcium,  730. 

of  epinephrin,  781. 

of  mercury,  756. 

of  opiates,  767. 

of  pituitary   substances,  784. 

of  purins,  778. 

of  sodium  chlorid,  720. 

of  uranium,  757. 

of  rectal  feeding,  812. 

—  work  on,  of  Bidder,  F.  W.  (1810- 
1894)  and  Schmidt,  C.  (born  1822), 
57. 

of  Rubner,  75. 

of  von  Voit,  Carl,  65. 

of  Zuntz,  76. 

Metchnikoff  hypothesis,  700. 
Methemoglobinemia,   744. 
Methylglucosides,  237. 
:Nrethylpentose3,  242. 
Microbic     response,     relation     between 

diet  and,  in  normal  nurslings,  691. 
Milk,  composition  of,  476. 
percentage  of,  of  human  milk  by 

periods,  477. 
rate  of  growth  and,   in   different 

species,  477. 
variation    in   as   between    human 

and  cow^s  milk,  478. 

—  constituents  of,  mineral,  478. 
table  of,  479. 

—  —  nonprotein  nitrogenous,  table  of, 
478. 

: table  of,  476. 

—  cow's,  artificial  feeding  of,  to  in- 
fants, 320. 


Milk,   of  different  species  of  animals, 
difference  in,  476. 

—  human,  mineral  constituents  of,  319. 

—  importance  of,  in  diet,  421. 

—  mineral  content  of,  478. 

—  physical  appearance  of,  476. 

—  reaction   of,  476. 

—  in  rectal  feeding,  812. 
Millon's  reaction,  98. 

Mineral   constituents   of  adult  human 
body,  303. 

—  alkalies,  315. 

—  arsenic,  308. 

—  of  the  blood,  306. 

calcium,  450. 

chlorids,  451. 

iron,  451. 

magnesium,  451. 

phosphates,  453. 

potassium,  450. 

sodium,  450. 

sulphates,  454. 

table  of,  307. 

—  calcium,  316. 

—  of  cerebrospinal  fluid,  473. 

—  of  different  organs,  303. 

Dennstedt  and  Rumpf's  table  of, 

304. 

Magnus-Levy's  table,  305. 

of  milk,  319,  478. 

table  of,  479. 

—  iodin,  332. 

—  iron,  326. 

—  magnesium,  323. 

—  of   muscles,    305. 
table  of,  462. 

I  — of  nervous  tissue,  Weil's  table,  306. 

—  phosphorus,  323. 

—  salt,  nutritive  value  of,  308. 
salt-poor  diet,   effect   of,  309. 

—  silica,   308. 

—  sodium  chlorid,  312. 

—  sulphur,  332. 

—  water,  311. 

Mineral  metabolism,  alkalies,  315. 

—  calcium,  316. 

—  disturbances        in,        accompanying 
pathological   conditions,   336, 

—  effect  on,  of  acids  and  alkalies,  736. 
of  aluminum,  732. 

of    anesthetics,    general,    chlo-" 

fonn  and  ether,  763. 

of  calcium,  726. 

of  carbon  monoxid,  74JJ. 

of  epinephrin,  782. 

of  magnesium,  727. 

of  mercury,  756. 

of  phosphorus,  750. 

of  purins,  780. 


TXDEX 


^finerol  metabolism,  effect  on,  of  saline 
cathartics,  719. 

of  sodium  chlorid,  719. 

■ of  uranium,   757. 

—  and  endocrin  jrlands,  336. 

—  of  infants   two   days   of  age,   table, 
.  636. 

—  iodin,  332. 

—  iron,  326. 

—  magnesium,  323. 

—  neutrality  regulation,  333. 

—  phosphorus,    323. 

—  sodium  chlorid,  312. 

—  sulphur,  332. 

—  water,  311. 

Mineral  requirements,  of  adult  organ- 
ism, 310. 

for  calcium,  317. 

magnesium,  323. 

phosphorus,   324,   325. 

for  sodium  chlorid,  312. 

for  water,  312. 

—  of  childhood  and  adolescence,  321. 

—  in  infants,  318. 
Mineral  waters,  845. 

—  alkaline    waters,    including    carbon- 
ated, 848. 

—  arsenic,  851. 

—  bitter  waters,  850. 

—  carbonated,  848. 

—  classification  of,  845. 

—  diuretic  property  of,  847. 

—  effect  of,  on  metabolism,  718. 

—  iron,  851. 

—  radioactive,    852. 

—  saline  w^aters,  846. 
— -sulphur,  851. 
Molisch  reaction,  98. 
Monominophosphatids  of  brain,  470. 
Monosaccharids,   special  properties  of, 

237. 
Monosaccharose,   conversion   of  higher 
to  lower,  227. 

—  synthesis  of  higher  forms  from,  226. 
Mouth-pieces    for    measuring    respira- 
tory exchange,  531. 

Mud  baths,  867. 

Muscle  power,  Frankland's  comparison 

of,  with  steam  engine,  von  Liebig's 

criticism  of,  54. 

—  source  of,  53. 

Muscles,  contraction  of,  by  electricity, 
894. 

—  creatin  content  of,  172. 

—  creatin  metabolism,  174. 

—  creatinin  metabolism  in,  177. 

—  extractives  of,  460. 

nitrogenous,  carnosin,  461. 

creatin,  460. 


Muscles,    extractives    of,    nitrogenous, 
purin  bases,  461. 

table  of,  462. 

uric  acid,  461. 

non-nitrogenous,,   glucose,    460. 

glycogen,  450. 

lactic  acid,  460. 

inositol,  460. 

—  magnesium  in,  323. 

—  metabolism  percentage  taking  place 
in,  during  rest  and  activity,  459. 

—  mineral  constituents  of,  305. 

—  mineral    content   of   muscles,   table, 
462. 

—  percentage    of    body    weight    com- 
prised  in,   459. 

—  proteins  of,  459. 

—  voluntary  and  involuntary,  459. 
Muscular    activity,    influence    of,    on 

basal  metabolism  of  children,  654. 

—  comparison  of  fat  and  carbohydrate 
as  a  source  of,  592. 

—  alcohol  and,  301. 

—  energy  of,  definitely  related  to  po- 
tential energy  of  food,  586. 

—  energy   production   of,   on   diiferent 
diets,   590. 

—  mechanical  energy  of,  586. 

—  relative    value    of    different    food- 
stuffs, as  a  source  of  energy  in,  590. 

Mustard  baths,  863. 
Mutarotatin,  221. 
Myelin,  in  brain,  470. 


Narcotics,    effect    of,    on    metabolism, 

760. 

body  temperature,  760. 

total  metabolism,  760. 

Nasal  mucosa,  effect  on,  of  temperature 

and  humidity,  901. 
Nephritic     conditions,     effect    on,     of 

purins,  778. 
Nephritis,  blood  lipoids  in,  446. 

—  chronic,  urea  nitrogen,  urin  acid, 
and  creatinin  of  blood  in,  439. 

uric     acid,     urea     nitrogen    and 

creatinin  of  blood  in,  439. 

—  disturbances  of  mineral  metabolism 
in,  336. 

—  injections  into  blood  of  sodium  bi- 
carbonate, 793. 

—  uranium,  alkaline  treatment  in,  735. 

—  uric  acid  in,  437. 

Nerve  and  endocrin  control  of  gly- 
cogenesis,  glycogenolysis  and  glu- 
colysis,  257. 

Nerves,  magnesium  in,  323. 

—  stimulation  of,  by  electricity,  894. 


044 


INDEX 


Nen^ous  tissue,  mineral  constituents  of, 
306. 

Neumann's  experiments  on  protein 
minimum  and  optimum,  402. 

Neutrality  rej^julation,  732. 

New-born  infant,  See  Infant,  new- 
born. 

Nitrobenzene  poisonin;;^,  I'lood  trans- 
fusion in,  833. 

Nitrogen,  amount  of,  excreted  in  urine, 
table  of,  405. 

—  blood,  comparative  nitrogen  parti- 
tion of  urine  and,  in  per  cent  of 
total  non-protein  nitrogen,  table, 
434. 

non-protein,  432. 

urea,   435. 

rest,  442. 

total,  432. 

uric  acid,  437. 

—  determination  of,  in  urine,  titra- 
tion  method   of  Liebig   for,    67. 

-Voit's  method,  68. 

—  elimination  of,  67. 

—  in  the  feces,  504. 

—  non-protein,  of  cerebrospinal  fluid, 
472. 

—  in  the  sweat,  513. 

—  urea,  in  nephritis,  table  of,  439. 

—  of  the  urine,  485. 

methods  of  calculating  from  re- 
spiratory exchange  and,   563. 

nitrogenous   substances,   507. 

Nitrogen  balance,  negative,  116. 

—  positive,  116. 

Nitrogen  gas,  "residual  air,"  discovery 

of,  by  Rutherford,  16. 
Nitrogen  intake,  lowest  value  for,  with 

maintenance  of  equilibrium,  407. 
Nitrogen    metabolism,    effect    on,    of 

antimony,  754. 

of  arsenic,  754. 

of  blood  transfusion,  828. 

of  cocain,  777. 

of  purins,  779. 

-of  sodium  chlorid,  721. 

Nitrogen  minimum,  401. 

Nitrogen  partition  of  urine  and  blood, 

comparative,    in    per    cent    of    total 

non-protein  nitrogen,  table  of,  434. 
Nitrogenous  constituents  of  milk,  478. 
Nitrogenous  equilibrium,  116. 

—  and  body  weight,  Abderhalden's  ex- 
periments on,  123,  124,  125. 

Nitrogenous  substances,  in  the  urine, 

507. 
Normal  leucin,  80,  109. 
Nose-pieces,  for  measuring  respiratory 

exchange,  532. 


Nucleic  acid,  animal,  145. 

—  chemical  part,   135. 

—  decomposition,    enzymatic,    of   com- 
bined purins,  158. 

—  distribution  of,  purin  ferments,  154. 

—  formation       of       oxy-purins       from 
amino-purins,   151. 

—  formation  of  uric  acid  from,  150. 
from   oxy-purins,  151. 

—  guanylic  acid,  14J,  142. 

—  inosinic   acid,   141. 

—  physiological  decomposition  of,  148. 

—  physiological  destruction  of  uric 
acid,  153. 

—  plant,  135. 

—  thymus,  partial  decomposition 
products  of,  147. 

—  yeast,  dextro-ribose,  136. 

—  yeast,  fundamental  groups  of,  136. 
nucleotides  of,  143. 

nucleotides  of,  139. 

nucleotide  linkages  of,  140. 

pentose,  136. 

purin  derivatives,  137. 

amino-purins,  adenin,  137. 

guanine,   137. 

chemical    relation    of    amino- 

and  oxy-purins,  138,  139. 

oxy-purins,    hypoxanthin,    137, 

138. 

uric  acid,  137,  138,  139. 

zanthin,  137,  138. 

pyrimidin   derivatives,  136. 

cytosin,  137. 

uracil,  137. 

six  substances  of,  136. 

Nudeoprotein,  formation  of  uric  acid 
in  urine  from,  495. 

Nucleotides,  yeast,  143. 

Nucleotide  linkages  of  yeast  nucleic 
acids,  140. 

Nucleotides  of  yeast  nucleic  acid,  139. 

Nurslings.     See  Infants. 

Nutrition,  level  of,  416. 

Nutrition,  and  energy  relations  in- 
volved, as  they  concern  the  animal 
organism,  69. 

Nutritive  value  of  alcohol,  297. 

Old  age,  energy  metabolism  of,  658. 
Opiates,     effect     of,     on     metabolism, 
7G5, 

acid-alkali,  766. 

body  temperature,  765. 

carbohydrate,  766. 

in  diabetes,  766. 

fat,  766. 

protein,  766. 

temperature  of  the  body,  765. 


IISTDEX 


945 


Opiates,  effect  of,  on  metabolism,  total, 
765. 

water,  767. 

Organic  acids,  salts  of,  effects  of,  on 
metabolism,  725. 

Organic  phosphorus,  752. 

Ornithin,  89,  113,  6S5. 

Osazones,  285. 

Osborne  and  Mendel's  experiments  il- 
lustrating physiological  value  of 
amino  acids,  127,  128,  129. 

Osones,  235. 

Osteomalacia,  and  mineral  metabolism, 
339. 

Oxalates,  effects  of,  on  metabolism,  725. 

Oxalic  acid,  in  urine,  499. 

Oxy  acids  and  derivatives,  aromatic, 
499. 

Oxidation,  of  carbohydrates,  227. 

—  of  glucose,  251. 

Oxygen,  from  arterial  blood,  by 
Humphrey  Davy,  31. 

—  in  the  blood,  455. 

content   of,   455. 

arterial,  456. 

in  pathological  conditions,  457. 

—  and  carbonic  acid  gas,  Spallanzani's 
experiments,  32. 

—  as  cause  of  metabolism,  passing  of 
conception  of,  71. 

—  discovery  of,  by  Priestley,  16. 
by  Scheele,  17. 

—  effect  of,  on  metabolism,  740. 
oxygen  deficiency,  740. 

—  relation  between  quantity  exhaled 
as  carbon  dioxid,  and  quantity  con- 
sumed, 41. 

Oxygen  capacity  of  blood,  effect  on,  of 

blood   transfusion,   823. 
Oxygen    consumption,    effects    on,    of 

hot  baths,  860,  861. 
Oxygen  deficiency,  740. 

—  blood  alkalinity  in,  741. 

—  lactic  acid  excretion  in,  741, 
Oxygen  requirement  for  combustion  of 

foods,  von  Liebig,  50. 
Oxyprolin,  90,  114. 
Oxy-purins,  chemical  relation  of,  with 

amino-purins,  13^^. 

—  formation  of, from  amino-purins,  151. 

—  formation  of  uric  acid  from,  151. 

—  hypoxanthin,  137,  138. 

—  uric  acid,  137,  13S,  139. 

—  xanthin,  137,  138. 

Pancreas,  influence  of,  on  glycogenesis, 
glycogenolysis  and  glucolysis,  257. 

Pancreatic  digestion,  influence  on,  of 
water,  289.         -     . 


Pancreatic  juice,  amount  of,  secreted, 
in  24  hours,  192. 

—  excitants  for  secretion  of,  192. 
Pancreatic  lipase,  action  of,  192. 

—  extraction  of,  from  gland,  193. 

—  secretion  and  activity  of,  193. 
Pancreatic  secretion,  effect  on,  of  al- 
kaline waters,  840. 

of  saline  waters,  847. 

—  as  factor  in  fat  digestion  and  ab- 
sorption, 197. 

Paracelsus  (1493-1591),  on  metabolism, 

7. 
Paraldeliyde,  effect  of,  on  metabolism, 

764. 
Parnmyelin,  470. 
Parasitism,   influence  of,   on   bacterial 

metabolism.  6C6. 
Parathyroid  gland  substances,  effect  of, 

on  metabolism,  785. 
Parturition,  energy  metabolism  before 

and  after,  table,  634. 
Parasitism,   influence  of,  on   bacterial 

metabolism.  666. 
Peat  baths,  867. 

Pellagra,  feces  in,  average  daily  com- 
position of,  509. 
Pentose,    136. 
Pentoses,  240. 

—  aldopentoses,  table  of,  241. 

—  1-arabinose,  241. 

—  methyl,  242. 

—  rhamnose,  242. 

—  d-ribose,  242. 

—  xylose,  241. 

Pernicious  anemia,  blood  transfusion 
in,  indications  for,  831. 

—  treatment  of,  by  x-rays,  886. 

—  urobilin  excreted  in,  168. 
"Perspiration,  insensible,"  Hippocrates 

on,  4. 

—  Sanctorius   (1561-1636),  7. 

von  Pettenkofer,  Max  (1818-1901), 
contribution  of,  to  study  of  meta- 
bolism, 64,  65. 

—  apparatus  of,  for  measuring  respira- 
tory exchange,  516. 

Pettenkofer  reaction  for  bile  salts,  65. 
Phenols,  formation  of,  680. 

—  effects  on,  of  utilizable  carbohy- 
drates, 685. 

Phenylalanin,  decomposition  of,  684. 
Phenylamin,  89,  113. 
Phenylethylamin,  686. 

—  eflect  of,  on  metabolism,  773. 
Phlogiston  theorj^  of  combustion,  11. 

—  demolished  by  Lavoisier  ^1783),  23. 
Phlorizin,  effect  of,  on  metabolism,  759. 
carbohydrate,  759. 


946 


INDEX 


Phlorizin,  effect  of,  fat,  759. 

protein,   759. 

total,  760. 

'Tliosoxygen,"  of  Humphrey  Davy,  31. 
Phosphates,   in   the   blood, 
- —  of  cerebrospinal  fluid,  473. 

—  of   the    urine,    501. 
Phospliatids,    of    the    grain,    cephalin, 

468. 

lecithin,  468. 

of  the  liver,  463. 

Phospholipoids,    185. 

—  cuorin,  186. 

Phosphorus,  cod  liver  oil  as  vehicle  for, 
753. 

—  distribution  of,  in  body,  324. 

—  effects  of,  on  metabolism,  748. 

acid-base,   750. 

carbohydrate,  749. 

fat,  748. 

mineral,  750. 

protein,  750. 

total  metabolism,  748. 

on  skeleton,  751. 

—  excretion  of,  in  urine  and  feces, 
326. 

—  in   the  feces,  511. 

—  in  human  body,  323. 

—  inorganic,  in  animal  and  plant  tis- 
sues,  324. 

—  organic,  752. 

—  requirements  for,  in  human  body, 
324. 

Phosphorus  deficiency,  751. 

Phosphorus  metabolism,  325. 

Phosphorus  jmisoning,  748. 

Pigments,  bile,  405, 

Pilocarpin,  effect  of,  on  metabolism, 
774. 

Pineal  gland  substances,  effect  of,  on 
metabolism,  785. 

Pituitary  gland,  influence  of,  on  gly- 
cogenesis,  glyeogenolysis  and  glu- 
colysis,  201. 

Pituitary  substances,  anterior  lobe,  ef- 
fect of,  on  metabolism,  785. 

—  effect  of,  on  metabolism,  784. 
Plant  nucleic  acid,  135. 

Platinum,    effect    of,    on    metabolism, 

758. 
Pneumonia,    treatment    of,    by    x-rays, 

886. 
Polymerization  of  simple  sugars,  225. 
Polysaccharids,  cellulose,  247. 

—  gums,  247. 

—  inulin,  247. 

—  starch,  247. 
Potassium,  in  the  blood,  450. 

—  in  the  brain,  471. 


Potassium,  in  cerebrospinal  fluid, 
473. 

—  etftnt  of,  on  metabolism,  724. 

—  in  t  he  urine,  502. 

Potassium  citrate,  in  milk,  human  and 

cow's,  478. 
Precipitating     reactions     of    proteins, 

Pregnancy,  calcium  in  blood  during, 
322. 

—  (Tcjttin  excretion  in,  170.    ^^^^ 

—  energy  metabolism  of,  621. 

before      and      after     parturition, 

631. 

comparison   of,   in   pregnant   and 

non-pregnant  women,   table,   625. 

Priestley  (1733-1804),  discovery  of  ox- 
ygen  by,  16. 

Prolamins,  83. 

Prolin,  90,  114. 

Prostjite  gland,  effect  of  feeding  of,  on 
metabolism,  785. 

Protamins,  83. 

Protein  diet,  optimum  versus  mini- 
mum, question  of,  119. 

Protein  factor,  obtaining  of,   116. 

Protein-liquefying  enzymes,  formation' 
of,  670. 

Protein  metabolism,  effect  on,  of  acids 
and  alkalies,  739. 

of  alcohol,  764. 

of  anesthetics,  general,  chloro- 
form and  ether,  760. 

of  antipyretics,  769. 

— -  —  of  atropin,   pilocarpin,   etc.,    774. 

of  blood  poisons,  744. 

of  carbon   monoxid,  743, 

of  cyanids,  748. 

of  epinephrin,   782. 

^.of  hot  baths,  861. 

of  mercury,  756. 

of  opiates,  766. 

of  phlorizin,  759. 

of  phosphorus,  750. 

of  saline  cathartics,  718. 

of  saline  waters,  847. 

of  thyroid  substances,  783. 

of  uranium,  757. 

of  rectal  feeding,  810. 

Protein  minimum   and  optimum,  401. 

—  experiments  on,  of  Chittenden,  402. 
of  Fisher,  405. 

of  McCay,  406. 

of  Neumann,  402. 

Protein  molecule,  role  of  amino  acids 
in  structure  of,  91. 

—  structure   of,   84. 
Proteins,  alcohol  soluble,  83. 

—  amino  acid  content  of,  96. 


INDEX 


94:7 


Proteins,  amino  acid  conjtent  of,  rela- 
tive, table  of,  97. 
ab;»nrbed,  fate  of,  in  blood,  104. 

—  amino  acids  or  "building  stones"  of, 
84. 

aromatic   amino    acids,    89. 

compounds  of,  93,  94. 

compounds    of,    possible,   number 

of,  95. 

diamino  acids,  88. 

dibasic  mono-amino  acids,  86. 

fate  of,  in  the  body,  table  sum- 
marizing, 115. 

of  non-nitrogenous  fraction  of, 

107. 

in  the  tissues,  105. 

heterocyclic  amino  acids,  90. 

hydroxy-  and  thio-a-amino  acids, 

87.  ^ 

monobasic  mono-amino  acids,  84. 

number  of,  95. 

role   of   in    structure   of   protein 

molecule,  91. 

—  amount  of,  required  in  diet,  392. 

—  blood,  427. 

—  blood  serum,  428. 

—  of  brain,  467. 

—  cell,  action  of  light  on,  891. 

—  in  cerebrospinal  fluid,  471. 

—  classification  of,  81. 

conjugated,  82. 

derived,  82. 

simple,  82. 

—  coagulation  and  denaturalization  of, 
100. 

—  conjugated,  82. 

—  decomposition  of,  by  bacteria, 
tryptophan,   682. 

tyrosin,  681. 

—  denaturalization  of,  100. 

—  derived,  82. 

—  digestion  of,  101. 

—  digestion  of,  absorption  of  products 
of,  from  the  gastro-intestinal  canal, 
103. 

schematic  illustration   of,   in   the 

gastro-intestinal  canal,  103. 

—  elementary  composition  of,  81. 

—  function  of,  in  diet,  121. 

—  general  nature  of  products  of  bac- 
terial growth,  arising  from  utiliza- 
tion of  carbohydrates  and,  for  en- 
ergy, 669. 

—  incomplete,  122. 

Abderhalden's     experiments     on, 

123,  124,  125. 

definition  of,  125. 

Hopkins  and  Willcock's  experi- 
ments with,  125,  126. 


Proteins,  incomplete,  Osborne  and 
Menders  experiments  illustrating 
physiological  value  of  amino  acids, 
127,  128,  129. 

—  influence  of,  on  metabolism,  130. 

—  intravenous   feeding  of,   817. 

—  of  the  liver,  463. 

—  and  their  metabolism.  See  Meta- 
bolism, protein. 

—  of   muscles,    459. 

—  precipitating  reactions  of,  99. 

—  precipitation  of,  relative  influence 
of  anions  and  actions  on,  100. 

—  reactions  of,  Adamkiewicz-IIopkins- 
Cole,  93. 

Biuret,    96. 

color,   96. 

Millon^s,  98. 

Molisch,  98. 

precipitating,  99. 

sulphur-lead,  98. 

—  —  triketohydrinden  hydrat,  98. 
xantho  proteic,   98. 

—  relation  to,  of  pathogenic  bacteria, 
673. 

—  respiratory  quotient  of,  561. 

—  salt  formation  of,  100. 

—  "salting  out"  of,  by  means  of  elec- 
trolytes, 99. 

—  simple,  albuminoids  or  scleropro- 
teins,  83. 

albumins,  82. 

globulins,   83. 

glutelins,  83. 

histones,  83. 

prolamins  or  alcohol  soluble  pro- 
teins, 83. 
protamins,  83. 

—  specific  dynamic  action  of,  130. 

—  in  subcutaneous  feeding,  815. 

—  thermal  quotient  for,  555. 
• — urea  formation,  105. 

—  value  of,  in  diet,  408. 
Ptomains,  685. 
Ptyalin,  action  of,  248. 

Pubertj',  influence  of,  on  basal  meta- 
bolism of  children,  654. 
Pulse,  effect  on,  of  hot  baths,  862. 
Purin  bases,  of  muscle  tissue,  461 

—  of  urine,  498. 

Purin    derivatives,    amino-purins, 

adenin,  137. 

guanin,  137. 

—  chemical  relation  of  amino-  and 
oxy-purins,  138,  139. 

—  oxy-purins,  138. 

hypozanthin,  137,  138. 

uric  acid,  137. 

zanthin,  137. 


948 


IOT3EX 


Purin  fermentation,  independent  fac- 
tors of,  153. 

Purin  ferments,  distribution  of,  154. 

adenase,  156. 

guanase,  156. 

uricase,    155. 

xanthin  oxidase,  156. 

Purin  metabolism,  effect  on,  of  acids 
and   alkalies,   730, 

—  effect  on,  of  atropin,  pilocarpin,  etc., 
774. 

• of  calcium,  732. 

• of  cinchophen  (atophan),  772. 

of  purins,  779. 

Purin  nucleotides,  and  hydrolysis,  140. 
Purins,    combined,    enzymatic    decom- 
position  of,   15S. 

—  effect  of,  on  metabolism,  778. 

in   nephritic   conditions,   778. 

Purpura       hemorrhagica,       idiopathic, 

blood  transfusion  for,  833. 
Putrefaction,   intestinal,   iniiuence  on, 

of  water,  291. 
Putrescin,  685. 
Pyrimidin  derivatives,  136. 

—  cytosin,  137. 

—  uracil,  137. 

Pyridimin  nucleotides,  and  hydrolysis, 
140. 

Quinin,  effect  of,  on  metabolism,  772. 
Quotients,    respirator^-.     See    Respira- 
tory Quotient. 

—  thermal.     See  Thermal  Quotieuts. 

Pachitis,  and  mineral  metalwlism,  339. 

Radiation  and  conduction  in  hot  cli- 
mates, 900. 

Radioactive  baths,  867. 

Radioactive  substances,  distribution 
and  elimination  of,  874. 

—  effect  of,  on  blood  and  blood-form- 
ing organs,  875. 

■ constitutional,  887. 

on  enzymes,  S78. 

on   inmiunity,  876. 

on  metabolism,  in  disease,  884. 

introduction  to,  871. 

• normal,  880. 

tissues,   874. 

—  measurement  (standardization)  of, 
872. 

—  theories  of  action  of.  889. 

—  treatment  by,  of  arthritis,  chronic, 
886. 

of  carcinoma,  887. 

of  gout,  885. 

of   leukemia,   chronic   lymphatic, 

884. 


Radioactive  substances,  treatment  by, 
of  sarcoma,  887. 

Radioactive  waters,  effects  and  thera- 
peutic value  of,  852. 

Radium,  effect  of,  on  metabolism,  758. 

Radiinn  emanation,  therapeutic  value 
of,  852. 

Reactions,  in  bacterial  metabolism,  de- 
composition of  proteins  by  bacteria, 
681. 

effects  of  utilizable  carbohy- 
drates upon  formation  of  phenols, 
indols  and  amins,  685. 

formation   of  phenols,   indol  and 

indican,  680. 

physiological   action  of  aromatic 

amins,  687. 

—  due  to  infusions,  800. 

—  of  sugars  with  substituted  hydra- 
zins,  232. 

Rectal  feeding,  809. 

—  formulae  for,  812. 

—  indications  for,  809. 

—  length  of  time  for  employment  of, 
809. 

—  metabolism  of,  810. 

—  carbohydrate,   811. 
fat,  811. 

protein,  810. 

salt  and   water,  812. 

—  physiology  of,  810. 

• — precautions  and  technic  in,  813. 

—  summary  of  results  of,  814. 

—  of  carbohydrates,  230. 
Regnard's  bag  method   for  measuring 

respiratory  exchange,  537. 
Regnault    and    Reiset's    apparatus    for 
measuring  respiratory  exchange,  521. 

—  monograph  of,  on  respiration  of  an- 
imals, 40. 

Renal  glucosuria,  253. 

Reproduction,  effect  on,  of  alcohol,  765. 

—  metabolism  of,  effect  on,  of  calcium, 
732. 

Reproduction  and  growth,  metabolism 
of,  effect  on,  of  antijiyretics,  769. 

Respiration,  of  animals,  monograph  on, 
of  Regnault  and  Reiset  (1849),  40. 

—  effect  on,  of  temperature  and  hu- 
midity, 901. 

—  in  history  of  metabolism,  Boerhaave 
(1668-1738),  11. 

Hales,  Stephen,  on,  (1677-1761), 

11. 
von  Haller,  Albrecht  (1708-1777), 

11. 

Mayow,  John  (1640-1679),  9. 

Willis  on   (1621-1675),  11. 

—  von   Liebig  on,  46. 


INDEX 


949 


Eespiration    experiments    on    man    of 

Lavoisier,  25. 
Respiratory    adaptation    to    high    alti- 
tudes, 908. 
Respiratory  exchange,  methods  of  cal- 
culating heat  production  from,  548. 
combustion  of  carbon  and  hydro- 
gen, 54. 

combustion  of  organic  foodstuffs, 

549. 

non-protein  respiratory  quotient, 

566. 
respiratory  quotient  and  its  sig- 
nificance, 559. 

thermal     quotients     of     O2     and 

CO.,  555. 

and  from  urinary  nitrogen,  563. 

method   of  successive   thermal 

quotients,  563. 

■ method  of  Zuntz  and  Schum- 

berg,  565. 
—  methods  of  measuring,  by  direct  con- 
nection   with    respiratory    passages, 
531. 

closed  circuit  instruments,  544. 

Benedict's,   544. 

Krogh's      modification      of 

Haldane  &  Douglas'  instrument,  544. 

open-circuit    instruments,    air 

analyzers,  Haldane's,  540. 

analysis     of     outdoor     air, 

541. 

bag    method    of    Regnard, 

537. 

collecting  apparatus,  534. 

of  Hanroit  and  Richet,  543. 

masks,  532. 

mouth-pieces,  531. 

nose-pieces,  532. 

spirometers,   634. 

valves,  533. 

Zuntz  and  Geppert's,  538. 

by  means  of  a  respiration  cham- 
ber, 516. 
closed   circuit   type   of  appar- 
atus, 521. 

Atwater  and  Benedict's,  524. 

of  Hoppe-Seyler,  522. 

of  Regnault  and  Reiset,  521. 

for  very  small  animals,  529. 

Krogh,  531. 

-  — Thumberg,  530. 

Winterstein,  530. 

open-circuit  type  of  apparatus, 

of  Atwater  and  Rosa,  518. 

of  Grafe,  B.,  519. 

Haldane's,    520. 

of  Jaquet,  519. 

Pettenkofer,   51P 


Respiratory  exchange,  methods  of  meas- 
uring, by  means  of  a  respiration 
chamber,  open-circuit  type  of  ap- 
paratus, of  Sonden  and  Tigerstedt. 
518. 

Respiratory  quotient,  of  Bidder  and 
Schmidt,  63. 

—  calculation  of  thermal  quotient  for 
oxygen  from,  562. 

—  effect   on,  of  hot  baths,  861. 

—  of  fats,   561. 

—  of  infants,  new-born,  627. 

Bailey  and  Murlin,  628. 

Benedict  and  Talbot,  630. 

for   first  eight   days,   631. 

Hjisselbach,  627. 

influence  of  food  on,  630. 

prematurely   born,   631. 

table  of,  629. 

from   two  weeks  to  one  year  of 

age,  640. 
— Lavoisier     and    La     Place     (1780), 

22. 

—  non-protein,   566. 

—  of  proteins,  561. 

—  and  its  significance,  559. 
Rest  nitrogen  of  the  blood,  442. 
Retention  acidosis,  735. 

Rey,  Jean,  (1645),  on  metabolism,  8. 

Rhamnose,  242. 

Rheumatoid  arthritis,  treatment  of,  by 
x-rays,  886. 

Richet,  Charles  (1850-  )  work  of, 
on  metabolism,  77. 

Rickets,  calcium  in,  727. 

Roentgen  rays,  distribution  and  elimi- 
nation of,  874. 

—  effect  of,  on  blood  and  blood-forming 
organs,  875. 

constitutional,  887.  .,   /-.,.- 

on  enzymes,  878. 

on  immunity,  876. 

on  metabolism,  in  disease,  884. 

introduction  to,  871. 

normal,  880. 

tissues,  874. 

toxic  constitutional  reaction  fol- 
lowing exposure,  888. 

—  measurement  (standardization)  of, 
872. 

—  theories  of  action  of,  889. 

—  treatment  by,  of  Basedow's  disease, 
887. 

of    chronic   lymphatic    leukemia, 

884. 

of  myeloid  leukemia,  884. 

of  pernicious  anemia,  886. 

of  pneumonia,  unresolved,  886. 

of  rheumatoid  arthritis,  886. 


950 


i:n'dex 


Kubner,  Max  (1854-        ),  work  of,  on 

metabolism,  75. 
Kutherforcl,    Daniel,    (1749-1819),    on 

"residual  air"  or  nitrogen  gas,  16. 

Saline  cathartics,  effects  of,  on  meta- 
bolism, 718. 

body  temperature,  718. 

carbohydrate  metabolism,  719. 

fat  metabolism,  718. 

mineral  metabolism,  719. 

protein  metabolism,  718. 

total  metabolism,  718. 

Saline  solutions,  for  intravenous  in- 
jection, normal  saline,  796. 

reactions,   801. 

sodium  chlorid,  797. 

Saline  waters,  diuretic  property  of, 
847. 

—  effects  of,  on  gastric  secretion,  846. 

on  pancreatic  secretion,  847. 

on  protein  metabolism,  847. 

Saliva,  composition  of,  474. 

—  constituents  of,  organic,  474. 

—  diastatic  action  of,  475. 

—  dilution  of,  effect  of  in  concentrated 
mixtures,  281. 

—  reaction  of,  474. 

—  thiocyanate  content  of,  475. 
Salivary    digestion,    of    carbohydrates, 

248. 

—  influence  on,  of  water,  281. 
Salivary  factor,  475. 

Salt,  nutritive  value  of,  308. 

—  in  rectal  feeding,  812. 

—  relation  of,  to  water  retention,  311, 
312. 

—  See  also   Sodium  Chlorid. 
Salt  baths,  863. 

Salt  fever,  720. 

Salt  formation  of  proteins,  100. 

Salt  glycosuria,  722. 

Salt  metabolism,  of  rectal  feeding,  812. 

Salt-poor  diet,  effect  of,  308,  313. 

Salt-rich  diet,  effects  of,  313. 

Salt    solution,    introduction    of,    into 

blood  stream,  for  hemorrhage,  791. 
Salt  starvation,  723. 
Salting  out  of  proteins  by  electrolysis, 

99. 
Salts,  aloin,  effect"  of,  on  metabolism, 

719. 

—  effects  of,  on  metabolism,  718. 
alion,  719. 

of  organic  acids,  acetates  and 

citrates,  726. 

benzoates,  726. 

oxalates,  725. 

tartrates,  726. 


Salts,  effects  of,  on  metabolism,  potas- 
sium, lithium  and  others,  724. 

saline  cathartics,  718. 

— ' salt  fever,  720. 

salt  glycosuria,  722. 

salt  star\'ation,  723. 

sodium  chlorid,  719. 

—  and  water  in  subcutaneous  feeding. 
816.  ^' 

Sanctorius,   (1561-1636),  on  food  and 
perspiration,  7. 

Sand  baths,  863. 

Santonin,    effect    of,    on    metabolism, 
776. 

Saprophytism,    influence    of,    on    bac- 
terial metabolism,  666. 

Sarcoma,  treatment  of,  by  radium,  887. 

Schcele   (1742-1786),   discovery  of  ox- 
ygen by,  experiments  of,  17,  18. 

Scleroprotoins,  83. 

Schmidt,  C.   (born  1822),  See  Bidder, 
F.   W.  and. 

Schmidt  test,  164. 

Season,  influence  of,  on  food  consump- 
tion, 387. 

Sepsin,  685. 

Sepsis,  blood  transfusion  in,  833. 

Serin,  87,  111. 

Serum  proteins,  428. 

Sex,  influence  of,  in  basal  metabolism, 
614. 

of  children,  652. 

new-born,  635. 

Shock,   indications   for  blood  transfu- 
sion in,  830. 

Silica,  distribution  of,  in  human  body, 
308. 

Skeleton,    effect    on,    of    phosphorus, 
751. 

Skin,  action  on,  of  light  euergj-,  891. 

—  foundations     of     hydrotherapy     in 
functions  and  activity  of,  855. 

—  loss  of  heat  from,  603. 
Socrates,  on  food,  4. 
Sodium,  in  the  blood,  450. 

—  in  cerebrospinal  fluid,  473. 

—  in  the  urine,  502. 

Sodium    bicarbonate,    intravenous    in' 

fusion  of,  in  acidosis,  792. 
reaction  of  urine  in,  attention  to 

793. 
as    routine    measure   before    and 

after  surgical  procedures,  793. 

—  solutions   of,   for   intravenous   infu- 
sion, 792,  793,  799. 

reactions,  801. 

Sodiu'n  chlorid,  content  of,  in  blood, 
31^^ 

—  efiecia    ^,  on  body  temperature,  700. 


INDEX 


951 


Sodium  chlorid,  effects  of,  on  metab- 
olism, 719. 

salt  glycosuria,  Y22. 

salt  starvation,  723. 

mineral,  719. 

on  nitrogen,  721. 

on  total,  721. 

water,  720. 

—  relation  of,  to  diet,  312. 

—  Sec  also  Salt. 
Sodium  chlorid  fever,  720. 

Sodium  salt,  in  milk,  human  and 
cow's,  478. 

Sonden  and  Tigerstedt's  apparatus  for 
measuring  respiratory  exchange,  516. 

Sour  milk  therapy,  in  bacillary  dysen- 
tery, 709. 

—  and  bacterial  metabolism,  700. 
Spallanzani    (1729-1799),    experiments 

relating  to  oxygen  and  carbonic  acid 

gas,  32. 
Sphingomyelin,  of  brain,  470. 
Spirom.eters,  for  measuring  respiratory 

exchange,  Boothby's,  535. 

Speck's,  534. 

Tissot  method,  535. 

Spleen,  effect  of,  on  metabolism,  785. 

—  role  of,  in  iron  metabolism,  331. 
Spoiled    air,   or   nitrogen,    of   Scheele, 

17. 
Stahl  (1660-1734),  phlogiston  theory  of 

combustion  of,  11. 
Starch,  247. 
Starch,   conversion  of,  into   fat,  Voit, 

73. 
Stark,  William,   (1740-1770),  on  diet, 

in  history  of  metabolism,  12. 
Starvation,  creatinin  excretion  during, 

178. 

—  metabolism  during,  protein.  116, 
117. 

—  salt,  723. 
Steapsin,  192. 
Sterols,   188. 

Stomach,  fat  metabolism  in,  absorp- 
tion, 190. 

digestion,   189. 

in    passage    from,    to    intestines, 

191. 

—  passage  from,  of  water,  286. 
Stools,  urobilin  in,  165. 

clinical  significance  of  increased 

amount  of,  167,  168. 

determination  of,  167. 

diagnostic  value  of,  169. 

Structural   chemical   requirements   for 

bacterial  development,   669. 
Strychnin,    effect    of,    on    metabolism, 

775. 


Subcutaneous  feeding,  814. 

—  of  carbohydrates,  816. 

—  of  fats,  815. 

—  of  protein,  815. 

—  of  salts   and  water,   816. 
Sucrose,  245. 

—  formula  for,  244. 

Sugar,  of  blood.    See  Blood  Sugar. 

—  in  cerebrospinal  fluid,  473. 

—  cleavage  of,  von  Liebig's  observa- 
tions on,  47. 

—  conversion  of  protein  into  fat  and, 
73. 

—  of  the  urine,  499. 

Sugars,  effects  of,  upon  intestinal  flora 
of  nurslings,  experimental  evidence 
of,  694. 

—  polymerization  of,  225. 

—  reactions  of,  with  substituted  hydra- 
zins,  232. 

—  reduction  of,  230. 

—  specific  rotations  of,  table  of,  225. 

—  terminology  of,  213. 
Sulphates,  in  the  blood,  454. 

—  in  the  urine,  502. 
Sulphatids,  of  brain,  470. 
Sulphonal,    effect   of,    on    metabolism, 

764. 

—  in  metabolism,  332. 
Sulphur  waters,  851. 
Sulphur  lead  reaction,  98. 

Surface  area  of  body,  heat  production 
in  infants  per  square  meter  of,  646. 

—  law  of,  594. 

criticism  of,  597. 

—  measurement  of,  595. 

—  relation  of,  to  body  weight,  table, 
598. 

—  relation  of  heat  radiation  to,  table, 
610. 

Sweat,  composition  of,  512. 
table  of,  513. 

—  diastatic  ferment  in,  513. 

—  methods  employed  to  collect,  512. 

—  nitrogen  content  of,  513. 

—  substances  excreted  in,  512. 

—  total  solids  in,  513. 

—  urea  in,  513. 

—  uric  acid,  in,  513. 

—  volume  eliminated,  512. 

Sweat  secretion,  baths  and,  867. 

Sympathetic  system  and  adrenals,  in- 
fluence of,  on  glycogenosis,  glyco- 
genolysis  and  glucolysis,  257. 

Syntheses,  in  blood  poisons,  745. 
Synthesis,  of  carbohydrates,  226. 

Tartaric  acid,  Pasteur's  studies  on, 
219. 


952 


JXDEX 


Tartrates,  effect  of,  on  metabolism, 
726. 

Temperature,  of  air,  heat  production 
as  affected  by,  in  coldblooded  ani- 
mals, Van't  Hoff's  law,  601. 

cooling  power  of  air  currents 

at  different  velocities,  604. 

in  warm-blooded  animals,  602. 

and     humidity,     effect     of,      on 

amount    of    blood    per    kilogram    of 
body  weight,  901. 

on     capacity     for     physical 

work,  901. 

on   circulator^'   system,   900. 

on  concentration  of  sugar  in 

blood,   901. 

on  metabolism,  902. 

on  nasal  mucosa,  901. 

on    respiration,    901. 

radiation       and       conduction, 

900. 

relation    of,    to    temperature    of 

body,  900. 

influence  of,  on  basal  metabolism 

of  new  born  infants,  638. 

Temperature,  of  the  body,  effect  on, 
of  acids  and  alkalies,  736. 

of  arsenic,  755. 

of     atropin,     pilocarpin,     etc., 

775. 

of  calcium,  730. 

of  cocain,  777. 

of  curare,  777. 

of  cyanids,  747. 

of  epinephrin,  781. 

of  hot  baths,  860,  861. 

of  mercury,  756. 

of  narcotics,  760. 

of  opiates,  765. 

of  purins,  779. 

of  saline  cathartics,  718. 

of  santonin,  776. 

of  sodium  chlorid,  720. 

of  uranium,  758. 

regulation  of,  as  related  to  hy- 
drotherapy,  855. 

relation  to,  of  temperature  of  the 

air,  900. 

Testis,  effect  of,  on  metabolism,  785. 

Tetany,  calcium  in,  728. 

—  as  a  condition  of  alkalosis  treat- 
ment for,  739. 

—  and  mineral  metabolism,  337. 
Tetroses,  242. 

Thermal  quotient,  of  COs,  558. 

variation    in    heat   equivalent    of 

CO2,  (Atwater  and  Benedict),  559. 

—  of  O2,  based  upon  experiments  on 
man,  (Atwater  and  Benedict),  557. 


Thermal  quotient,  of  O^,  calculation  of, 
from  respiratory  quotient,  562. 

—  of  O2  during  muscular  work  (At- 
water and  Benedict),  558. 

—  O2  and  CO2  for  carbohydrate,  556. 
for  fat,  556. 

in  a  lacto-vegetarian  diet,  557. 

for  mixed  diet,  556. 

for   protein,   555. 

Thermal   quotients,   successive,   663. 

Thumberg's  apparatus  for  measuring 
respiratory  exchange,  530. 

Thymus  gland  substances,  effect  of,  on 
metabolism,  785. 

Thymus  nucleic  acids,  partial  decom- 
position products  of,  147. 

Thyroid  gland,  influence  of,  on  gly co- 
genesis,  glycogenolysis  and  glu- 
colysis,  260. 

Thyroid  gland  substance,  effect  of,  on 
metabolism,  782. 

Tissue  fluid,  788. 

Tissues,  action  on,  of  light  energy, 
891. 

—brain,  467. 

—  connective,  466. 

—  liver.     See  Liver. 

—  muscles.    See  Muscles. 

—  creatin  content  of,  172. 

—  effect  on,  of  roentgen  rays  and  radio- 
active substances,   874. 

—  fat  in,  changes  in,  206. 
storing  of,  205. 

Tissues,  fate  in,  of  amino  acids,  105. 
Tolerance,  carbohydrate,  254. 

glucolysis  and,  256. 

glycogenesis  and,  255. 

Total  metabolism,  effect  on,  of  acids 
and  alkalies,  736. 

—  of  alcohol,  764. 

of  antipyretics,  767. 

of  arsenic,  754. 

of  atropin,  pilocarpin,  etc.,  774. 

of  carbon  monoxid,  742. 

of  epinephrin,  780. 

of  mercury,  756. 

of  narcotics,  760. 

of  opiates,  765. 

of  phlorhizin,  760. 

of  phosphorus,  748. 

of  pituitary  substances,  784. 

of  purins,  779. 

of  thyroid  substances,  783. 

of   uranium,    758. 

Toxemia,  intravenous  injection  of 
fluids  in,  794. 

—  blood  transfusion   in,  833. 

Toxic  constitutional  reaction  follow- 
ing exposure  to  x-rays,  888. 


IISTDEX 


95ri 


Toxin,  diphtheria,  669. 

Transfusion     of     blood.      See     Blood 

Transfusion. 
Triketohydrinden    hydrat    reaction    of 

proteins,  98. 
Trioses,  242. 
Tryptophan,  91,  115. 
Tryptophan  decomx)osition  l>y  bacteria, 

682. 
Tuberculosis,  disturbances  in  mineral 

metabolism  in,  336. 
Tyramin,  686. 

—  change  of,  688. 

—  effect  of,  on  metabolism,  773. 
Tyrosin,  90,  113. 

—  in   the  brain,  471. 

—  change  of,  685. 

—  decomposition  of,  by  bacteria,  681. 

Undernutrition,  414. 

—  creatinuria  accompanying,  177. 
Uracil,  137. 

—  and  cytosin,  137. 

Uranium,    effects    of,    on    metabolism, 

757. 

carbohydrate,  757. 

fat,  758. 

mineral,  757. 

protein,  757. 

total,  758. 

water,  757. 

Uranium  nephritis,  alkaline  treatment 

in,  735. 
Urea,  in  blood,  435. 
conditions   with   significant   urea 

nitrogen  findings,  436. 

—  origin  of,  675. 

—  as  principal  end  product  of  metabol- 
ism, 675. 

—  in  sweat,  513. 

—  of  the  urine,  486,  487,  488. 
Urea  formation  in  liver,  464. 

—  in  protein  metabolism,  105. 

Urea  nitrogen,  in  nephritis,  chronic, 
table  of,  439. 

Urethan,  effect  of,  on  metabolism,  764. 

Uric  acid,  137,  138,  139. 

— content  of,  in  human  blood,  437. 

acids  affecting,  438. 

Uric  acid,  elimination  of,  acids  affect- 
ing, 438. 

—  fate  of,  in  man  and  in  animals, 
497. 

—  formation  of,  from  nucleic  acid,  150. 
from  oxy-purins,  151. 

—  in  gout,  438. 

—  increased  elimination  of,  498. 

—  in  leucemia,  437. 

—  in  muscle  tissue,  461. 


Uric  acid,  in  nephritis,  437. 
chronic,  table  of,  439. 

—  physiological  destruction  of,  153. 

—  precursors  of,  497. 

—  in  sweat,  513. 

—  of  urine,  495. 

formation  of,  495. 

Uric  acid  eliminants,  498. 

Uric  acid  excretion,  effect  on,  of  ar- 
senic  and   antimony,  754. 

Uricase,  distribution  of,  155. 

Uricolysis,  496. 

Urinary  elimination  of  iron,  329. 

Urinary-  nitrogen,  calculation  of  heat 
production  from  the  respiratory  ex- 
change and,  563. 

Urine,  481. 

—  alkalinization  of,  849. 

—  amino-acids  of,  490. 

—  ammonia  of,  489. 

— ^  amount  of  nitrogen  excreted  in, 
405. 

—  aromatic  oxyacids  and  derivatives, 
499. 

—  calcium  in,  316,  503. 

—  chlorids  of,  500. 

—  composition  of,  influence  of  food  on, 
64. 

—  creatin  of,  493. 

and  arginin,  as  source  of,  494. 

excretion  of,  493,  494. 

—  creatin  metabolism  in,  176. 

—  ceatinin   of,   490. 
elimination  of,  490. 

origin  of,  in  creatin  of  the  mus- 
cle, 492,  493,  494. 

—  ereatinin  metabolism  in,  177. 

—  endogenous  and  exogenous  origin  of 
different  w^aste  products,  486. 

—  hippuric  acid  of,  498. 

—  inorganic  constituents  of,  500. 
calcium,  503. 

chlorids,  500. 

iron,  503. 

magnesium,   503. 

phosphates,  501. 

potassium  of,  502. 

sodium,  502. 

sulphates,  502. 

—  iron  of,  503. 

—  magnesium  of,  503. 

—  mechanism  of  kidney  secretion,  482. 

—  nitrogen  of,  485. 

amino-acids,  490. 

ammonia,   489. 

components  of,  486. 

creatin,  493. 

ereatinin,  490. 

distribution  of,  486, 


954 


INDEX 


Urine,  nitrogen  of,  urea,  486,  487,  488. 
uric  acid,  405. 

—  organic     constituents     of,     amino- 
acids,  490. 

aromatic    oxyacids    and    deriva- 
tives, 499. 

ammonia,  489. 

creatin,  493. 

ereatinin,   490. 

hippuric  acid,  498. 

nitrogen,  485. 

oxalic  acid,  499. 

purin  bases,  498. 

sugar,  499. 

urea,  486,  487,  488. 

uric  acid,  495. 

—  oxalic  acid  of,  499. 

—  phosphates   of,   501. 

—  physical    properties    of,    color,    483. 
odor,  483. 

reaction  and  acidity,  483. 

specific   gravity,   483. 

titratable      acidity,      and      true 

acidity,  484. 

transparency  of,  485. 

volume,  482. 

—  potassium  of,  502. 

—  purin  bases  of,  498. 

—  sodium  of,  502. 

—  sugar  of,  499. 

—  sulphates  of,  502. 

—  urea  of,  486,  487,  488. 

—  uric  acid  of,  495. 

fate  of,  in  man  and  in  animals, 

497. 

formation  of,  495. 

increased    elimination   of,   498. 

precursors  of,  497. 

—  urobilin    in,    165. 

clinical  significance  of  increased 

amount  of,  1C7,  168. 

determination  of,  167. 

diagnostic  value  of,  169. 

Urobilin,  in  the  bile,  165. 

clinical  significance  of  increased 

amount  of,  168. 

determination   of,   168. 

diagnostic  value  of,  169. 

—  chemistry  of,  163. 

—  clinical  significance  of,  in  urine,  in- 
creased amount,  167,  168. 

—  derivation  of,   169. 

—  description   of,   by   Jaffe,   163. 

—  determination  of,  165. 

—  diagnostic  value  of,  168. 

—  in   duodenal    contents,    clinical   sig- 
nificance of,  168. 

determination  of,  167. 

—  formation  of,  mechanism  of,  165. 


Urobilin,  mechanism  of  formation  of, 
165. 

—  obtained  from  urobilinogen,  164. 

—  occurrence  of,  164. 

in  bile,  165. 

in  blood,  165. 

in  serum,  165.  ^ 

in  stools,  165. 

in  urine,  165. 

—  in  pernicious  anemia,  168, 

—  Schmidt  test  with,  164. 

—  in  stools,  165. 

clinical  significance  of  increased 

amount  of,  167,  168. 

determination  of,  167. 

diagnostic  value  of,  169. 

—  in  urine,  165. 

clinical  significance  of  increased 

amount  of,  167,  168. 

determination  of,  167. 

diagnostic  value  of,  169. 

Urobilinogen,  chemistry  of,  163. 

—  description   of,    164. 

—  empirical  formula  of,  163. 

—  structural  formula  of,  163. 

—  synthesization  of,  Fischer,  H,,  164. 

—  treated  with  para-dimethylamino- 
benzaldehyd,  164. 

—  urobilin  obtained  from,  164. 

—  See  also  Urobilin. 
Urobilinuria,   167. 

Urorosein,  mother  substance  of,  684. 

Valin,  85. 

—  fate  of,  109. 

Valves,  for  measuring  respiratory  ex- 
change, 533. 

Van  Helmont  (1577-1744),  on  metabo- 
lism and  carbonic  acid  gas,  8. 

Van't  Hoff's  law  of  heat  production  as 
affected  by  external  temperature,  in 
cold-blooded  animals,  601. 

Vegetables,  feeding  of,  to  young  babies, 
319. 

Vegetarianism,  399. 

—  basal  metabolism  in,  400. 

—  disadvantages  of,  400, 

Da   Vinci,  Leonardo,  on   nourishment, 

6. 
Vitamins,    antineuritic    (water-soluble 

B),  342. 
distribution  of,  in  food,  346. 

—  antiscorbutic  (0  Factor),  345. 
sources  of,  346. 

—  chemical  nature  and  physical  prop- 
erties of,  342. 

antineuritic  vitamin  (water-solu- 
ble B),  342. 
antiscorbutic  (C  factor),  345. 


I2^DEX 


955 


Vitamins,  chemical  nature  and  physical 
properties  of,  fat-soluble  vitamin 
(fat-soluble  A),  345. 

—  discovery  of,  341. 

—  distribution  of,  in  food,  346. 

—  fat-soluble  (fat-soluble  A),  345. 
distribution  of,  in  food,  346. 

—  metabolism  of,  341. 

digestion  and  absorption,  347. 

end,  350. 

intermediary,    and    physiological 

action,  347. 
special  features  of,  351. 

—  table  of,  352,  355. 

Voit,  Carl,  on  metabolism,  5,  65. 

von  Haller,  Albrecht    (170S-1777),   on 

respiration,  in  history  of  metabolism, 

11. 
von  Liebig,  Justus  (1803-1873),  44. 

—  caloric  value  of  meat,  49. 

—  classes  of  foodstuffs  according  to,  50. 

—  isodynamic  equivalents,  49. 
table  of,  50. 

—  Munich  period  of,  53. 

—  on  alcohol,  comm.ents,  49. 

—  on  energy  production,  47. 

—  on  formation  of  fat,  49. 

—  on  formation  of  feces  and  absorption 
of  bile,  49. 

on  metabolism,  difficulties  of  cal- 
culating, 48. 

—  on  metabolism  in  fasting,  46. 

—  on  metabolism  of  a  horse,  48. 

—  on  muscle  power,  criticism  of 
Frankland's  comparison  of  vnth 
steam  engine,  54. 

source  of,  53. 

—  on  respiration,  46. 

—  on  sugar,  cleavage  of,  47. 

—  on  oxidation  of  various  foods,  49. 

—  oxygen  requirement  for  combustion 
of  foods,  50. 

—  plagiarism  of  ideas  of,  51,  52. 

—  ultimate  disposal  of  products  of  me- 
tabolism according  to,  51. 

—  Voit's  description  of  services  of,  46. 

War  edema,  415. 

Water,  content  of,  in  blood,  311. 

in  body,  311. 

—  deficiency  of,  effect  of,  on  metabo- 
lism, 717. 

—  as  a  dietary  constituent,  275. 
drinking  with  meals,  280. 

influence  of  diminished  water  in- 
take on  metabolism,  279. 

influence  of  increased  water  in- 
gestion on  metabolism,  277. 

on  basal  metabolism,  279. 


Water,  discovery  of  composition  of,  by 
Cavendish,  15. 

—  distilled,  292. 

—  drinking  of,   with   meals,   280,   283, 
287,  288,  294. 

—  effect  of,  on  metabolism,  717. 

deficiency  of,  717. 

mineral   waters,    718. 

—  experiments  of  Lavoisier  on  nature 
of,  19. 

—  external  use  of,  for  therapeutic 
measures.    See  Hydrotherapy. 

—  ice,  293, 

—  importance  of,  to  human  body,  276. 

—  influence  of,  on  absorption,  291. 
on  blood  pressure  and  blood  vol- 
ume, 291. 

on  gastric  digestion,  281. 

on  intestinal  flora  and  putrefac- 
tion, 291. 

on  pancreatic  digestion,  289. 

on  salivary  digestion,  281. 

—  influence  of  diminished  water  in- 
take on  metabolism,  279. 

—  influence  of  increased  ingestion  of, 
on  metabolism,  277. 

on  basal  metabolism,  279. 

—  passage  of,  from  stomach,  286. 

—  percentage  of,  in  organs,  tissues  and 
secretions  of  body,  275. 

—  regulation  of  intake  of,  in  certain 
conditions,  294. 

—  requirement  of  body  for,  312. 

—  and  salts,  subcutaneous  feeding  of, 
816. 

—  stimulatoi-y  power  of,  281. 

Water  metabolism,  effect  on,  of  acids 
and  alkalies,  736. 

of  anesthetics,  general,  chloro- 
form and  ether,  763. 

of  antipyretics,  770. 

of  arsenic,  755. 

■ of  atropin,  pilocarpin,  etc.,  774. 

of  calcium,  730. 

of  epinephrin,  781 . 

of  mercury,  756. 

of  opiates,  767. 

of  pituitary  substances,  784. 

of  purins,  778. 

of  sodimn  chlorid,  720. 

of  uranium,  757. 

—  of  rectal  feeding,  812. 

Water  retention,  edema  due  to,  311. 

—  relation  of  salt  to,  311,  312. 
Waters,  mineral,  845. 

alkaline  waters,  including  carbo- 
nated, 848. 

arsenic,  851. 

bitter  Avaters,  850. 


1)5G 


Waters,  mineral,  carbonated,  818. 

classification  of,  S-ii>. 

diuretic  property  of,  847. 

iron,  851. 

radioactive,  852. 

saline  waters,  846. 

sulphur,  851. 

Waxes,  as  simple  lipoids,  185. 

beeswax,  185. 

cetin,  185. 

wool  wax  (lanolin),  185. 

Wei«:ht,   relation   of,   to   surface   area, 

598. 
Willis   (1C21-1675),  on  respiration,  in 

history  of  metabolism,  11. 
Winds,  effects  of,  902. 
Winterstein's  apparatus  for  measuring 

respirator^'  exchange,  530. 
W^ool  wax,  J  85. 


Work,  influence  of,  on  food  consump- 
tion, 391. 

Xanthin,  in  muscle  tissue,  461. 
Xanthin  oxidase,  distribution  of,  156. 
Xantho  proteic  reaction,  98. 
Xylose,  241. 

Yeast  cells,   activity   of,  von   Liebig's 

discussion  of,  54. 
Yeast     nucleic     acid,     fundamental 

groups  of,  136. 

Zanthin,  137,  138. 

Zinc,  effect  of,  on  metabolism,  758. 

Zuntz,  Nathan  (1847-1920),  work  of. 
On.  metabolism,  76. 

Zuntz  and..Geppert's  method  of  measur- 
ing rl^piratofy  Exchange,  538. 


^1) 


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